WorldWideScience

Sample records for 11c labeled erlotinib

  1. [11C] labeled erlotinib as a new radiotracer for identification of patients responding to erlotinib treatment

    DEFF Research Database (Denmark)

    Memon, Ashfaque Ahmed; Weber, Britta; Jakobsen, Steen;

    2009-01-01

    Erlotinib (Tarceva®) is a tailored drug targeting the Epidermal Growth Factor Receptor (EGFR), which is commonly overexpressed in various human cancers including lung cancer. The purpose of this study was to develop a method for identification of lung cancer patients that respond to erlotinib...... treatment by PET scanning. We demonstrate that erlotinib can be labeled with [11C] by reacting the normethyl precursor with [11C] methyl iodide followed by HPLC purification. First we tested [11C] erlotinib on nude mice xenografted with lung cancer cell lines with either a high (A549, NCI358) or low (HCC827...

  2. Synthesis of some /sup 11/C-labelled alkaloids

    Energy Technology Data Exchange (ETDEWEB)

    Laangstroem, B.; Antoni, G.; Halldin, H.; Svaerd, H.; Bergson, G. (Univ. of Uppsala (Sweden) Inst. of Chemistry)

    1982-01-01

    Using (/sup 11/C)-methyl iodide in N-alkylation reactions in dimethylformamide (DMF), the alkaloids N-(/sup 11/C-methyl)-morphine, N-(/sup 11/C-methyl)-codeine, 6-N(methyl)-9, 10-dihydroergotamine, 6-N-(/sup 11/C-methyl)-bromocriptine and N-(/sup 11/C-methyl)-nicotine have been synthesized in radiochemical yields of 50-95%, within 5-10 min of introducing (/sup 11/C)-methyl iodide into the reaction vial. (/sup 11/C)-Methyl iodide was obtained within 4-7 min from (/sup 11/C)-carbon dioxide prepared by the /sup 14/N(p,..cap alpha..)/sup 11/C reaction.

  3. Pd-mediated rapid cross-couplings using [(11) C]methyl iodide: groundbreaking labeling methods in (11) C radiochemistry.

    Science.gov (United States)

    Doi, Hisashi

    2015-03-01

    Prof. Bengt Långström is a pioneer in the field of chemistry-driven positron emission tomography (PET) imaging. He has developed a variety of excellent radiolabeling methodologies using the methods of organic chemistry, with the aim of widening the potential of PET in the study of life. Among his groundbreaking achievements in (11) C radiochemistry, there is the discovery of the Pd-mediated rapid cross-coupling reaction using [(11) C]methyl iodide. It was first reported by his Uppsala group in 1994-1995 and was further investigated by his and other groups with a view of enhancing its generality and practicability. This reaction is currently considered one of the basic methods for (11) C-labeling of low-weight organic compounds. This paper presents a short summary of the background and the development of Pd-mediated rapid cross-couplings of [(11) C]methyl iodide, with a focus not only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compounds. All these reactions have proven to be dependable (11) C-labeling methodologies that use chemically reliable carbon-carbon bond formation reactions.

  4. Synthesis of [1-{sup 11}C]octanoic acid, [{sup 11}C]raclopride and [{sup 11}C]nicergoline with a general-purpose automated synthesis apparatus of {sup 11}C-labeled radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Yajima, Kazuyosi; Kawashima, Hidefumi; Cui, Ying-she; Hashimoto, Naoto; Miyake, Yoshihiro [National Cardiovascular Center, Suita, Osaka (Japan)

    1997-06-01

    We have developed a general-purpose automated synthesis apparatus of {sup 11}C-labeled radiopharmaceuticals for PET, which can be adopted to both one-pot and two-or-more-pot reactions. The features of the apparatus were shown in the successful preparation of [(1-{sup 11})C]octanoic acid in a one-pot reaction and [{sup 11}C]raclopride and [{sup 11}C]nicergoline in two-pot reactions, the latter being a novel radiopharmaceutical. (author).

  5. Development of a modular system for the synthesis of PET [{sup 11}C]labelled radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Boschi, Stefano [PET Radiopharmacy, Nuclear Medicine, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi, Via Massarenti 9, 40138 Bologna (Italy)], E-mail: stefano.boschi@aosp.bo.it; Lodi, Filippo [PET Radiopharmacy, Nuclear Medicine, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi, Via Massarenti 9, 40138 Bologna (Italy); Cicoria, Gianfranco [Medical Physics, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi (Italy); Raul Ledesma, Jorge [Fundacion Escuela de Medicina Nuclear, Mendoza (Argentina); Knopp, Roger [Eckert Ziegler-Eurotope, Berlin (Germany); Rizzello, Anna; Di Pierro, Donato; Trespidi, Silvia [PET Radiopharmacy, Nuclear Medicine, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi, Via Massarenti 9, 40138 Bologna (Italy); Marengo, Mario [Medical Physics, Azienda Ospedaliero Universitaria di Bologna, Policlinico S.Orsola-Malpighi (Italy)

    2009-10-15

    [{sup 11}C]labelled radiopharmaceuticals as N-[{sup 11}C]methyl-choline ([{sup 11}C]choline), L-(S-methyl-[{sup 11}C])methionine ([{sup 11}C]methionine) and [{sup 11}C]acetate have gained increasing importance in clinical PET and for the routine production of these radiopharmaceuticals, simple and reliable modules are needed to produce clinically relevant radioactivity. On the other hand, flexible devices are needed not only for the routine synthesis but also for more complex applications as the development of new tracers. The aim of this work was the adaptation of an Eckert Ziegler modular system for easy routine synthesis of [{sup 11}C]choline, [{sup 11}C]methionine and [{sup 11}C]acetate using components that account for straightforward scaling up and upgrades.

  6. (11)C-labeling and preliminary evaluation of vortioxetine as a PET radioligand

    DEFF Research Database (Denmark)

    Lykke Andersen, Valdemar; Hansen, Hanne D; Herth, Matthias M;

    2014-01-01

    Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with [(11)C]MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Prelimin...

  7. The synthesis of 5-(1- sup 11 C)ethyl barbiturates from labelled malonic esters

    Energy Technology Data Exchange (ETDEWEB)

    Gee, A.; Laangstroem, B. (Uppsala Univ. (Sweden). Dept. of Organic Chemistry)

    1991-01-01

    The synthesis of ({sup 11}C)phenobarbital, ({sup 11}C)pentobarbital and({sup 11}C)amobarbital labelled in the 5-(1-{sup 11}C)ethyl position is reported. The malonic esters R- CH(CO{sub 2}Et){sub 2} R phenyl-, 1-methylbutyl-, and 3- methylbutyl- were alkylated with (1-{sup 11}C)ethyl iodide prepared from ({sup 11}C)carbon dioxide. Ring closure of the 2-(1-{sup 11}C)ethyl-labelled malonic esters with urea afforded 5-(1-{sup 11}C)ethyl-phenobarbital,-phenobarbital, -pentobarbital and -amobarbital synthesis times of 42-47 min, counted from ({sup 11}C) carbon dioxide. In typical syntheses starting with 3 GBq pentobarbitol and (81 mCi) ({sup 11}C)carbon dioxide, 150-215 MBq (4-6 mCi) were produced in 25-30% decay corrected -amobarbital radiochemical yields with radiochemical purities greater than 98%. (author).

  8. Synthesis of O-[{sup 11}C]acetyl CoA, O-[{sup 11}C]acetyl-L-carnitine, and L-[{sup 11}C]carnitine labelled in specific positions, applied in PET studies on rhesus monkey

    Energy Technology Data Exchange (ETDEWEB)

    Jacobson, Gunilla B.; Watanabe, Yasuyoshi; Valind, Sven; Kuratsune, Hirohiko; Laangstroem, Bengt

    1997-07-01

    The syntheses of L-carnitine, O-acetyl CoA, and O-acetyl-L-carnitine labelled with {sup 11}C at the 1- or 2-position of the acetyl group or the N-methyl position of carnitine, using the enzymes acetyl CoA synthetase and carnitine acetyltransferase, are described. With a total synthesis time of 45 min, O-[1-{sup 11}C]acetyl CoA and O-[2-{sup 11}C]acetyl CoA was obtained in 60-70% decay-corrected radiochemical yield, and O-[1-{sup 11}C]acetyl-L-carnitine and O-[2-{sup 11}C]acetyl-L-carnitine in 70-80% yield, based on [1-{sup 11}C]acetate or [2-{sup 11}C]acetate, respectively. By an N-methylation reaction with [{sup 11}C]methyl iodide, L-[methyl-{sup 11}C]carnitine was obtained within 30 min, and O-acetyl-L-[methyl-{sup 11}C]carnitine within 40 min, giving a decay-corrected radiochemical yield of 60% and 40-50%, respectively, based on [{sup 11}C]methyl iodide. Initial data of the kinetics of the different {sup 11}C-labelled L-carnitine and acetyl-L-carnitines in renal cortex of anaesthetized monkey (Macaca mulatta) are presented.

  9. Biodistribution and radiation dosimetry of {sup 11}C-labelled docetaxel in cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Veldt, Astrid A.M. van der; Mooijer, Martien P.J.; Rijnders, Anneloes Y.; Windhorst, Albert D.; Lammertsma, Adriaan A.; Lubberink, Mark [VU University Medical Center, Department of Nuclear Medicine and PET Research, P.O. Box 7057, Amsterdam (Netherlands); Hendrikse, N.H. [VU University Medical Center, Department of Nuclear Medicine and PET Research, P.O. Box 7057, Amsterdam (Netherlands); VU University Medical Center, Department of Clinical Pharmacology and Pharmacy, Amsterdam (Netherlands); Smit, Egbert F. [VU University Medical Center, Department of Pulmonology, Amsterdam (Netherlands); Gerritsen, Winald R. [VU University Medical Center, Department of Medical Oncology, Amsterdam (Netherlands); Hoeven, Jacobus J.M. van der [Medical Center Alkmaar, Department of Internal Medicine, Alkmaar (Netherlands)

    2010-10-15

    Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter {sup 11}C. Non-invasive measurements of [{sup 11}C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [{sup 11}C]docetaxel in humans. Biodistribution of [{sup 11}C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [{sup 11}C]docetaxel uptake) or CT (low [{sup 11}C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Gall bladder and liver demonstrated high [{sup 11}C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 {+-} 9%. [{sup 11}C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [{sup 11}C]docetaxel uptake in tumours was moderate and highly variable between tumours. The effective dose of [{sup 11}C]docetaxel was 4.7 {mu}Sv/MBq. As uptake in normal lung is low, [{sup 11}C]docetaxel may be a promising tracer for tumours in the thoracic region. (orig.)

  10. Carbon-11 labelling of an inhibitor of acetylcholinesterase: [[sup 11]C]physostigmine

    Energy Technology Data Exchange (ETDEWEB)

    Bonnot-Lours, S.; Crouzel, C.; Prenant, C.; Hinnen, F. (CEA, 91 - Orsay (France). Service Hospitalier Frederic Joliot)

    1993-01-01

    Physostigmine, an alkaloid from calabar bean is a strong inhibitor of acetylcholinesterase and has been used clinically in the treatment of glaucoma, atropine intoxication, myasthenia gravis and more recently, in experimental trials in Alzheimer's disease. In order to study the AChE activity in the brain by positron emission tomography, we have undertaken the labelling of physostigmine with carbon-11. The synthesis involves the reaction of [[sup 11]C]methylisocyanate with eseroline. [[sup 11]C]Methylisocyanate was obtained by heating [[sup 11]C]acetylchloride with tetrabutylammonium azide in toluene. The synthesis of [[sup 11]C]CH[sub 3]COC1 involves the carbonation of methylmagnesium bromide in THF with cyclotron produced [[sup 11]C]carbon dioxide and the addition of phthaloyl dichloride. The [[sup 11]C]methylisocyanate is distilled into a solution of eseroline in ether with a small piece of sodium. After 10 minutes at 25[sup o]C, the solution is purified by HPLC and the appropriate fraction collected. Starting with 55.5 GBq (1.5 Ci) of [[sup 11]C]carbon dioxide, 0.92-1.48 GBq (25-40 mCi) of [[sup 11]C]Physostigmine are obtained 57 minutes after EOB. (author).

  11. Exploration of the labeling of [11C]Tubastatin A at the hydroxamic acid site with [11C]carbon monoxide

    Science.gov (United States)

    Lu, Shuiyu; Zhang, Yi; Kalin, Jay; Cai, Lisheng; Kozikowski, Alan P.; Pike, Victor W.

    2015-01-01

    We aimed to label tubastatin A (1) with carbon-11 (t1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 (HDAC6) in vivo with positron emission tomography (PET). Initial attempts at a one-pot Pd-mediated insertion of [11C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (< 5%) of [11C]1. Labeling was achieved in useful radiochemical yields (16.1 ± 5.6%, n = 4) through a two-step process based on Pd-mediated insertion of [11C]carbon monoxide between the aryl iodide (2) and p-nitrophenol to give the [11C]p-nitrophenyl ester ([11C]5), followed by ultrasound-assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in DMSO/THF mixture in the presence of a strong phosphazene base P1-t-Bu. However, the success in labeling the hydroxamic acid group of [11C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids. PMID:26647018

  12. Synthesis of the sup 11 C-labelled. beta. -adrenergic receptor ligands atenolol, metoprolol and propanolol

    Energy Technology Data Exchange (ETDEWEB)

    Antoni, G.; Ulin, J.; Laangstroem, B. (Uppsala Univ. (Sweden). Dept. of Organic Chemistry)

    1989-01-01

    The {sup 11}C-labelled {beta}-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using (2-{sup 11}C)isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from ({sup 11}C)carbon dioxide and obtained in 40% radiochemical yield within 14 min reaction time. The total reaction times for compounds 1-3, counted from the start of the isopropyl iodide synthesis and including purification were 45-55 min. The products were obtained in 5-15% radiochemical yields and with radiochemical purities higher than 98%. The specific activity ranged from 0.4 to 4 GBq/{mu}mol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained. (author).

  13. [11C]-dimethylamine as a labeling agent for PET biomarkers.

    Science.gov (United States)

    Jacobson, Orit; Mishani, Eyal

    2008-02-01

    The dimethylamine functional group is a common component of the chemical structure of numerous drugs. The most commonly used synthetic route for carbon-11 labeled radiopharmaceuticals which contain the dimethylamine group is via C-11 methylation of the monomethyl amine precursors. Here we describe the radiosynthesis of [11C]dimethylamine (1) and its application in the direct labeling of several positron emission tomography (PET) imaging agents by-passing the preparation of the monomethyl amine precursors.

  14. Development of a 11C-labeled tetrazine for rapid tetrazine–trans-cyclooctene ligation

    DEFF Research Database (Denmark)

    Herth, Matthias Manfred; Andersen, Valdemar L.; Lehel, Szabolcs

    2013-01-01

    Tetrazine–trans-cyclooctene ligations are remarkably fast and selective reactions even at low micro-molar concentrations. In bioorthogonal radiochemistry, tools that enable conjugation of radioactive probes to pre-targeted vectors are of great interest. Herein, we describe the successful developm...... development of the first 11C-labelled tetrazine and its reaction with trans-cyclooctenol....

  15. Synthesis of 1-/sup 11/C-labelled ethyl, propyl, butyl and isobutyl iodides and examples of alkylation reactions

    Energy Technology Data Exchange (ETDEWEB)

    Laangstroem, B.; Antoni, G.; Gullberg, P.; Halldin, C.; Naagren, K.; Rimland, A.; Svaerd, H.

    1986-01-01

    New /sup 11/C-labelled precursors (1-/sup 11/C)ethyl,(1-/sup 11/C)propyl, (1-/sup 11/C)butyl, and (1-/sup 11/C)isobutyl iodides have been prepared by a 3-step reaction route using a one-pot system. The labelled iodides were obtained in 20-55% radiochemical yields and 65-95% radiochemical purities, with a total time for synthesis of the order of 10-14 min. The labelled iodides have been used in alkylation reactions with nitrogen, oxygen and carbon nucleophiles. The nitrogen alkylation reactions are exemplified by the synthesis of the analgetics N-(1-/sup 11/C-ethyl)iodocaine and N-(1-/sup 11/C-butyl) bupivacaine. The synthesis of 3-nitrophenyl(1-/sup 11/C)propyl ether is also presented in this paper as an example of an oxygen alkylation.

  16. Preparation of a carbon-11 labelled analgesic -(N-methyl-/sup 11/C)meptazinol

    Energy Technology Data Exchange (ETDEWEB)

    Turton, D.R.; Luthra, S.K.; Pike, V.W.; Kensett, M.J.

    1987-09-01

    A procedure for labelling the novel analgesic, meptazinol ((+)1-methyl-3-ethyl-3-(m-hydroxyphenyl)tetrahydroazepine), with the positron-emitting radionuclide, carbon-11 has been developed in order to permit the pharmacokinetics of this analgesic to be studied in man. The procedure involves the reaction of (/sup 11/C)iodomethane with normeptazinol in ethanol, evaporation of any unreacted (/sup 11/C)iodomethane, purification by HPLC and removal of solvent. Subsequent solubilisation of the radioactive product in ethanol plus isotonic saline and sterilisation by filtration produces a safely-injectable solution of (N-methyl- /sup 11/C)meptazinol in 14% radiochemical yield. The specific activity of the product is up to 7.4 GBq/..mu..mol at the end of radiosynthesis. Preparations have been shown to be radiochemically pure and to be free of normeptazinol by analytical HPLC and TLC. That the radioactive product is (N-methyl- /sup 11/C)meptazinol has been unequivocally demonstrated by co-inclusion of /sup 13/C-enriched iodomethane in the radiosynthesis and examination of the product by broad-band proton-decoupled Fourier transform /sup 13/C-NMR spectroscopy.

  17. Cu(I)-catalyzed (11)C carboxylation of boronic acid esters: a rapid and convenient entry to (11)C-labeled carboxylic acids, esters, and amides.

    Science.gov (United States)

    Riss, Patrick J; Lu, Shuiyu; Telu, Sanjay; Aigbirhio, Franklin I; Pike, Victor W

    2012-03-12

    Rapid and direct: the carboxylation of boronic acid esters with (11)CO(2) provides [(11)C]carboxylic acids as a convenient entry into [(11)C]esters and [(11)C]amides. This conversion of boronates is tolerant to diverse functional groups (e.g., halo, nitro, or carbonyl).

  18. Kinetics of 11C-labeled opiates in the brain of rhesus monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Hartvig, P.; Bergstroem, K.; Lindberg, B.; Lundberg, P.O.; Lundqvist, H.; Langstroem, B.; Svaerd, H.; Rane, A.

    1984-07-01

    The regional uptake in the brain of Rhesus monkeys of i.v. administered 11C-labeled morphine, codeine, heroin and pethidine was studied by means of positron emission tomography. The technique measures the sum of parent drug and radiolabeled metabolites. (For the sake of simplicity the drug derived radioactivity is denoted by the drug name.) Morphine had a limited uptake to discrete areas of the brain. The maximum normalized uptake, with respect to dose per kilogram body weight, was about 0.2, i.e., 20% of the calculated activity if the drug had been evenly distributed throughout the body of the monkey. Maximum radioactivity appeared 30 to 45 min after injection. Morphine left the brain slowly with an estimated half-life of more than 2 hr. An area with a normalized uptake of about 1.0 was detected centrally in the lowest horizontal transsection of the skull. The origin of this area was identified as the pituitary. Codeine, heroin and pethidine were taken up to the brain to a larger extent than morphine, with maximum normalized uptakes of 2.6, 4.6 and 6.3, respectively. Maximum radioactivities of these drugs were achieved earlier and the elimination rates were faster than for morphine. Differences in the uptake of these drugs to the brain, as well as differences in time to maximal normalized uptake and rate of disappearance are considered to reflect differences in the lipophilic character between the drugs. Pethidine had the most rapid and extensive uptake followed by heroin, codeine and morphine in order of decreasing lipophilicity.

  19. A restricted access material for rapid analysis of [(11)C]-labeled radiopharmaceuticals and their metabolites in plasma

    DEFF Research Database (Denmark)

    Gillings, N.

    2009-01-01

    , sensitive and robust method for the measurement of plasma samples from PET studies using [(11)C]-labeled radiopharmaceuticals. METHODS: Unadulterated plasma samples were analyzed directly, following a simple filtration, by the use of a small extraction column, containing a restricted access material...

  20. Radiosynthesis of [{sup 11}C]D.P.A.-713, [{sup 11}C]D.P.A.-715 and [{sup 11}C]clinme, selected carbon-11-labelled novel potential radioligands for imaging the peripheral benzodiazepine receptors with PET

    Energy Technology Data Exchange (ETDEWEB)

    Dolle, F.; Thominiaux, C.; Hinnen, F.; Demphel, S.; Le helleix, S.; Chauveau, F.; Boutin, H.; Herard, A.S.; Hantraye, P.; Tavitian, B. [Service Hospitalier Frederic Joliot, I2BM/DSV, 91 - Orsay (France); Kassiou, M.; James, M.; Creelman, A.; Fulton, R. [Sydney Univ., Brain and Mind Research Institute, NSW (Australia); Kassiou, M. [Sydney Univ., Discipline of Medical Radiations, Sciences and School of Chemistry, NSW (Australia); Katsifis, A.; Greguric, I.; Mattner, F.; Loch, C. [Radiopharmaceuticals Research Institute, ANSTO, NSW (Australia); Selleri, S. [Degli Studi di Firenze Univ., Dipt. di Scienze Farmaceutiche (Italy)

    2008-02-15

    {sup 11}C P.K.11195 is not only the oldest, but also the most widely used PET radiotracer for in vivo imaging of the peripheral benzodiazepine receptors (P.B.R. or translocator protein (18 kDa, T.S.P.O.). With the aim of developing a new PET imaging probe for the in vivo study of the P.B.R., two pyrazol [1,5-a]pyrimidineacetamides (D.P.A.-713 and D.P.A.-715) and one imidazol[1,2-a]pyridine-acetamide (C.L.I.N.M.E.) were radiolabelled with the positron emitters carbon{sup 11} (half life: 20.38 min) [1-5]. Briefly, C.L.I.N.M.E. (2-[6-chloro-2(4-iodophenyl)-imidazol[1,2-a]pyridin-3-yl] -N-ethyl-N-methyl-acetamide) was labelled at its methyl-acetamide moity chain from the corresponding nor-analogue using[{sup 11}C]methyl iodide (in D.M.S.O./D.M.F (100/200 {mu}L) containing powdered K.O.H. (3-5 mg) at 110 degrees C for 3 min. D.P.A.-713 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin -3-yl]acetamide) and D.P.A.-715 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-bis-tri-fluoro-methyl-pyrazolo [1,5-a]pyrimidin-3-yl]acetamide) were labelled at their aromatic methoxy groups from the corresponding nor-derivatives using [{sup 11}C]methyl triflate (in acetone (300{mu}L) containing aq. 3 M NaOH (4{mu}L) at 110 degrees C for 1 min). All radioligands were purified using semi preparative Zorbax reverse phase H.P.L.C., were adequately formulated for in vivo injection within 30 min and were found to be > 95% chemically and radiochemically pure. (N.C.)

  1. Synthesis and in vivo distribution in rat brain of /sup 11/C-labelled N-alkylated ADTN derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Werf, J.F. van der; Vaalburg, W.; Korf, J.; Kuilman, T.; Wiegman, T. (Rijksuniversiteit Groningen (Netherlands). Hospital)

    1984-05-01

    A method for the rapid production and purification of /sup 11/C-labelled N-alkylated derivatives of the dopamine agonist 2-amino-6,7-dihydroxytetralin (ADTN) is described. The label is introduced by N-methylation with no-carrier-added /sup 11/CH/sub 3/I of the corresponding secondary amines via their lithium salts. Following systemic injection in rats a uniform distribution of radioactivity in the brain was found for both the labelled 2-(N-methyl-N-n-propylamino)- and 2-(N,N-dimethylamino)-6,7-dihydroxytetralin.

  2. Synthesis and in vivo distribution in rat brain of /sup 11/C-labelled N-alkylated ADTN derivatives

    Energy Technology Data Exchange (ETDEWEB)

    van der Werf, J.F.; Vaalburg, W.; Korf, J.; Kuilman, T.; Wiegman, T.

    1984-05-01

    A method for the rapid production and purification of /sup 11/C-labelled N-alkylated derivatives of the dopamine agonist 2-amino-6,7-dihydroxytetralin (ADTN) is described. The label is introduced by N-methylation with no-carrier-added /sup 11/CH/sup 3/I of the corresponding secondary amines via their lithium salts. Following systemic injection in rats a uniform distribution of radioactivity in the brain was found for both the labelled 2-(N-methyl-N-n-propylamino)- and 2-(N,N-dimethylamino)-6,7-dihydroxytetralin.

  3. In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N,N-(/sup 11/C)dimethyltryptamine

    Energy Technology Data Exchange (ETDEWEB)

    Yanai, Kazuhiko; Ido, Tatsuo; Ishiwata, Kiichi; Takahashi, Toshihiro; Iwata, Ren; Hatazawa, Jun; Matsuzawa, Taiju

    1986-07-01

    The endogenous hallucinogen, N,N-dimethyltryptamine (DMT), was labeled with carbon-11 and its regional distribution in rat brain studied. (/sup 11/C)DMT showed higher accumulation in the cerebral cortex, caudate putamen, and amygdaloid nuclei. Studies of the subcellular distribution of (/sup 11/C)DMT revealed the specific localization in the fractions enriched with serotonin receptors only when a very low dose was injected into rats. The proportions of the radioactivity in receptor-rich fractions were greatly enhanced by pretreatment with the monoamine oxidase inhibitor, pargyline. Specific binding of (/sup 11/C)DMT to serotonin receptors in dog brain was demonstrated by a positron emission tomographic study in which 5-methoxy-N,N-dimethyltryptamine caused approximately 20% displacement of the radioligand from the receptors.

  4. Synthesis of sup 11 C-labeled imipramine and its biodistribution in mice; A potential tracer for positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hitoshi; Edo, Kiyoto; Hishinuma, Takanori; Mizugaki, Michinao (Tohoku University Hospital, Sendai (Japan). Department of Pharmaceutical Sciences); Takahashi, Toshihiro; Ido, Tatsuo

    1989-12-01

    A tricyclic antidepressant, {sup 11}C-labeled imipramine was synthesized by N-methylation of desipramine with {sup 11}CH{sub 3}I to assist in the imaging of the human imipramine receptor by positron emission tomography. The radiochemical yield after purification of {sup 11}C-imipramine by high performance liquid chromatography was 28-63% at a specific activity of 26-53 Ci/mmol. The time required for synthesis, including purification was 30 min from the end of {sup 11}CH{sub 3}I trapping. The organ distribution of {sup 11}C-imipramine was investigated in mice at various times after i.v. injection. The main accumulation of radioactivity was in the kidney, followed by the lung and the heart. In the brain, the radioactivity levels in the hypothalamus and striatum were the highest and remained constant, differentiating them from other portions of the brain. Furthermore, the result of a binding assay with {sup 3}H-labeled imipramine suggested that the regional distribution of {sup 11}C-imipramine in the same mouse brain correlated to that of the high affinity imipramine binding site. (author).

  5. sup 11 C-labelling of the analgesic Tramadol and its major metabolites by selective O- and N-methylation

    Energy Technology Data Exchange (ETDEWEB)

    Gail, R.; Coenen, H.H.; Hamacher, K.; Stoecklin, G. (Forschungzentrum Juelich GmbH (Germany). Inst. fuer Nuklearchemie)

    1992-09-01

    For in vivo pharmacokinetic studies with PET, the analgesic Tramadol(1-(3-methoxyphenyl)-2-dimethylaminomethyl-cyclohexan-1-ol) and its major O- and N-desmethylated metabolites M1 and M2 were labelled with carbon-11. Starting with the corresponding desmethyl precursors, (O-methyl-{sup 11}C)Tramadol and racemic(N-methyl-{sup 11}C)Tramadol were prepared by methylation with n.c.a. ({sup 11}C)methyl iodide in DMSO with radiochemical yields of 85 and 90%, respectively. Specific n.c.a. N-methylation of bis-desmethyl-Tramadol (M5) was achieved with 90% radiochemical yield. However, a selective O-methylation of M5 was not possible even with an excess of NaOH, and only 70% of (O-methyl-{sup 11}C)M2 was obtained. Quaternization of Tramadol or M1 was >15 times slower than O-methylation, and was only observed in the presence of added CH{sub 3}I carrier. (author).

  6. (11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand

    DEFF Research Database (Denmark)

    Andersen, Valdemar L; Hansen, Hanne D; Herth, Matthias M;

    2015-01-01

    Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson's disease. Here, we detail the (11)C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [(11)C......]Pimavanserin was obtained by N-methylation of an appropriate precursor using [(11)C]MeOTf in acetone at 60°C giving radiochemical yields in the range of 1-1.7GBq (n=4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs....... However, this binding could not be blocked by either ketanserin or pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [(11)C]pimavanserin is not selective for the 5-HT2AR in pigs....

  7. Positron emitting nuclides and their synthetic incorporation in radiopharmaceuticals. [Labeled with /sup 11/C, /sup 13/N, and /sup 18/F

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, J.S.

    1976-01-01

    /sup 11/C, /sup 13/N, and /sup 15/O has potential applicability to the study of metabolism in humans. Problems in the synthesis of radiopharmaceuticals labeled with /sup 11/C, /sup 13/N, and /sup 18/F are described: quality control, radiation exposure, carboxylic acids, glucose, amines, amino acids, nitrosources, fluoroethanol. 54 references. (DLC)

  8. Enzymatic syntheses of carbamyl phosphate, L-citrulline, and N-carbamyl L-aspartate labeled with either 13N or 11C.

    Science.gov (United States)

    Gelbard, A S; Kaseman, D S; Rosenspire, K C; Meister, A

    1985-01-01

    [13N]- and [11C]carbamyl phosphate, L-[omega-13N]citrulline, L-[ureido-11C]citrulline, [carbamyl-13N]- and [carbamyl-11C]carbamyl-L-aspartate were synthesized using carbamyl phosphate synthetase co-immobilized with either aspartate transcarbamylase or ornithine transcarbamylase. Carbamyl L-[13N]aspartate was enzymatically prepared from carbamyl phosphate and L-[13N]aspartate. The tissue distribution of radioactivity in mice after injection of radiolabeled ammonia, carbamyl phosphate or citrulline was studied. The tissue distribution of isotope derived from [13N]carbamyl phosphate and [13N]ammonia were similar, with the exception of liver, brain and pancreas, in which 13NH3 uptake was higher after retroorbital injection. The distribution of label derived from L-[omega-13N]- and L-[ureido-11C]citrulline was similar. Substantial tumor (Sarcoma-180) uptake of label from L-citrulline was observed.

  9. Radiosynthesis and in vivo evaluation of [{sup 11}C]-labelled pyrrole-2-carboxamide derivates as novel radioligands for PET imaging of monoamine oxidase A

    Energy Technology Data Exchange (ETDEWEB)

    De Bruyne, Sylvie [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium); La Regina, Giuseppe [Istituto Pasteur, Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita di Roma, I-00185 Rome (Italy); Staelens, Steven [IBITECH-Medisip, Ghent University-IBBT, 9000 Ghent (Belgium); Wyffels, Leonie [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium); Deleye, Steven [IBITECH-Medisip, Ghent University-IBBT, 9000 Ghent (Belgium); Silvestri, Romano [Istituto Pasteur, Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita di Roma, I-00185 Rome (Italy); De Vos, Filip [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium)], E-mail: filipx.devos@ugent.be

    2010-05-15

    Introduction: Since MAO-A is an enzyme involved in the metabolism of neurotransmitters, fluctuations in MAO-A functionality are associated with psychiatric and neurological disorders as well as with tobacco addiction and behaviour. This study reports the radiolabelling of two [{sup 11}C]-labelled pyrrole-2-carboxamide derivates, RS 2315 and RS 2360, along with the characterization of their in vivo properties. Methods: The radiolabelling of [{sup 11}C]-RS 2315 and [{sup 11}C]-RS 2360 was accomplished by alkylation of their amide precursors with [{sup 11}C]CH{sub 3}I. Biodistribution, blocking and metabolite studies of both tracers were performed in NMRI mice. Finally, a PET study in Sprague-Dawley rats was performed for [{sup 11}C]-RS 2360. Results: Both tracers were obtained in a radiochemical yield of approximately 30% with radiochemical purity of >98%. Biodistribution studies showed high brain uptake followed by rapid brain clearance for both radiotracers. In the brain, [{sup 11}C]-RS 2360 was more stable than [{sup 11}C]-RS 2315. Blocking studies in mice could not demonstrate specificity of [{sup 11}C]-RS 2315 towards MAO-A or MAO-B. The blocking and imaging study with [{sup 11}C]-RS 2360 on the other hand indicated specific binding in MAO-A at the earliest time points. Conclusions: [{sup 11}C]-RS 2315 displayed a high nonspecific binding and is therefore not suitable for visualization of MAO-A in vivo. [{sup 11}C]-RS 2360 on the other hand has potential for mapping MAO-A since specific binding is demonstrated.

  10. Simple automated system for simultaneous production of {sup 11}C-labeled tracers by solid supported methylation

    Energy Technology Data Exchange (ETDEWEB)

    Quincoces, Gemma [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Penuelas, Ivan [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain)]. E-mail: ipenuelas@unav.es; Valero, Marta [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Serra, Patricia [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Collantes, Maria [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Marti-Climent, Josep [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Arbizu, Javier [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Jose Garcia-Velloso, Maria [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain); Angel Richter, Jose [Department of Nuclear Medicine, University Hospital, University of Navarra School of Medicine, Av. Pio XII 36, 31008 Pamplona (Spain)

    2006-07-15

    We herein describe a simple setup for the automated simultaneous synthesis of L-[methyl-{sup 11}C]methionine and N-[methyl-{sup 11}C]choline by solid-supported methylation . The setup is extremely simple and easy to adapt to other automated systems and due to its versatility, the method can be utilized for the production of other radiopharmaceuticals requiring a simple [{sup 11}C]methylation step. Furthermore, it can be used for multiple simultaneous synthesis.

  11. {sup 11}C-labeled stilbene derivatives as A{beta}-aggregate-specific PET imaging agents for Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Ono, Masahiro; Wilson, Alan; Nobrega, Jose; Westaway, David; Verhoeff, Paul; Zhuang Zhiping; Kung Meiping; Kung, Hank F. E-mail: kunghf@sunmac.spect.upenn.edu

    2003-08-01

    A series of stilbene derivatives as potential diagnostic imaging agents targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of the stilbenes were successfully achieved by a simple Wadsworth-Emmons reaction between diethyl (4-nitrobenzyl)phosphonate and 4-methoxybenzaldehyde. 4-N,N-dimethylamino-4'-methyoxy and the corresponding 4-N-monomethylamino-, 4'-hydroxy stilbenes showed good binding affinities towards A{beta} aggregates in vitro (K{sub i} < 10 nM). The {sup 11}C labeled 4-N-methylamino-4'-hydroxystilbene, [{sup 11}C]4, was prepared by {sup 11}C methylation of 4-amino-4'-hydroxystilbene. The [{sup 11}C]4 displayed a moderate lipophilicity (log P = 2.36), and showed a very good brain penetration and washout from normal rat brain after an iv injection. In vitro autoradiography of transgenic AD mouse brain sections showed a high specific labeling of {beta}-amyloid plaques, whereas the control sections showed no binding. Taken together the data suggest that a relatively simple stilbene derivative, [{sup 11}C]4, N-[{sup 11}C]methylamino-4'-hydroxystilbene, may be useful as a positron emission tomography (PET) imaging agent for mapping A{beta} plaques in the brain of patients with Alzheimer's disease.

  12. Labeling and preliminary in vivo evaluation of the 5-HT7 receptor selective agonist [(11)C]E-55888

    DEFF Research Database (Denmark)

    Hansen, Hanne D; Andersen, Valdemar L; Lehel, Szabolcs

    2015-01-01

    E-55888 has been identified as a selective serotonin 7 (5-HT7) receptor agonist. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]E-55888 as a radioligand for positron emission tomography (PET) imaging. [(11)C]E-55888 was obtained by N-methylation of an app...

  13. (11) C-labeled and (18) F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain.

    Science.gov (United States)

    Funke, Uta; Vugts, Danielle J; Janssen, Bieneke; Spaans, Arnold; Kruijer, Perry S; Lammertsma, Adriaan A; Perk, Lars R; Windhorst, Albert D

    2013-01-01

    The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1 R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1 R occupancy. The H3 R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3 R PET imaging studies in humans have been reported. The H4 R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4 R-specific (11) C-labeled ligands have been synthesized, and the imaging of the H4 R in vivo is in the early stage.

  14. (11)C- and (18)F-Labeled Radioligands for P-Glycoprotein Imaging by Positron Emission Tomography.

    Science.gov (United States)

    Cantore, Mariangela; Benadiba, Marcel; Elsinga, Philip H; Kwizera, Chantal; Dierckx, Rudi A J O; Colabufo, Nicola Antonio; Luurtsema, Gert

    2016-01-01

    P-Glycoprotein (P-gp) is an efflux transporter widely expressed at the human blood-brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P-gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2-[2-(2-methyl-((11)C)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(11)C]-5); 2-[2-(2-fluoromethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline ([(18)F]-6); and 2-[2-(2-fluoroethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(18)F]-7), were tested in several in vitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P-gp. Methyl derivative [(11)C]-5 is a potent P-gp substrate, whereas the corresponding fluoroethyl derivative [(18)F]-7 is a P-gp inhibitor. Fluoromethyl compound [(18)F]-6 is classified as a non-transported P-gp substrate, because its efflux increases after cyclosporine A modulation. These studies revealed a promising substrate and inhibitor, [(11)C]-5 and [(18)F]-7, respectively, for in vivo imaging of P-gp by using PET.

  15. Evaluation of S-[[sup 11]C]citalopram as a radioligand for in vivo labelling of 5-hydroxytryptamine uptake sites

    Energy Technology Data Exchange (ETDEWEB)

    Hume, S.P.; Lammertsma, A.A.; Bench, C.J.; Pike, V.W.; Pascali, C.; Cremer, J.E. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit); Dolan, R.J. (Royal Free Hospital, London (United Kingdom))

    1992-11-01

    The biologically active S-enantiomer of [N-methyl-[sup 11]C]citalopram was evaluated as a radioligand for in vivo labelling of the 5-hydroxytryptamine uptake site in brain, using ex vivo tissue counting in rats and positron emission tomography in man. In rats, the maximal signal for total versus non-specific binding was approx. 2 at 60-120 min after radioligand injection. Subsequent studies in man failed to identify a specific signal over a 90 min scanning period, due to prolonged retention of non-specific label. (author).

  16. Fully automatic, microprocessor-controlled system for the production of /sup 11/CO/sub 2/, /sup 11/CH/sub 3/I and /sup 11/C-labeled radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Vandewalle, T.; Vandecasteele, C.; Guchteneire, F. de; Meulewaeter, L.; Haver, D. van; Denutte, H.; Goethals, P.; Slegers, G. (Ghent Rijksuniversiteit (Belgium))

    1985-06-01

    An automated system for the production of /sup 11/C-labeled radiopharmaceuticals, using /sup 11/C-CH/sub 3/I as a precursor, has been developed. The whole procedure, including irradiation, production of /sup 11/C-CH/sub 3/I, synthesis of the labeled molecule and isolation of the final product is controlled by a microprocessor. Between 30 and 80 mCi of 5 different radiopharmaceuticals are produced routinely with this system.

  17. Treatment, rationale, and study design of TALISMAN study: a randomized phase II open-label study of second-line erlotinib versus intermittent erlotinib dosing with docetaxel in the treatment of former-smoker men affected by recurrent squamous non-small-cell lung cancer.

    Science.gov (United States)

    Gridelli, Cesare; Rossi, Antonio; Venturino, Paola; de Marinis, Filippo

    2011-01-01

    We present the treatment rationale and study design of the TALISMAN (TArceva and docetaxeL In former-Smokers MAle patients with recurrent Non-small-cell lung cancer) study, an open-label, randomized phase II trial of erlotinib (arm A) or intermittent erlotinib and docetaxel (arm B) in male former smokers affected by recurrent squamous non-small-cell lung cancer (NSCLC). In arm A, treatment consists of erlotinib 150 mg daily orally until progression or inacceptable toxicity; in arm B, treatment consists of docetaxel 75 mg/m² on day 1 and erlotinib 150 mg orally on days 2-16, recycled every 3 weeks up to 4 cycles followed, in patients not progressed, by erlotinib 150 mg daily orally until disease progression or inacceptable toxicity. The primary endpoint of this study is the rate of patients without progression at 6 months, and secondary objectives include median progression-free survival, median overall survival, activity, and toxicity. In addition, translational research evaluating EGFR and KRAS mutational status will be investigated for both arms.

  18. Erlotinib hydrochloride.

    Science.gov (United States)

    Minna, John D; Dowell, Jonathan

    2005-05-01

    Erlotinib hydrochloride (Tarceva; OSI Pharmaceuticals/Genentech/Roche), a member of a class of targeted anticancer drugs that inhibit the activity of the epidermal growth factor receptor, was approved by the US FDA in November 2004 for the treatment of advanced non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. It is the first such drug to demonstrate an increase in survival in Phase III trials in patients with advanced non-small-cell lung cancer.

  19. [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.

    Science.gov (United States)

    Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen; Gormsen, Lars C; Munk, Ole L; Frøkiær, Jørgen; Jessen, Niels

    2016-06-01

    Metformin is the most commonly prescribed oral antidiabetic drug, with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic cation transporters (OCT), including multidrug and toxin extrusion proteins (MATE), are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic positron emission tomography with [(11)C]-labeled metformin ([(11)C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1 and OCT2 significantly reduced the distribution of metformin in the liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [(11)C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies.

  20. Utility of 11C-methionine and 11C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous 111In-labelled leukocytes, 99mTc-DPD, and 18F-FDG

    Science.gov (United States)

    Afzelius, Pia; Alstrup, Aage KO; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99mTc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers’ diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, 11C-methionine and 11C-donepezil PET, 99mTc-DPD and 111In-labelled leukocytes scintigraphy, and 18F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 79%, 11C-methionine in 79%, 11C-donepezil in 58%, and 99mTc-DPD in none. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT and 11C-methionine in marking infectious lesions. PMID:28078182

  1. Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous (111)In-labelled leukocytes, (99m) Tc-DPD, and (18)F-FDG.

    Science.gov (United States)

    Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m) Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F-FDG) PET to improve detection of osteomyelitis. The tracers' diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, (18)F-FDG accumulated in 100%, (111)In-leukocytes in 79%, (11)C-methionine in 79%, (11)C-donepezil in 58%, and (99m) Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions.

  2. Utility of 11C-donepezil and 11C-methionine for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: Comparison to autologous 111In-labelled leukocytes, 18F-FDG, and 99mTc-MPD

    DEFF Research Database (Denmark)

    Afzelius, Pia; Alstrup, Aage Kristian Olsen; Schønheyer, Henrik C.

    2016-01-01

    The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99mTc-MDP single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers...... a sequential scan protocol with 18F-FDG, 11C-methionine, 11C-donepezil, 99mTc- methylene diphosphonate (MDP), and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 22 osteomyelitis...... lesions, 5 lesions characterized as abscesses and pulmonary abscesses in one pig. By comparing the 22 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 86%, 11C-methionine in 86%, 11C-donepezil in 63%, and 99mTc-MDP in none. Overall, 18F-FDG PET was slightly superior to 111In...

  3. Evaluation in vitro and in animals of a new {sup 11}C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain

    Energy Technology Data Exchange (ETDEWEB)

    Zanotti-Fregonara, Paolo; Liow, Jeih-San; Zoghbi, Sami S.; Clark, David T.; Morse, Cheryl; Pike, Victor W. [National Institute of Mental Health, National Institutes of Health, Molecular Imaging Branch, Bethesda, MD (United States); Barth, Vanessa N.; Rhoads, Emily; Siuda, Edward; Heinz, Beverly A.; Nisenbaum, Eric; Dressman, Bruce; Joshi, Elizabeth; Luffer-Atlas, Debra; Fisher, Matthew J.; Masters, John J.; Goebl, Nancy; Kuklish, Steven L.; Tauscher, Johannes [Eli Lilly and Co., Indianapolis, IN (United States); Innis, Robert B. [National Institute of Mental Health, National Institutes of Health, Molecular Imaging Branch, Bethesda, MD (United States); National Institute of Mental Health, Molecular Imaging Branch, Bethesda, MD (United States)

    2013-02-15

    Two allosteric modulators of the group I metabotropic glutamate receptors (mGluR1 and mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1. LY2428703, a full mGluR1 antagonist (IC{sub 50} 8.9 nM) and partial mGluR5 antagonist (IC{sub 50} 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC{sub 50} 35.3 nM and 10.2 nM, respectively) were successfully labeled with {sup 11}C and evaluated as radioligands for mGluR1. The pharmacology of LY2428703 was comprehensively assessed in vitro and in vivo, and its biodistribution was investigated by liquid chromatography-mass spectrometry/mass spectrometry, and by PET imaging in the rat. In contrast, LSN2606428 was only evaluated in vitro; further evaluation was stopped due to its unfavorable pharmacological properties and binding affinity. {sup 11}C-LY2428703 showed promising characteristics, including: (1) high potency for binding to human mGluR1 (IC{sub 50} 8.9 nM) with no significant affinity for other human mGlu receptors (mGluR2 through mGluR8); (2) binding to brain displaceable by administration of an mGluR1 antagonist; (3) only one major radiometabolite in both plasma and brain, with a negligible brain concentration (with 3.5 % of the total radioactivity in cerebellum) and no receptor affinity; (4) a large specific and displaceable signal in the mGluR1-rich cerebellum with no significant in vivo affinity for mGluR5, as shown by PET studies in rats; and (5) lack of substrate behavior for efflux transporters at the blood-brain barrier, as shown by PET studies conducted in wild-type and knockout mice. {sup 11}C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents. (orig.)

  4. An open label phase II study evaluating first-line EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer patients with tumors showing high EGFR gene copy number

    Science.gov (United States)

    Kowalczyk, Anna; Suszko-Kazarnowicz, Malgorzata; Duchnowska, Renata; Szczesna, Aleksandra; Ratajska, Magdalena; Sowa, Aleksander; Limon, Janusz; Biernat, Wojciech; Burzykowski, Tomasz; Jassem, Jacek; Dziadziuszko, Rafal

    2017-01-01

    Background First-line treatment with epidermal growth factor receptor (EGFR) inhibitors in NSCLC is effective in patients with activating EGFR mutations. The activity of erlotinib in patients harboring high EGFR gene copy number has been considered debatable. Patients and Methods A multicenter, open-label, single-arm phase II clinical trial was performed to test the efficacy of erlotinib in the first-line treatment of NSCLC patients harboring high EGFR gene copy number defined as =4 copies in =40% of cells. Findings Between December 2007 and April 2011, tumor samples from 149 subjects were screened for EGFR gene copy number by fluorescence in-situ hybridization (FISH), Out of 49 patients with positive EGFR FISH test, 45 were treated with erlotinib. Median PFS in the intent-to-treat population was 3.3 months (95%CI: 1.83.9 months), and median overall survival was 7.9 months (95% CI: 5.112.6 months). Toxicity profile of erlotinib was consistent with its known safety profile. The trial was stopped prematurely at 63% of originally planned sample size due to accumulating evidence that EGFR gene copy number should not be used to select NSCLC patients to first-line therapy with EGFR TKI. Data on erlotinib efficacy according to EGFR, KRAS and BRAF mutations are additionally presented. Interpretation This trial argues against using high gene copy number for selection of NSCLC patients to first-line therapy with EGFR TKIs. The study adds to the discussion on efficacy of other targeted agents in patients with target gene amplified tumors. PMID:27924059

  5. Study of the production yields of {sup 18}F, {sup 11}C, {sup 13}N and {sup 15}O positron emitters from plasma-laser proton sources at ELI-Beamlines for labeling of PET radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Amato, Ernesto [Section of Radiological Sciences, Department of Biomedical and Dental Sciences and of Morphologic and Functional Imaging, University of Messina (Italy); Italiano, Antonio, E-mail: italianoa@unime.it [Istituto Nazionale di Fisica Nucleare, Gruppo Collegato di Messina (Italy); Margarone, Daniele [Institute of Physics ASCR, v.v.i. (FZU), ELI-Beamlines Project, 182 21 Prague (Czech Republic); Pagano, Benedetta [Nuclear Medicine Unit, University Hospital “G. Martino”, Messina (Italy); Baldari, Sergio [Section of Radiological Sciences, Department of Biomedical and Dental Sciences and of Morphologic and Functional Imaging, University of Messina (Italy); Nuclear Medicine Unit, University Hospital “G. Martino”, Messina (Italy); Korn, Georg [Institute of Physics ASCR, v.v.i. (FZU), ELI-Beamlines Project, 182 21 Prague (Czech Republic)

    2016-03-01

    The development of novel compact PET radionuclide production systems is of great interest to promote the diffusion of PET diagnostics, especially in view of the continuous development of microfluidics labeling approaches. We studied the feasibility to produce clinically-relevant amounts of PET isotopes by means of laser-accelerated proton sources such that expected at the ELI-Beamlines facility. {sup 18}F, {sup 11}C, {sup 13}N and {sup 15}O production yields were calculated through the TALYS software, by taking into account the broad proton spectra expected. With the hypothesized proton fluencies, clinically-relevant amounts of radionuclides can be obtained, suitable to prepare single doses of {sup 18}F-, {sup 11}C- and {sup 13}N-labeled radiopharmaceuticals exploiting fast and efficient microfluidic labeling systems.

  6. Labelling and biological evaluation of [{sup 11}C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Evens, Nele [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium); Bosier, Barbara [Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200 (Belgium); Lavey, Brian J.; Kozlowski, Joseph A. [Schering Plough Research Institute, Kenilworth, NJ 07033 (United States); Vermaelen, Peter [Division of Nuclear Medicine, K.U.Leuven, Leuven 3000 (Belgium); Baudemprez, Luc; Busson, Roger [Laboratory of Medicinal Chemistry, K.U.Leuven, Leuven 3000 (Belgium); Lambert, Didier M. [Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200 (Belgium); Van Laere, Koen [Division of Nuclear Medicine, K.U.Leuven, Leuven 3000 (Belgium); Verbruggen, Alfons M. [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium); Bormans, Guy M. [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium)], E-mail: guy.bormans@pharm.kuleuven.be

    2008-10-15

    Introduction: The cannabinoid type 2 receptor (CB{sub 2} receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[{sup 11}C]methoxyphenyl)sulfonyl) -phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([{sup 11}C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB{sub 2} receptors. Methods: Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [{sup 11}C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [{sup 11}C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined. Results: [{sup 11}C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/{mu}mol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps. Conclusion: [{sup 11}C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB{sub 2} receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.

  7. Comparison of {sup 68}Ga-labelled PSMA-11 and {sup 11}C-choline in the detection of prostate cancer metastases by PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Schwenck, Johannes [Eberhard Karls University, Department of Nuclear Medicine and Clinical Molecular Imaging, Tuebingen (Germany); Eberhard Karls University, Department of Preclinical Imaging and Radiopharmacy, Tuebingen (Germany); Rempp, Hansjoerg; Nikolaou, Konstantin; Pfannenberg, Christina [Eberhard Karls University, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany); Reischl, Gerald [Eberhard Karls University, Department of Preclinical Imaging and Radiopharmacy, Tuebingen (Germany); Kruck, Stephan; Stenzl, Arnulf [Eberhard Karls University, Department of Urology, Tuebingen (Germany); La Fougere, Christian [Eberhard Karls University, Department of Nuclear Medicine and Clinical Molecular Imaging, Tuebingen (Germany); German Cancer Consortium, German Cancer Research Center Partner Site, Heidelberg (Germany)

    2017-01-15

    Prostate-specific membrane antigen (PSMA) is expressed ubiquitously on the membrane of most prostate tumors and its metastasis. While PET/CT using {sup 11}C-choline was considered as the gold standard in the staging of prostate cancer, PET with radiolabelled PSMA ligands was introduced into the clinic in recent years. Our aim was to compare the PSMA ligand {sup 68}Ga-PSMA-11 with {sup 11}C-choline in patients with primary and recurrent prostate cancer. 123 patients underwent a whole-body PET/CT examination using {sup 68}Ga-PSMA-11 and {sup 11}C-choline. Suspicious lesions were evaluated visually and semiquantitatively (SUVavg). Out of these, 103 suffered from a confirmed biochemical relapse after prostatectomy and/or radiotherapy (mean PSA level of 4.5 ng/ml), while 20 patients underwent primary staging. In 67 patients with biochemical relapse, we detected 458 lymph nodes suspicious for metastasis. PET using {sup 68}Ga-PSMA-11 showed a significantly higher uptake and detection rate than {sup 11}C-choline PET. Also {sup 68}Ga-PSMA-11 PET identified significantly more patients with suspicious lymph nodes as well as affected lymph nodes regions especially at low PSA levels. Bone lesions suspicious for prostate cancer metastasis were revealed in 36 patients' biochemical relapse. Significantly more bone lesions were detected by {sup 68}Ga-PSMA-11, but only 3 patients had only PSMA-positive bone lesions. Nevertheless, we detected also 29 suspicious lymph nodes and 8 bone lesions, which were only positive as per {sup 11}C-choline PET. These findings led to crucial differences in the TNM classification and the identification of oligometastatic patients. In the patients who underwent initial staging, all primary tumors showed uptake of both tracers. Although significantly more suspicious lymph nodes and bone lesions were identified, only 2 patients presented with bone lesions only detected by {sup 68}Ga-PSMA-11 PET. Thus, PET using {sup 68}Ga-PSMA-11 showed a higher

  8. Studies toward labeling cytisine with [11C]phosgene: rapid synthesis of a delta-lactam involving a new chemoselective lithiation-annulation method.

    Science.gov (United States)

    Rouden, Jacques; Seitz, Thomas; Lemoucheux, Laurent; Lasne, Marie-Claire

    2004-05-28

    With the aim of the radiolabeling of cytisine, a potent agonist of nicotinic receptors, with [(11)C]phosgene, the rapid synthesis of a lactam model of our target has been studied. The key step of the delta-lactam formation is a new chemoselective lithiation-annulation method, under high dilution, of a suitable piperidinylcarbamoyl chloride. This precursor was obtained from (2-hydroxyethyl)piperidine in a linear synthetic sequence involving a Corey-Fuchs olefination of the corresponding aldehyde, followed by a selective reduction, using a diimide equivalent, of an iodoalkyne into a (Z)-iodopropene piperidine. This alkene served as main precursor to study the cyclization according to several procedures using phosgene as the required carbonylating reagent.

  9. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study).

    Science.gov (United States)

    Cicènas, Saulius; Geater, Sarayut Lucien; Petrov, Petar; Hotko, Yevgeniy; Hooper, Gregory; Xia, Fan; Mudie, Nadejda; Wu, Yi-Long

    2016-12-01

    The phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer (NSCLC) that had not progressed following four cycles of platinum-based chemotherapy. Patients had stage IIIB/IV NSCLC, no known epidermal growth factor receptor (EGFR)-activating mutation, and objective response or disease stabilization after platinum-based induction chemotherapy. Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing. Patients were randomized to receive blinded maintenance erlotinib 150mg/day ('early erlotinib') or placebo. Those who progressed on placebo received open-label erlotinib ('late erlotinib'); patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care. Primary endpoint: overall survival (OS). 643 patients were randomized to receive maintenance erlotinib (n=322) or placebo (n=321). As of March 23, 2015, 242 (75.2%) OS events had occurred with 'early erlotinib' versus 235 (73.2%) with 'late erlotinib'. Median OS was 9.7 and 9.5 months with 'early erlotinib' and 'late erlotinib', respectively (HR, 1.02, 95% CI: 0.85-1.22; log-rank p=0.82). No progression-free survival, objective response rate, or disease control rate benefit was observed with maintenance erlotinib. 410 patients entered the second-line phase of the study: 160 patients (50%) from the maintenance erlotinib arm and 250 patients (78%) from the maintenance placebo arm. The pattern of adverse events (AEs) was consistent with previous trials; 11 patients who received blinded erlotinib and 3 who received placebo died during the blinded maintenance phase due to nontreatment-related AEs. OS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation. Safety results were consistent with the established safety profile of erlotinib. Thus

  10. 1-/sup 11/C-D-glucose and related compounds

    Energy Technology Data Exchange (ETDEWEB)

    Shiue, C.Y.; Wolf, A.P.

    1982-01-26

    The novel compounds 1-/sup 11/C-D-glucose, 1-/sup 11/C-D-mannose, 1-/sup 11/C-D-galactose, 2-/sup 11/C-D-glucose, 2-/sup 11/C-D-mannose and 2-/sup 11/C-D-galactose which can be used in nuclear medicine to monitor the metabolism of glucose and galactose can be rapidly prepared by reaction of the appropriate aldose substrate with an alkali metal /sup 11/C-labeled cyanide followed by reduction with a Raney alloy in formic acid.

  11. Disclosure of Erlotinib as a Multikinase Inhibitor in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Laura Conradt

    2011-11-01

    Full Text Available A placebo-controlled phase 3 trial demonstrated that the epidermal growth factor receptor (EGFR inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response, and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work, we observed high erlotinib IC50 values in a panel of human and murine PDAC cell lines. Using EGFR small interfering RNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets, we used an unbiased chemical proteomics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture. In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (Kd = 0.09-0.358 μM than the EGFR (Kd 0.434 μM. We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multikinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.

  12. Synthesis and sup 11 C-labelling of the ACTH fragment analogue H-Met(O sub 2 )-Glu-His-Phe-D-Lys-Phe-OH (Org 2766) via its homocystine-containing precursor

    Energy Technology Data Exchange (ETDEWEB)

    Nispen, J.W. van; Janssen, W.P.A.; Melgers, P.A.T.A.; Janssen, P.S.L. (Organon Scientific Development Group, Oss (Netherlands)); Jansen, J.F.G.A.; Vaalburg, W. (Dept. of Nuclear Medicine, University Hospital Groningen, Groningen (Netherlands))

    1990-01-01

    The hexapeptide dimer (H-Hcy-Glu-His-Phe-D-Lys-Phe-OH){sub 2} was synthesized using solution methods and characterized. Its conversion into H-Met(O{sub 2})-Glu-His-Phe-D-Lys-Phe-OH, Org 2766, was studied on a small scale in as short a time as possible; reduction of the disulfide bond using Na/NH{sub 3}, reaction with CH{sub 3}I, oxidation with H{sub 2}O{sub 2} and catalyst and purification by HPLC were carried out starting with 2 mg of the dimer in a total preparation time of approximately 22 min, starting with the addition of CH{sub 3}I. The preparation of the {sup 11}C-labelled analogue was carried out by methylation with {sup 11}CH{sub 3}I. Restrictions imposed by working with carbon-11 will be discussed. (author).

  13. No-carrier-added [1.sup.11 c]putrescine

    Science.gov (United States)

    McPherson, Daniel W.; Fowler, Joanna S.; Wolf, Alfred P.

    1989-01-01

    The invention relates to a new radiolabeled imaging agent, no-carrier-added [1-.sup.11 C]putrescine, and to the use of this very pure material as a radiotracer with positron emission tomography for imaging brain tumors. The invention further relates to the synthesis of no-carrier-added [1-.sup.11 C]putrescine based on the Michael addition of potassium .sup.11 C-labeled cyanide to acrylonitrile followed by reduction of the .sup.11 C-labeled dinitrile. The new method is rapid and efficient and provides radiotracer with a specific activity greater than 1.4 curies per millimol and in a purity greater than 95%.

  14. Use of a column-switching high-performance liquid chromatography method to assess the presence of specific binding of (R)- and (S)-[{sup 11}C]rolipram and their labeled metabolites to the phosphodiesterase-4 enzyme in rat plasma and tissues

    Energy Technology Data Exchange (ETDEWEB)

    Kenk, Miran; Greene, Michael [Cardiovascular PET Molecular Imaging Program, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 (Canada); Lortie, Mireille; Kemp, Robert A. de [Cardiovascular PET Molecular Imaging Program, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7 (Canada); Beanlands, Rob S. [Cardiovascular PET Molecular Imaging Program, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 (Canada); DaSilva, Jean N. [Cardiovascular PET Molecular Imaging Program, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7 (Canada); Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 (Canada)], E-mail: jdasilva@ottawaheart.ca

    2008-05-15

    Introduction: To complement recent studies using the high-affinity {sup 11}C-labeled phosphodiesterase-4 (PDE4) inhibitor (R)-rolipram and the less active enantiomer (S)-[{sup 11}C]rolipram for in vivo quantification of PDE4 levels, we evaluated the presence of radiolabeled metabolites and their potential binding to PDE4 in the rat plasma, brain, heart, pancreas, skeletal muscle and brown adipose tissue. Methods: A reverse-phase capture and analytical HPLC column-switch method was used to detect (R)-[{sup 11}C]rolipram, (S)-[{sup 11}C]rolipram and their radiolabeled metabolites in rat plasma and tissue extracts. The relative proportion of PDE4-specific binding of the radiotracers and their labeled metabolites was analyzed following co-injections with a saturating dose of unlabeled (R)-rolipram at 45 min post-tracer injection in tissue extracts. Results: Radiolabeled metabolites were found in the plasma (72-75% of total radioactive signal), and in the heart, skeletal muscle, pancreas and brown adipose tissue (44-52%), but not in the brain. In comparison to polar labeled metabolites, the proportion of unchanged (R)-[{sup 11}C]rolipram was reduced in PDE4-rich organs by co-injection of unlabeled (R)-rolipram. Conversely, no changes were obtained in brown adipose tissue, or with (S)-[{sup 11}C]rolipram, suggesting that radiolabeled metabolites of (R)-[{sup 11}C]rolipram display no specific binding to PDE4. Conclusions: Radiolabeled hydrophilic metabolites are unlikely to compete with (R)-[{sup 11}C]rolipram for PDE4-specific retention. However, due to the high proportion of the radioactive metabolites in the total radioactive signal, any kinetic modeling calculations in the peripheral tissues will need to take into account the presence of labeled metabolites.

  15. Evaluation of the P-glycoprotein- and breast cancer resistance protein-mediated brain penetration of {sup 11}C-labeled topotecan using small-animal positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Nengaki, Nobuki; Ogawa, Masanao; Yoshida, Yuichiro [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); SHI Accelerator Service, Ltd., Tokyo 141-8686 (Japan); Wakizaka, Hidekatsu [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Yanamoto, Kazuhiko [Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871 (Japan); Fukumura, Toshimitsu [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Zhang Mingrong, E-mail: zhang@nirs.go.jp [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)

    2011-07-15

    Introduction: Topotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood-brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [{sup 11}C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [{sup 11}C]TPT using small-animal PET. Methods: [{sup 11}C]TPT was synthesized by the reaction of a desmethyl precursor with [{sup 11}C]CH{sub 3}I. In vitro study using [{sup 11}C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [{sup 11}C]TPT was determined using small-animal PET and the dissection method in mice. Results: The transport of [{sup 11}C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b{sup -/-}Bcrp1{sup -/-} mice, PET results indicated that the brain uptake of [{sup 11}C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [{sup 11}C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [{sup 11}C]TPT, although the radioactivity in the blood decreased with time. Conclusions: We demonstrated the increase of brain penetration of [{sup 11}C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

  16. JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor.

    Science.gov (United States)

    Zhang, Fu-quan; Yang, Wen-tao; Duan, Shan-zhou; Xia, Ying-chen; Zhu, Rong-ying; Chen, Yong-bing

    2015-06-10

    Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.

  17. Synthesis, in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101,606, ({+-})threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[{sup 11}C]methoxyphenyl) peridino]-1-propanol, as a PET tracer for NR2B subunit-containing NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Haradahira, Terushi E-mail: terushi@nirs.go.jp; Maeda, Jun; Okauchi, Takashi; Zhang, Ming-Rong; Hojo, Junko; Kida, Takayo; Arai, Takuya; Yamamoto, Fumihiko; Sasaki, Shigeki; Maeda, Minoru; Suzuki, Kazutoshi; Suhara, Tetsuya

    2002-07-01

    A carbon-11 labeled methoxyl analog of CP-101,606, ({+-})threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[{sup 11}C]methoxyphenyl) piperidino]-1-propanol [({+-})[{sup 11}C]1], was synthesized as a new subtype-selective PET radioligand for NMDA receptors. The in vitro binding studies using rat brain slices demonstrated that ({+-})[{sup 11}C]1 shows an extremely high-specific binding to the NR2B subunit of NMDA receptors. In contrast to the in vitro binding, the in vivo binding to mouse and monkey brains showed no apparent specific localization of the radioactivity in any of the brain regions. Metabolism and physicochemical properties such as the lipophilicity of ({+-})[{sup 11}C]1 seemed unlikely to affect the in vivo ({+-})[{sup 11}C]1 binding. Among the various endogenous ligands acting at the NMDA receptors, polyamines (spermine and spermidine) and divalent cations (Mg{sup 2+,} Zn{sup 2+,} and Ca{sup 2+}) strongly inhibited the in vitro ({+-})[{sup 11}C]1 binding. Thus, the present studies point to the possibility that the polyamines and cations behave as endogenous inhibitors for ({+-})[{sup 11}C]1 binding, leading to the loss of the specific binding in vivo.

  18. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  19. Erlotinib-related bilateral anterior uveitis

    Science.gov (United States)

    Ali, Kashif; Kumar, Indu; Usman-Saeed, Muniba; Usman Saeed, Muhammad

    2011-01-01

    The authors report the case of a 68-year-old woman with secondary adenocarcinoma of the lungs from an unknown primary. Erlotinib was started which produced symptoms suggestive of uveitis. Erlotinib was stopped and restarted a month later at a lower dose, which resulted in severe bilateral anterior uveitis. The uveitis settled after stopping erlotinib and treatment with topical steroids and cycloplegics. To the best of the authors’ knowledge, this is the first case of erlotinib-related anterior uveitis. PMID:22694887

  20. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study).

    Science.gov (United States)

    Aranda, E; Manzano, J L; Rivera, F; Galán, M; Valladares-Ayerbes, M; Pericay, C; Safont, M J; Mendez, M J; Irigoyen, A; Arrivi, A; Sastre, J; Díaz-Rubio, E

    2012-07-01

    Skin rash is an adverse event which might be associated with longer survival in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors. The aim of this nonrandomised phase II clinical trial is to prospectively evaluate the relationship between skin rash and overall survival (OS) in advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine. Patients were given gemcitabine (1000 mg/m2/week, 3 weeks every 4 weeks) plus erlotinib (100 mg/day orally continuously) until disease progression/unacceptable toxicity. The primary end point was OS. A total of 153 eligible patients were enrolled (grade≥2 rash, 25%; grade<2 rash, 75%). OS was longer in patients with grade≥2 rash versus grade<2 (11 versus 5 months; P<0.001). Progression-free survival was longer in patients with grade≥2 rash versus grade<2 (6 versus 3 months; P<0.001) and shorter in those without rash versus grade 1 (2 versus 4 months; P=0.005) or grade≥2 (2 versus 6 months; P<0.001). Patients with grade≥2 rash showed higher rates of overall response (21% versus 7%; P<0.05) and disease control (84% versus 43%; P<0.05) versus grade<2. This study prospectively confirms the relationship between rash and longer OS in unresectable locally advanced/metastatic pancreatic cancer treated with erlotinib plus gemcitabine.

  1. Follow-up of erlotinib related uveitis

    Science.gov (United States)

    Kumar, Indu; Ali, Kashif; Usman-Saeed, Muniba; Saeed, Muhammad Usman

    2012-01-01

    The authors report the follow-up of a 68-year-old lady with bilateral anterior uveitis secondary to erlotinib. Erlotinib was started and stopped after symptoms and signs suggestive of severe bilateral anterior uveitis were noted. The patient developed signs of a non-ST elevation myocardial infarction, 12 days after stopping the erlotinib, and recovered without major problems. The patient also reported intermittent low-grade fever since starting erlotinib which resolved after stopping this drug. No further symptoms of uveitis were noted up to 6 month follow-up. The patient reported improved well being, resolution of ocular symptoms and intermittent low-grade fever at last follow-up (6 months after stopping erlotinib). PMID:22892235

  2. Utility of 11C-methionine and 11C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model

    DEFF Research Database (Denmark)

    Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C

    2016-01-01

    The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m) Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F...... in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross......-methionine in 79%, (11)C-donepezil in 58%, and (99m) Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions....

  3. Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model

    DEFF Research Database (Denmark)

    Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C;

    2016-01-01

    The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m) Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F...... in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross......-methionine in 79%, (11)C-donepezil in 58%, and (99m) Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions....

  4. Second-line Erlotinib or Intermittent Erlotinib plus Docetaxel in Male Ex-smokers with Squamous NSCLC: The TALISMAN Randomized Trial.

    Science.gov (United States)

    Gridelli, Cesare; Chella, Antonio; Valmadre, Giuseppe; Allegrini, Giacomo; Brighenti, Matteo; Bidoli, Paolo; Rossi, Antonio; Maione, Paolo; Migliorino, Maria Rita; Ricciardi, Serena; DE Marinis, Filippo

    2016-12-01

    The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC). Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m(2) on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months. The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progression-free survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs). Results do not support further investigation of the combination of erlotinib and docetaxel in this setting. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. [11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

    DEFF Research Database (Denmark)

    Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø;

    2014-01-01

    -azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [11C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [11C]methanolate...... on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET....

  6. Erlotinib

    Science.gov (United States)

    ... feet, ankles, or lower legs darkening of skin hair loss changes in the appearance of the hair and nails Some side effects can be serious. ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

  7. Synthesis and evaluation of inhaled [11C]butane and intravenously injected [11C]acetone as potential radiotracers for studying inhalant abuse.

    Science.gov (United States)

    Gerasimov, Madina R; Ferrieri, Richard A; Pareto, Deborah; Logan, Jean; Alexoff, David; Ding, Yu-Shin

    2005-02-01

    The phenomenon of inhalant abuse is a growing problem in the US and many countries around the world. Yet, relatively little is known about the pharmacokinetic properties of inhalants that underlie their abuse potential. While the synthesis of 11C-labeled toluene, acetone and butane has been proposed in the literature, none of these compounds has been developed as radiotracers for PET studies. In the present report we extend our previous studies with [11C]toluene to include [11C]acetone and [11C]butane with the goal of comparing the pharmacokinetic profiles of these three volatile abused substances. Both [11C]toluene and [11C]acetone were administered intravenously and [11C]butane was administered via inhalation to anesthesized baboons. Rapid and efficient uptake of radiolabeled toluene and acetone into the brain was followed by fast clearance in the case of toluene and slower kinetics in the case of acetone. [11C]Butane was detected in the blood and brain following inhalation, but the levels of radioactivity in both tissues dropped to half of the maximal values over the period of less than a minute. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled acetone and butane in nonhuman primates. These data provide insight into the pharmacokinetic features possibly associated with the abuse liability of toluene, acetone and butane.

  8. Synthesis and evaluation of (/sup 11/C)cyanoimipramine

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji; Kojima, Masaharu; Inoue, Osamu; Suzuki, Kazutoshi; Yamasaki, Toshiro

    1987-01-01

    (/sup 11/C)Cyanoimipramine has been prepared by methylation of the desmethyl cyanoimipramine with (/sup 11/C)methyl iodide. The chemically and radiochemically pure labelled product was obtained with a high specific activity (> 300 mCi..mu..mol). When /sup 11/C (or /sup 3/H)-cyanoimipramine was intravenously administered in mice, high accumulations were shown in brain and lung. The regional distribution of radioactivity in the rat brain 30 min after i.v. injection of (/sup 11/C)cyanoimipramine showed that the radioactivity was high in receptor rich areas (striatum, cerebral cortex etc.) but low in receptor poor area (cerebellum). The in vivo stability of (/sup 3/H)cyanoimipramine was quite stable in the mouse brain for at least 30 min. Thirty minutes after injection, the radioactivity in the cerebral cortex of the carrier-added state was reduced as compared with the carrier-free state. Taken together, the in vivo specific binding of (3H)cyanoimipramine in the cerebral cortex was estimated at about 40-50% of the total radioactivity. Furthermore, the distribution of (/sup 3/H)cyanoimipramine in the mice forced to swim was examined. Significant changes in the distribution of (/sup 3/H)cyanoimipramine were observed in the cerebral cortex

  9. Erlotinib and the Risk of Oral Cancer

    Science.gov (United States)

    William, William N.; Papadimitrakopoulou, Vassiliki; Lee, J. Jack; Mao, Li; Cohen, Ezra E.W.; Lin, Heather Y.; Gillenwater, Ann M.; Martin, Jack W.; Lingen, Mark W.; Boyle, Jay O.; Shin, Dong M.; Vigneswaran, Nadarajah; Shinn, Nancy; Heymach, John V.; Wistuba, Ignacio I.; Tang, Ximing; Kim, Edward S.; Saintigny, Pierre; Blair, Elizabeth A.; Meiller, Timothy; Gutkind, J. Silvio; Myers, Jeffrey; El-Naggar, Adel; Lippman, Scott M.

    2016-01-01

    IMPORTANCE Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking. OBJECTIVE To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs. DESIGN The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients. INTERVENTIONS Oral erlotinib treatment (150mg/d) or placebo for 12 months. MAIN OUTCOMES AND MEASURES Oral cancer–free survival (CFS). RESULTS A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74%and 70%, respectively (hazard ratio [HR], 1.27; 95%CI, 0.68–2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74%vs 87%, HR, 2.19; 95%CI, 1.25–3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01). CONCLUSIONS AND RELEVANCE In this trial, LOH was validated as a marker of oral cancer risk and

  10. [11C]PR04.MZ, a promising DAT ligand for low concentration imaging: synthesis, efficient 11C-0-methylation and initial small animal PET studies

    Energy Technology Data Exchange (ETDEWEB)

    Riss, P.J.; Hooker, J.; Alexoff, D.; Kim, Sung-Won; Fowler, J.S.; Roesch, F.

    2009-05-01

    PR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [{sup 11}C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [{sup 11}C]MeI mediated synthesis of [{sup 11}C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb{sub 2}CO{sub 3} in DMF in up to 95 {+-} 5% labelling yield. A preliminary {mu}PET-experiment demonstrates the reversible, highly specific binding of [{sup 11}C]PR04.MZ in the brain of a male Sprague-Dawley rat.

  11. Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Heath, C. Hope; Deep, Nicholas L.; Nabell, Lisle; Carroll, William R.; Desmond, Renee; Clemons, Lisa; Spencer, Sharon; Magnuson, J. Scott [Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama (United States); Rosenthal, Eben L., E-mail: oto@uab.edu [Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama (United States)

    2013-04-01

    Purpose: To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Methods and Materials: This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. Results: The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%). Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%. Conclusions: Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.

  12. Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer.

    Science.gov (United States)

    Mehić, Bakir; Stanetić, Mirko; Tinjić, Ljuljeta; Smoljanović, Vlatka

    2008-11-01

    HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).

  13. Dopamine transporter binding in rat striatum: a comparison of [O-methyl-{sup 11}C]{beta}-CFT and [N-methyl-{sup 11}C]{beta}-CFT

    Energy Technology Data Exchange (ETDEWEB)

    Yoder, Karmen K.; Hutchins, Gary D.; Mock, Bruce H.; Fei, Xiangshu; Winkle, Wendy L. [Department of Radiology, Indiana University School of Medicine, L3-208, Indianapolis, IN 46202 (United States); Gitter, Bruce D.; Territo, Paul R. [Lilly Center for Anatomical and Molecular Imaging, Integrative Biology Division, Lilly Research Laboratories, Greenfield, IN 46140 (United States); Zheng Qihuang [Department of Radiology, Indiana University School of Medicine, L3-208, Indianapolis, IN 46202 (United States)], E-mail: qzheng@iupui.edu

    2009-01-15

    Introduction: Positron emission tomography scanning with radiolabeled phenyltropane cocaine analogs is important for quantifying the in vivo density of monoamine transporters, including the dopamine transporter (DAT). [{sup 11}C]{beta}-CFT is useful for studying DAT as a marker of dopaminergic innervation in animal models of psychiatric and neurological disorders. [{sup 11}C]{beta}-CFT is commonly labeled at the N-methyl position. However, labeling of [{sup 11}C]{beta}-CFT at the O-methyl position is a simpler procedure and results in a shorter synthesis time [desirable in small-animal studies, where specific activity (SA) is crucial]. In this study, we sought to validate that the O-methylated form of [{sup 11}C]{beta}-CFT provides equivalent quantitative results to that of the more commonly reported N-methyl form. Methods: Four female Sprague-Dawley rats were scanned twice on the IndyPET II small-animal scanner, once with [N-methyl-{sup 11}C]{beta}-CFT and once with [O-methyl-{sup 11}C]{beta}-CFT. DAT binding potentials (BP{identical_to}B'{sub avail}/K{sub d}) were estimated for right and left striata with a nonlinear least-squares algorithm, using a reference region (cerebellum) as the input function. Results: [N-Methyl-{sup 11}C]{beta}-CFT and [O-methyl-{sup 11}C]{beta}-CFT were synthesized with 40-50% radiochemical yields (HPLC purification). Radiochemical purity was >99%. SA at end of bombardment was 258{+-}30 GBq/{mu}mol. Average BP values for right and left striata with [N-methyl-{sup 11}C]{beta}-CFT were 1.16{+-}0.08 and 1.23{+-}0.14, respectively. BP values for [O-methyl-{sup 11}C]{beta}-CFT were 1.18{+-}0.08 (right) and 1.22{+-}0.16 (left). Paired t tests demonstrated that labeling position did not affect striatal DAT BP. Conclusions: These results suggest that [O-methyl-{sup 11}C]{beta}-CFT is quantitatively equivalent to [N-methyl-{sup 11}C]{beta}-CFT in the rat striatum.

  14. EGFR mutation frequency and effectiveness of erlotinib

    DEFF Research Database (Denmark)

    Weber, Britta; Hager, Henrik; Sorensen, Boe S;

    2014-01-01

    OBJECTIVES: In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line. MATERIALS...

  15. Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy.

    Science.gov (United States)

    Felip, Enriqueta; Hirsh, Vera; Popat, Sanjay; Cobo, Manuel; Fülöp, Andrea; Dayen, Charles; Trigo, José M; Gregg, Richard; Waller, Cornelius F; Soria, Jean-Charles; Goss, Glenwood D; Gordon, James; Wang, Bushi; Palmer, Michael; Ehrnrooth, Eva; Gadgeel, Shirish M

    2017-06-23

    In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health-related quality of life (QoL) in these patients are presented. Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Synthesis of N1`-([{sup 11}C]methyl)naltrindole ([{sup 11}C]MeMNTI): a radioligand for positron emission tomographic studies of delta opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lever, J.R.; Dannals, R.F. [Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Environmental Health Sciences]|[TRW Space Technology Labs., Redondo Beach, CA (United States); Kinter, C.M.; Mathews, W.B. [Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Environmental Health Sciences; Ravert, H.T.; Musachio, J.L. [TRW Space Technology Labs., Redondo Beach, CA (United States)

    1995-02-01

    A delta opioid receptor antagonist, Nl`-methylnaltrindole (MeNTI), has been labeled with carbon-11. The precursor for radiolabeling was prepared in 71% yield by benzylation of the phenolic moiety of naltrindole. Alkylation of the indole nitrogen using [{sup 11}C]iodomethane and aqueous tetra(n-butyl)ammonium hydroxide at 80{sup o}C in dimethylformamide followed by hydrogenolysis (H{sub 2}, 10% Pd-C) of the benzyl protecting group gave [{sup 11}C]MeNTI. The average (n = 10) time for radiosynthesis, HPLC purification and formulation was 24 min from end-of-bombardment. [{sup 11}C]MeNTI of high radiochemical purity was obtained at end-of-synthesis with an average specific activity of 2050 mCi/{mu}mol and radiochemical yield, based on [{sup 11}C]iodomethane, of 6%. (Author).

  17. Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC Using Two Different Schedules.

    Directory of Open Access Journals (Sweden)

    Natalia Sutiman

    Full Text Available This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV and metronomic (MSV dosing schedules in patients with advanced non-small cell lung cancer (NSCLC.This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16 and at 100 mg/week in the MSV group (N = 14. Erlotinib was administered orally daily.The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13% and hyponatremia (N = 1; 6% in the CSV group, and neutropenia (N = 5; 36% in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group.Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups.ClinicalTrials.gov NCT00702182.

  18. Erlotinib-induced rash spares previously irradiated skin

    Energy Technology Data Exchange (ETDEWEB)

    Lips, Irene M.; Vonk, Ernest J.A. [Radiotherapeutisch Instituut Stedendriehoek en Omstreken (RISO), Deventer (Netherlands). Dept. of Radiation Oncology; Koster, Mariska E.Y. [Deventer Hospital (Netherlands). Dept. of Lung Diseases; Houwing, Ronald H. [Deventer Hospital (Netherlands). Dept. of Dermatology

    2011-08-15

    Erlotinib is an epidermal growth factor receptor inhibitor prescribed to patients with locally advanced or metastasized non-small cell lung carcinoma after failure of at least one earlier chemotherapy treatment. Approximately 75% of the patients treated with erlotinib develop acneiform skin rashes. A patient treated with erlotinib 3 months after finishing concomitant treatment with chemotherapy and radiotherapy for non-small cell lung cancer is presented. Unexpectedly, the part of the skin that had been included in his previously radiotherapy field was completely spared from the erlotinib-induced acneiform skin rash. The exact mechanism of erlotinib-induced rash sparing in previously irradiated skin is unclear. The underlying mechanism of this phenomenon needs to be explored further, because the number of patients being treated with a combination of both therapeutic modalities is increasing. The therapeutic effect of erlotinib in the area of the previously irradiated lesion should be assessed. (orig.)

  19. Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer.

    Directory of Open Access Journals (Sweden)

    Jasmine G Lee

    Full Text Available Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib resistance (ER in non-small cell lung cancer is being recognized as a major problem. Therefore, understanding the mechanism behind ER and developing effective regimens are needed. Autophagy's role in cancer has been controversial and remains unclear. In this study, we examined the effectiveness of low dose erlotinib-cisplatin combination in erlotinib resistant lung adenocarcinoma (ERPC9 cells and the role of autophagy in ER. ERPC9 cells were established from erlotinib sensitive PC9 cells. Appropriate treatments were done over two days and cell survival was quantified with Alamar Blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA was utilized to inhibit translation of the protein of interest. In ERPC9 cells, combination treatment induced synergistic cell death and a significant decrease in autophagy. At baseline, ERPC9 cells had a significantly higher LC3II and lower p-mTOR levels compared to PC9 cells. The addition of rapamycin increased resistance and 3-methyladenine sensitized ERPC9 cells, indicating autophagy may be acting as a protective mechanism. Further examination revealed that ERPC9 cells harbored high baseline Atg3 levels. The high basal Atg3 was targeted and significantly lowered with combination treatment. siRNA transfection of Atg3 resulted in the reversal of ER; 42.0% more cells died in erlotinib-alone treatment with transfection compared to non-transfected ERPC9 cells. We reveal a novel role for Atg3 in the promotion of ER as the inhibition of Atg3 translation was able to result in the re-sensitization of ERPC9 cells to erlotinib-alone treatment. Also, we demonstrate that combination erlotinib-cisplatin is an effective treatment against erlotinib resistant cancer by

  20. Pharmacological evaluation of [{sup 11}c]donepezil as tracer for visualization of acetylcholinesterase by PET

    Energy Technology Data Exchange (ETDEWEB)

    Vos, F. de E-mail: filipx.devos@rug.ac.be; Santens, P.; Vermeirsch, H.; Dewolf, I.; Dumont, F.; Slegers, G.; Dierckx, R.A.; Reuck, J. de

    2000-11-01

    Donepezil is a highly potent and selective reversible acetylcholinesterase inhibitor. [{sup 11}C]Donepezil is prepared by methylation with [{sup 11}C]CH{sub 3}I of the corresponding 6'-O-desmethylprecursor. Tissue distribution in mice revealed a high uptake in brain and rapid clearance from the blood. Metabolization studies in mice indicated the formation of one {sup 11}C-labeled polar metabolite that didn't penetrate the blood-brain barrier. Regional brain distribution in rabbits didn't reflect the measured achetylcholinesterase distribution in rabbit brain.

  1. In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

    Directory of Open Access Journals (Sweden)

    Jun Toyohara

    Full Text Available BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11C]A-582941 and [(11C]A-844606 for their potential as novel positron emission tomography (PET tracers. METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711. Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11C]A-582941 and [(11C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11C]A-582941 and [(11C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11C]A-582941 and [(11C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

  2. 11C-Carfentanil的质量控制%Quality Control of 11 C-Carfentanil

    Institute of Scientific and Technical Information of China (English)

    张晓军; 向晓辉; 张锦明; 田嘉禾

    2013-01-01

    11C标记的卡芬太尼(11C-Carfentanil)中载体(12C-Carfentanil)的含量对该药物的安全使用至关重要.利用高效液相色谱系统测量11C-Carfentanil注射液的化学纯度和放化纯度;液质联用方法测量比活度;应用快速内毒素检测器PTS检测产品中内毒素含量.结果表明:合成产品为无色透明澄清11C-Carfentanil溶液,放化纯度大于98%,比活度为1.69×1014Bq/g,内毒素含量小于5 EU/mL.以上结果表明:11 C-Carfentanil注射液的质量符合药用要求,可满足实验和临床安全使用要求.%To study the quality control of 11C-Carfentanil injection, physical, chemical and biological identification were used. The chemical and radiochemical purity of 11C-Carfentanil Injection were detected by HPLC and Flower Count system; measured the quantity of product by LC-MS, specific activity was calculated later; The PTS was used to detect endotox-in, and other quality control methods were put up to guarantee the security of its clinical application. The produce appeared colorless and transparent, the radiochemical purity was more than 98%, content of the endotoxin was less than 5 EU/mL. The result showed that 11C-Carfentanil injection had fulfilled pharmaceutical quality control request and could be applied safely to animal experiment and clinical diagnosis.

  3. Synthesis of [3-N-(11) C-methyl]temozolomide via in situ activation of 3-N-hydroxymethyl temozolomide and alkylation with [(11) C]methyl iodide.

    Science.gov (United States)

    Eriksson, Jonas; Van Kooij, Rolph; Schuit, Robert C; Froklage, Femke E; Reijneveld, Jaap C; Hendrikse, N Harry; Windhorst, Albert D

    2015-03-01

    Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3-N-(11) C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [(11) C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-(11) C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [(11) C]methyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 ± 0.38 GBq (n = 5), the specific activity was 88 ± 25 GBq/µmol and the radiochemical purity was 98.5 ± 1.9%. (13) C-NMR spectroscopy confirmed the labelled position after colabelling with (11) C and (13) C.

  4. In Vivo Imaging of Human 11C-Metformin in Peripheral Organs: Dosimetry, Biodistribution, and Kinetic Analyses.

    Science.gov (United States)

    Gormsen, Lars C; Sundelin, Elias Immanuel; Jensen, Jonas Brorson; Vendelbo, Mikkel Holm; Jakobsen, Steen; Munk, Ole Lajord; Hougaard Christensen, Mette Marie; Brøsen, Kim; Frøkiær, Jørgen; Jessen, Niels

    2016-12-01

    Metformin is the most widely prescribed oral antiglycemic drug, with few adverse effects. However, surprisingly little is known about its human biodistribution and target tissue metabolism. In animal experiments, we have shown that metformin can be labeled by (11)C and that (11)C-metformin PET can be used to measure renal function. Here, we extend these preclinical findings by a first-in-human (11)C-metformin PET dosimetry, biodistribution, and tissue kinetics study.

  5. Improved synthesis of the peripheral benzodiazepine receptor ligand [{sup 11}C]DPA-713 using [{sup 11}C]methyl triflate

    Energy Technology Data Exchange (ETDEWEB)

    Thominiaux, C. [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Dolle, F. [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); James, M.L. [Department of Pharmacology, University of Sydney, NSW 2006 (Australia)] (and others)

    2006-05-15

    Recently, the pyrazolopyrimidine, [{sup 11}C] N,N-Diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl]acetamide (DPA-713) has been reported as a new promising marker for the study of peripheral benzodiazepine receptors with positron emission tomography. In the present study, DPA-713 has been labelled from the corresponding nor-analogue using [{sup 11}C]methyl triflate (CH{sub 3}OTf). Conditions for HPLC were also modified to include physiological saline (aq. 0.9% NaCl)/ethanol:60/40 as mobile phase making it suitable for injection. The total time of radiosynthesis, including HPLC purification, was 18-20 min. This reported synthesis of [{sup 11}C]DPA-713, using [{sup 11}C]CH{sub 3}OTf, resulted in an improved radiochemical yield (30-38%) compared to [{sup 11}C]methyl iodide (CH{sub 3}I) (9) with a simpler purification method. This ultimately enhances the potential of [{sup 11}C]DPA-713 for further pharmacological and clinical evaluation. These improvements make this radioligand more suitable for automated synthesis which is of benefit where multi-dose preparations and repeated syntheses of radioligand are required.

  6. Phase II Trials of Erlotinib or Gefitinib in Patients with Recurrent Meningioma

    Science.gov (United States)

    Norden, Andrew D.; Raizer, Jeffrey J.; Abrey, Lauren E.; Lamborn, Kathleen R.; Lassman, Andrew B.; Chang, Susan M.; Yung, W.K. Alfred; Gilbert, Mark R.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Cloughesy, Timothy F.; Robins, H. Ian; Aldape, Kenneth; Dancey, Janet; Prados, Michael D.; Lieberman, Frank; Wen, Patrick Y.

    2013-01-01

    There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted. PMID:19562255

  7. Development of additive [{sup 11}C]CO{sub 2} target system in the KOTRON-13 cyclotron and its application for [{sup 11}C]radiopharmaceutical production

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Byung Seok; Lee, Hong Jin [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Lee, Won Kyung [Technical Support Team, Duchembio, Seoul 121-844 (Korea, Republic of); Hur, Min Goo; Yang, Seung Dae [Radiation Instrumentation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Lee, Byung Chul, E-mail: leebc2001@gmail.com [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 443-270 (Korea, Republic of); Kim, Sang Eun [Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 463-707 (Korea, Republic of); Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 443-270 (Korea, Republic of); Smart Humanity Convergence Center, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 443-270 (Korea, Republic of)

    2015-08-01

    The KOTRON-13 cyclotron, which was developed in South Korea for the production of medical radioisotopes, has the structural limitation of only one beam-output port, restricting the production of the carbon-11 isotope. In the present study, we investigate the design of a switchable target system and develop an effective carbon-11 target in the KOTRON-13 cyclotron, for combination with the fluorine-18 target. The target system was designed by introducing a sliding-type element between the fluorine-18 and carbon-11 targets, a tailor-made C-11 target and its cooling system. For the efficient production of [{sup 11}C]CO{sub 2}, the desirable target shape and internal volume were determined by a Stopping and Range of Ions in Matter (SRIM) simulation program, and the target grid was modified to resist the cavity pressure during beam irradiation. We evaluated the [{sup 11}C]CO{sub 2} production while varying the material and thickness of the target foil, oxygen content of the nitrogen gas, and target loading pressure. Using sliding-type equipment including an additional gate valve and a high vacuum in a beam line, the bi-directional conversion between the fluorine-18 and carbon-11 targets was efficient regarding the accurate beam irradiation on both targets. The optimal [{sup 11}C]CO{sub 2} production for 30 min irradiation at 60 μA (86.6 ± 1.7 GBq in the target at EOB) was observed at a thickness of 19 μm with HAVAR® material as a target foil and a target loading pressure of 24 bar with nitrogen plus 300 ppb of oxygen gas. Additionally, the coolant cavity system in the target grid and target chamber is useful to remove the heat transferred to the target body by the internal convection of water and thereby ensure the stability of the [{sup 11}C]CO{sub 2} production under a high beam current. In the application of C-11 labeled radiopharmaceuticals such as [{sup 11}C]PIB, [{sup 11}C]DASB, [{sup 11}C]PBR28, [{sup 11}C]Methionine and [{sup 11}C]Clozapine, the radiochemical

  8. Radiosynthesis and evaluation of [{sup 11}C]BTA-1 and [{sup 11}C]3'-Me-BTA-1 as potential radiotracers for in vivo imaging of {beta}-amyloid plaques

    Energy Technology Data Exchange (ETDEWEB)

    Neumaier, B.; Deisenhofer, S.; Fuerst, D.; Thees, S.; Buck, A.K.; Glatting, G.; Landwehrmeyer, G.B.; Krause, B.J.; Reske, S.N.; Mottaghy, F.M. [Dept. of Nuclear Medicine, Univ. Hospital Ulm (Germany); Arnim, C.A.F. von [Dept. of Neurology, Univ. Hospital Ulm (Germany); Mueller, H.D.; Sommer, C. [Dept. of Neuropathology, Univ. of Mainz (Germany)

    2007-07-01

    Aim: To evaluate the in vitro and in vivo characteristics of [N-methyl-{sup 11}C]2-(4'-(methylaminophenyl))-benzothiazole ([{sup 11}C]BTA-1) as well as [N-methyl-{sup 11}C]2-(3'-methyl-4'-(methylamino)phenyl)-benzothiazole ([{sup 11}C]3'-Me-BTA-1) as diagnostic markers of amyloid-{beta} (A{beta}) in Alzheimer's disease (AD). Material, methods: Brain uptake and clearance was determined in wild-type mice. Binding affinities (K{sub i}) of [{sup 11}C]BTA-1 and [{sup 11}C]3'-Me-BTA-1 for aggregated A{beta}(1-40) fibrils were assessed. Autoradiography was performed on brain sections of AD patients. To demonstrate binding specificity in vivo BTA-1 was injected i.p. in transgenic mice (Tg2576). Brain sections were analysed consecutively. Additionally, a [{sup 11}C]BTA-1 PET study of an AD patient and a healthy control was performed. Results: In mice brain uptake and clearance of [{sup 11}C]BTA-1 is compatible with the half life of {sup 11}C (2 min: 12.7% ID/g; 30 min: 4.6% ID/g). In contrast clearance rate of [{sup 11}C]3'-Me-BTA-1 is too slow (2 mm 4% ID/g; 30 min 12% ID/g) to achieve sufficient clearance of free and non specifically bound radioactivity. K{sub i} of [{sup 11}C]BTA-1 is 11 nmol/l and that of [{sup 11}C]3'-Me-BTA-1 27 nmol/l. Both radioligands label A{beta} selectively and specifically in AD patients and transgenic mice in vitro. The in vivo stained brain sections show a labelling of A{beta} plaques. The AD patient has a higher pre-frontal, parietal and striatal [{sup 11}C]BTA-1 accumulation than the healthy control. Metabolite analysis revealed approximately 75% intact [{sup 11}C]BTA-1 after 30min in plasma. [{sup 11}C]BTA-1 is favourable for in vivo imaging of A{beta} due to its rapid brain entry, sufficient clearance and good binding affinity for A{beta}. Conclusion: The ability to label A{beta} plaques in vivo in human subjects supports the suitability of [{sup 11}C]BTA-1 as a plaque imaging agent. (orig.)

  9. (/sup 11/C)clorgyline and (/sup 11/C)-L-deprenyl and their use in measuring functional monoamine oxidase activity in the brain using positron emission tomography

    Science.gov (United States)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1986-04-17

    This invention involves a new strategy for imaging the activity of the enzyme monoamine oxidase in the living body by using /sup 11/C-labeled enzyme inhibitors which bind irreversibly to an enzyme as a result of catalysis. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  10. [{sup 11}C]-GR89696, a potent kappa opiate receptor radioligand; in vivo binding of the R and S enantiomers

    Energy Technology Data Exchange (ETDEWEB)

    Ravert, Hayden T. E-mail: htr@jhu.edu; Scheffel, Ursula; Mathews, William B.; Musachio, John L.; Dannals, Robert F

    2002-01-01

    The R and S enantiomers of [{sup 11}C]GR89696, [{sup 11}C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl] -1-piperazinecarboxylate, were synthesized from their appropriate chiral precursors and [{sup 11}C]methyl chloroformate. The [{sup 11}C]-labeled R enantiomer of GR89696, also known as GR103545, demonstrated high affinity in mouse brain with region to cerebellar ratios at 90 minutes of 11.4 and 8.7 for the hypothalamus and olfactory tubercle, respectively. The [{sup 11}C]-labeled S enantiomer showed low affinity and region to cerebellar ratios of 1 for all brain regions. The [{sup 11}C]-labeled GR103545 exhibited a selective and saturable binding for the kappa opioid receptor.

  11. Synthesis and 11C-Radiolabelling of 2-Carboranyl Benzothiazoles

    Directory of Open Access Journals (Sweden)

    Kiran B. Gona

    2015-04-01

    Full Text Available Dicarba-closo-dodecaboranes, commonly known as carboranes, possess unique physico-chemical properties and can be used as hydrophobic moieties during the design of new drugs or radiotracers. In this work, we report the synthesis of two analogues of 2-(4-aminophenylbenzothiazole (a compound that was found to elicit pronounced inhibitory effects against certain breast cancer cell lines in vitro in which the phenyl ring has been substituted by a m-carborane cage. Two different synthetic strategies have been used. For the preparation of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl-benzo-thiazole, the benzothiazole group was first introduced on one of the cluster carbon atoms of m-carborane and the amine group was further attached in three steps. For the synthesis of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl-6-hydroxybenzothiazole, iodination was performed before introducing the benzothiazole group, and the amino group was subsequently introduced in six steps. Both compounds were radiolabelled with carbon-11 using [11C]CH3OTf as the labelling agent. Radiolabelling yields and radiochemical purities achieved should enable subsequent in vitro and in vivo investigations.

  12. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

    DEFF Research Database (Denmark)

    Nielsen, Ole L.; Afzelius, Pia; Bender, Dirk;

    The aim of this study was to compare 111In-labeled leukocyte single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose 11C-methionine, 11C-PK11195...... and 68Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan...... protocol with 18F-FDG, 68Ga-citrate, 11C-methionine, 11C-PK11195, 99mTc-Nanocoll and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions...

  13. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

    DEFF Research Database (Denmark)

    Nielsen, Ole Lerberg; Afzelius, Pia; Bender, Dirk;

    2015-01-01

    The aim of this study was to compare (111)In-labeled leukocyte single-photon emission computed tomography (SPECT) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose (11)C-methionine, (11......)C-PK11195 and (68)Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using...... a sequential scan protocol with (18)F-FDG, (68)Ga-citrate, (11)C-methionine, (11)C-PK11195, (99m)Tc-Nanocoll and (111)In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis...

  14. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous Staphylococcus aureus osteomyelitis model

    DEFF Research Database (Denmark)

    Nielsen, Ole Lehberg; Afzelius, Pia; Bender, Dirk;

    2014-01-01

    The aim of this study was to compare 111In-labeled leukocyte single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose 11C-methionine, 11C-PK11195...... and 68Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan...... protocol with 18F-FDG, 68Ga-citrate, 11C-methionine, 11C-PK11195, 99mTc-Nanocoll and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions...

  15. Facile synthesis of ( sup 11 C)buprenorphine for positron emission tomographic studies of opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lever, J.R.; Dannals, R.F.; Wagner, H.N. Jr. (Johns Hopkins Univ., Baltimore, MD (USA). School of Hygiene and Public Health Johns Hopkins Univ., Baltimore, MD (USA). Dept. of Radiology); Mazza, S.M. (Johns Hopkins Univ., Baltimore, MD (USA). School of Hygiene and Public Health); Ravert, H.T.; Wilson, A.A. (Johns Hopkins Univ., Baltimore, MD (USA). Dept. of Radiology)

    1990-01-01

    We have developed a simple and rapid method for the production of buprenorphine (BPN), a potent opioid partial agonist, labelled with carbon-11 at the 6-methoxy position. The procedure uses a precursor synthesized in high yield (89%) from BPN in two steps and employs ({sup 11}C)iodomethane as the radiolabelling reagent. ({sup 11}C)BPN of 97% radiochemical purity can be prepared in high specific activity (41 GBq/{mu}mol; 1120 mCi/{mu}mol) in a radiochemical yield of 10% at end-of-synthesis (not decay corrected). The ({sup 11}C)BPN is available for use in studies of cerebral opioid receptors by positron emission tomography within 24 min from end-of-bombardment, including radiosynthesis, purification, formulation for i.v. injection and determination of specific activity. (author).

  16. Evaluation of [{sup 11}C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats

    Energy Technology Data Exchange (ETDEWEB)

    Luurtsema, Gert [Department of Nuclear Medicine and PET Research, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam (Netherlands)], E-mail: g.luurtsema@vumc.nl; Schuit, Robert C.; Klok, Rob P.; Verbeek, Joost; Leysen, Josee E.; Lammertsma, Adriaan A.; Windhorst, Albert D. [Department of Nuclear Medicine and PET Research, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam (Netherlands)

    2009-08-15

    At present, P-glycoprotein (P-gp) function can be studied using positron emission tomography (PET) together with a labelled P-gp substrate such as (R)-[{sup 11}C]verapamil. Such a tracer is, however, less suitable for investigating P-gp (over)expression. Laniquidar is a third-generation P-gp inhibitor, which has been used in clinic trials for modulating multidrug resistance transporters. The purpose of the present study was to develop the radiosynthesis of [{sup 11}C]laniquidar and to assess its suitability as a tracer of P-gp expression. The radiosynthesis of [{sup 11}C]laniquidar was performed by methylation of the carboxylic acid precursor with [{sup 11}C]CH{sub 3}I. The product was purified by HPLC and reformulated over a tC{sub 18} Seppak, yielding a sterile solution of [{sup 11}C]laniquidar in saline. For evaluating [{sup 11}C]laniquidar, rats were injected with 20 MBq [{sup 11}C]laniquidar via a tail vein and sacrificed at 5, 15, 30 and 60 min after injection. Several tissues and distinct brain regions were dissected and counted for radioactivity. In addition, uptake of [{sup 11}C]laniquidar in rats pretreated with cyclosporine A and valspodar (PSC 833) was determined at 30 min after injection. Finally, the metabolic profile of [{sup 11}C]laniquidar in plasma was determined. [{sup 11}C]Laniquidar could be synthesized in moderate yields with high specific activity. Uptake in brain was low, but significantly increased after administration of cyclosporine A. Valspodar did not have any effect on cerebral uptake of [{sup 11}C]laniquidar. In vivo rate of metabolism was relatively low. Further kinetic studies are needed to investigate the antagonistic behaviour of [{sup 11}C]laniquidar at tracer level.

  17. Investigation of SN2 [11C]cyanation for base-sensitive substrates: an improved radiosynthesis of L-[5-11C]-glutamine.

    Science.gov (United States)

    Gleede, Tassilo; Riehl, Barbara; Shea, Colleen; Kersting, Lena; Cankaya, Aylin Sibel; Alexoff, David; Schueller, Michael; Fowler, Joanna S; Qu, Wenchao

    2015-03-01

    Carbon-11 (β(+) emitter, t1/2 = 20.4 min) radiolabeled L-glutamine is a potentially useful molecular imaging agent that can be utilized with positron emission tomography for both human oncological diagnosis and plant imaging research. Based upon a previously reported [(11)C]cyanide end-capping labeling method, a systematic investigation of nucleophilic cyanation reactions and acidic hydrolysis reaction parameters, including base, metal ion source, phase transfer catalyst, solvent, reaction temperature and reaction time, was conducted. The result was a milder, more reliable, two-step method which provides L-[5-(11)C]-glutamine with a radiochemical yield of 63.8 ± 8.7% (range from 51 to 74%, n = 10) with >90% radiochemical purity and >90 % enantiomeric purity. The total synthesis time was 40-50 min from the end of bombardment. In addition, an Fmoc derivatization method was developed to measure the specific activity of this radiotracer.

  18. Renal PET-imaging with 11C-metformin in a transgenic mouse model for chronic kidney disease

    OpenAIRE

    Pedersen, Lea; Jensen, Jonas Brorson; Wogensen, Lise; Munk, Ole Lajord; Jessen, Niels; Frøkiær, Jørgen; Jakobsen, Steen

    2016-01-01

    Background Organic cation transporters (OCTs) in the renal proximal tubule are important for the excretion of both exo- and endogenous compounds, and chronic kidney disease (CKD) alter the expression of OCT. Metformin is a well-known substrate for OCT, and recently, we demonstrated that positron emission tomography (PET) with 11C-labelled metformin (11C-metformin) is a promising approach to evaluate the function of OCT. The aim of this study is therefore to examine renal pharmacokinetics of 1...

  19. [{sup 11}C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Mingrong E-mail: zhang@nirs.go.jp; Kida, Takayo; Noguchi, Junko; Furutsuka, Kenji; Maeda, Jun; Suhara, Tetsuya; Suzuki, Kazutoshi

    2003-05-01

    DAA1106 (N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for peripheral benzodiazepine receptors (PBR) in mitochondrial fractions of rat (K{sub i}=0.043 nM) and monkey (K{sub i}=0.188 nM) brains. This compound was labeled by [{sup 11}C]methylation of a corresponding desmethyl precursor (DAA1123) with [{sup 11}C]CH{sub 3}I in the presence of NaH, with a 72{+-}16% (corrected for decay) incorporation yield of radioactivity. After HPLC purification, [{sup 11}C]DAA1106 was obtained with {>=}98% radiochemical purity and specific activity of 90-156 GBq/{mu}mol at the end of synthesis. After iv injection of [{sup 11}C]DAA1106 into mice, high accumulations of radioactivity were found in the olfactory bulb and cerebellum, the high PBR density regions in the brain. Coinjection of [{sup 11}C]DAA1106 with unlabeled DAA1106 and PBR-selective PK11195 displayed a significant reduction of radioactivity, suggesting a high specific binding of [{sup 11}C]DAA1106 to PBR. Although this tracer was rapidly metabolized in the plasma, only [{sup 11}C]DAA1106 was detected in the brain tissues, suggesting the specific binding in the brain due to the tracer itself. These findings revealed that [{sup 11}C]DAA1106 is a potential and selective positron emitting radioligand for PBR.

  20. Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial.

    Science.gov (United States)

    William, William N; Papadimitrakopoulou, Vassiliki; Lee, J Jack; Mao, Li; Cohen, Ezra E W; Lin, Heather Y; Gillenwater, Ann M; Martin, Jack W; Lingen, Mark W; Boyle, Jay O; Shin, Dong M; Vigneswaran, Nadarajah; Shinn, Nancy; Heymach, John V; Wistuba, Ignacio I; Tang, Ximing; Kim, Edward S; Saintigny, Pierre; Blair, Elizabeth A; Meiller, Timothy; Gutkind, J Silvio; Myers, Jeffrey; El-Naggar, Adel; Lippman, Scott M

    2016-02-01

    Standard molecularly based strategies to predict and/or prevent oral cancer development in patients with oral premalignant lesions (OPLs) are lacking. To test if the epidermal growth factor receptor inhibitor erlotinib would reduce oral cancer development in patients with high-risk OPLs defined by specific loss of heterozygosity (LOH) profiles. Secondary objectives included prospective determination of LOH as a prognostic marker in OPLs. The Erlotinib Prevention of Oral Cancer (EPOC) study was a randomized, placebo-controlled, double-bind trial. Accrual occurred from November 2006 through July 2012, with a median follow-up time of 35 months in an ambulatory care setting in 5 US academic referral institutions. Patients with OPLs were enrolled in the protocol, and each underwent LOH profiling (N = 379); they were classified as high-risk (LOH-positive) or low-risk (LOH-negative) patients based on their LOH profiles and oral cancer history. The randomized sample consisted of 150 LOH-positive patients. Oral erlotinib treatment (150 mg/d) or placebo for 12 months. Oral cancer-free survival (CFS). A total of 395 participants were classified with LOH profiles, and 254 were classified LOH positive. Of these, 150 (59%) were randomized, 75 each to the placebo and erlotinib groups. The 3-year CFS rates in placebo- and erlotinib-treated patients were 74% and 70%, respectively (hazard ratio [HR], 1.27; 95% CI, 0.68-2.38; P = .45). The 3-year CFS was significantly lower for LOH-positive compared with LOH-negative groups (74% vs 87%, HR, 2.19; 95% CI, 1.25-3.83; P = .01). Increased EGFR gene copy number correlated with LOH-positive status (P < .001) and lower CFS (P = .01). The EGFR gene copy number was not predictive of erlotinib efficacy. Erlotinib-induced skin rash was associated with improved CFS (P = .01). In this trial, LOH was validated as a marker of oral cancer risk and found to be associated with increased EGFR copy number (the target of the intervention

  1. Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-{sup 11}C]propionyl L-carnitine for pharmacokinetic studies

    Energy Technology Data Exchange (ETDEWEB)

    Davenport, R.J.; Pike, V.W.; Dowsett, K.; Turton, D.R.; Poole, K. [Hammersmith Hospital, London (United Kingdom). MRC Cyclotron Unit

    1997-07-30

    Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t{sub 1/2} = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [{sup 11}C]propionyl chloride as labelling agent via {sup 11}C-carboxylation of ethylmagnesium bromide with cyclotron-produced [{sup 11}C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [{sup 11}C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [{sup 11}C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [{sup 11}C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier added (NCA) level of specific radioactivity. [{sup 11}C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [{sup 11}C]carbon dioxide and hydrolysis. NCA [{sup 11}C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [{sup 11}C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [{sup 11}C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [{sup 11}C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [{sup 11}C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [{sup 11}C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo. (Author).

  2. Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

    DEFF Research Database (Denmark)

    Dimke, Henrik Anthony; van der Wijst, Jenny; Alexander, Todd R;

    2010-01-01

    A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg(2+) transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg(2+) homeostasis, however, remains unknown. Here, we...... in renal expression of transient receptor potential melastatin 6 (TRPM6) protein, the channel that mediates Mg(2+) reabsorption. Patch clamp analysis in TRPM6-expressing cells demonstrated that 30 muM erlotinib inhibited EGF-induced changes in TRPM6 current density and tyrosine phosphorylation of EGFR; 0...... that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg(2+) concentrations....

  3. Rapid radiosynthesis of [11C] and [14C]azelaic, suberic, and sebacic acids for in vivo mechanistic studies of systemic acquired resistance in plants

    Energy Technology Data Exchange (ETDEWEB)

    Best M.; Fowler J.; Best, M.; Gifford, A.N.; Kim, S.W.; Babst, B.; Piel, M.; Roesch, F.; Fowler, J.S.

    2011-11-25

    A recent report that the aliphatic dicarboxylic acid, azelaic acid (1,9-nonanedioic acid) but not related acids, suberic acid (1,8-octanedioic acid) or sebacic (1,10-decanedioic acid) acid induces systemic acquired resistance to invading pathogens in plants stimulated the development of a rapid method for labeling these dicarboxylic acids with {sup 11}C and {sup 14}C for in vivo mechanistic studies in whole plants. {sup 11}C-labeling was performed by reaction of ammonium [{sup 11}C]cyanide with the corresponding bromonitrile precursor followed by hydrolysis with aqueous sodium hydroxide solution. Total synthesis time was 60 min. Median decay-corrected radiochemical yield for [{sup 11}C]azelaic acid was 40% relative to trapped [{sup 11}C]cyanide, and specific activity was 15 GBq/{micro}mol. Yields for [{sup 11}C]suberic and sebacic acids were similar. The {sup 14}C-labeled version of azelaic acid was prepared from potassium [{sup 14}C]cyanide in 45% overall radiochemical yield. Radiolabeling procedures were verified using {sup 13}C-labeling coupled with {sup 13}C-NMR and liquid chromatography-mass spectrometry analysis. The {sup 11}C and {sup 14}C-labeled azelaic acid and related dicarboxylic acids are expected to be of value in understanding the mode-of-action, transport, and fate of this putative signaling molecule in plants.

  4. The gene expression profile of CD11c

    NARCIS (Netherlands)

    W. Beumer (Wouter); J.M.C. Welzen-Coppens (Jojanneke); C.G. van Helden-Meeuwsen; S.M. Gibney (Sinead); H.A. Drexhage (Hemmo); M.A. Versnel (Marjan)

    2014-01-01

    textabstractTwo major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c+CD8α- DCs (strong CD4+ T cell proliferation inducers) and the CD8α+CD103+ DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c

  5. Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Lu; Hu, Lingna; Yang, Baofang; Fang, Xianying; Gao, Zhe; Li, Wanshuai; Sun, Yang; Shen, Yan; Wu, Xuefeng [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093 (China); Shu, Yongqian [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029 (China); Gu, Yanhong, E-mail: guluer@163.com [Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029 (China); Wu, Xudong, E-mail: xudongwu@nju.edu.cn [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093 (China); Xu, Qiang, E-mail: molpharm@163.com [State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093 (China)

    2014-07-01

    Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients. - Highlights: • Erlotinib destroyed barrier integrity both in vitro and in vivo. • Erlotinib induced inflammation both in vitro and in vivo. • Erlotinib induced apoptosis both in vitro and in vivo. • ER stress contributed to erlotinib-induced barrier dysfunction.

  6. Synthesis of /sup 11/C-methylated inulin as a radiopharmaceutical for imaging brain edema and pulmonary edema

    Energy Technology Data Exchange (ETDEWEB)

    Hara, Toshihiko; Iio, Masaaki; Inagaki, Keizo

    1988-07-01

    /sup 11/C-methylated inulin, supposedly useful for imaging of brain edema and pulmonary edema, was prepared using cyclotron produced /sup 11/CO/sub 2/. The synthesis consists of the production of /sup 11/C-methyl iodide and its coupling with inulin alkoxide sodium in dimethylsulfoxide as solvent. /sup 11/C labeled inulin was purified by alcohol precipitation. The radiochemical yield of pure /sup 11/C-inulin was 34% of /sup 11/CO/sub 2/ 30 min after the end of bombardment. The blood clearance and body distribution of /sup 11/C was observed in rabbits after i.v. injection of /sup 11/C-inulin. The blood clearance curve was composed of a sum of three exponential functions. The gamma camera image showed that the /sup 11/C activity in blood moved quickly to kidneys and urine and a small dose of radioactivity remained persistently in edematous tissues, i.e. the edematous lung tissues produced by oleic acid treatment.

  7. Evaluation of [{sup 11}C]RTI-121 as a selective radioligand for PET studies of the dopamine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Hume, Susan P.; Luthra, Sajinder K.; Brown, David J.; Opacka-Juffry, Jolanta; Osman, Safiye; Ashworth, Sharon; Myers, Ralph; Brady, Frank; Carroll, F. Ivy; Kuhar, Michael J.; Brooks, David J

    1996-04-01

    The cocaine analogue RTI-121 (3{beta}-(4-iodophenyl)tropane-2{beta}-carboxylic acid isopropyl ester), when labeled with carbon-11, was evaluated in rats as a potential PET ligand for the dopamine transporter. The compound gave in vivo striatum:cerebellum ratios that were similar to those obtained with the related ligand [{sup 11}C]RTI-55 (2{r_reversible}-(4-iodophenyl)tropane-2{beta}-carboxylic acid methyl ester) but showed a much greater selectivity for the dopamine compared with the 5-HT uptake site. The results indicate that [{sup 11}C]RTI-121 could be used in preference to [{sup 11}C]RTI-55 in man. Experimentally, [{sup 11}C]RTI-121 has potential in the quantification of dopamine terminal function in rat models of disease, using a combination of autoradiography, postmortem sampling, and in vivo tomography.

  8. Novel synthesis of [11C]GVG (Vigabatgrin) for pharmacokinetic studies of addiction treatment

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Studenov, A.R.; Zhang, Z.; Gerasimov, M.; Schiffer, W.; Dewey, S.L.; Telang, F.

    2001-06-10

    We report here a novel synthetic route to prepare the precursor and to efficiently label GVG with C-11. 5-Bromo-3-(carbobenzyloxy)amino-1-pentene was synthesized in five steps from homoserine lactone. This was used in a two step radiosynthesis, displacement with [{sup 11}C]cyanide followed by acid hydrolysis to afford [{sup 11}C]GVG with high radiochemical yields (> 35%, not optimized) and high specific activity (2-5 Ci/{micro}mol). The [{sup 11}C]cyanide trapping was achieved at {minus}5 C with a mixture of Kryptofix and K{sub 2}CO{sub 3} without using conventional aqueous trapping procedure [7]. At this temperature, the excess NH{sub 3} from the target that may interfere with the synthesis would not be trapped [8]. This procedure would be advantageous to any moisture sensitive radiosynthetic steps, as it was the case for our displacement reaction. When conventional aqueous trapping procedure was used, any trace amount of water left, even after prolonged heating, resulted in either no reaction or extremely low yields for the displacement reaction. The entire synthetic procedure should be extendible to the labeling of the pharmacologically active S- form of GVG when using S-homoserine lactone.

  9. Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

    Science.gov (United States)

    2003-01-01

    Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in

  10. A simple Tracerlab module modification for automated on-column [{sup 11}C]methylation and [{sup 11}C]carboxylation

    Energy Technology Data Exchange (ETDEWEB)

    Lodi, Filippo [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Trespidi, Silvia [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Di Pierro, Donato [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Marengo, Mario [Medical Physics Department, S. Orsola Hospital, Bologna Italy (Italy); Farsad, Mohsen [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Fanti, Stefano [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Franchi, Roberto [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy); Boschi, Stefano [Nuclear Medicine Unit, S. Orsola Hospital, Bologna (Italy)]. E-mail: sboschi@aosp.bo.it

    2007-06-15

    A modification of commercial [{sup 11}C]methylation module which can be implemented for both on-column [{sup 11}C]methylation and [{sup 11}C]carboxylation in the same automated system is described. This module configuration was applied to the solid-phase synthesis of N-[{sup 11}C]methyl-choline ([{sup 11}C]choline) and L-(S-methyl-[{sup 11}C])methionine ([{sup 11}C]methionine), using [{sup 11}C]CH{sub 3}I as methylating agent, as well as to the synthesis of [{sup 11}C]acetate by [{sup 11}C]carboxylation with [{sup 11}C]CO{sub 2} of methylmagnesium chloride with high and reproducible radiochemical yields in short reaction time, demonstrating to be a fast and reliable tool for the production of these [{sup 11}C]radiopharmaceuticals for clinical use.

  11. Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

    Science.gov (United States)

    Prados, Michael D.; Chang, Susan M.; Butowski, Nicholas; DeBoer, Rebecca; Parvataneni, Rupa; Carliner, Hannah; Kabuubi, Paul; Ayers-Ringler, Jennifer; Rabbitt, Jane; Page, Margaretta; Fedoroff, Anne; Sneed, Penny K.; Berger, Mitchel S.; McDermott, Michael W.; Parsa, Andrew T.; Vandenberg, Scott; James, C. David; Lamborn, Kathleen R.; Stokoe, David; Haas-Kogan, Daphne A.

    2009-01-01

    Purpose This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. Patients and Methods Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. Results Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. Conclusion Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted. PMID:19075262

  12. Erlotinib-induced florid acneiform rash complicated by extensive impetiginization

    NARCIS (Netherlands)

    Kardaun, S. H.; van Duinen, K. F.

    2008-01-01

    Erlotinib (Tarceva(TM)) is an epidermal growth factor receptor (EGFR) inhibitor, a member of a new group of molecular targeted drugs that combine high efficacy against tumours with less, often self-limiting, toxicity, compared with traditional chemotherapeutics. It is used for treatment of solid-org

  13. Imaging of canine tumors with /sup 11/C-methylputrescine

    Energy Technology Data Exchange (ETDEWEB)

    Miller, T.R.; Siegel, B.A.; Fair, W.R.; Smith, E.K.; Welch, M.J.

    1978-10-01

    The polyamines--putrescine, spermidine, and spermine--are present in elevated concentrations in rapidly growing cell lines and in several neoplasms. Five dogs with benign or malignant tumors and one normal dog were imaged with a rectilinear scanner following I.V. administration of 2 to 8 mCi /sup 11/C-methylputrescine. High concentrations of /sup 11/C-methylputrescine were found in the liver, and in the kidneys and urine in the dogs with good renal function. Concentrations were higher in tumors than in skeletal muscle, blood, or lung. The tumor/blood ratio varied from 2 to 21; tumors were demonstrated by imaging in four dogs in which the ratio exceeded 4.0. /sup 11/C-methylputrescine is a possible tumor imaging agent.

  14. Preclinical PET Neuroimaging of [11C]Bexarotene

    Directory of Open Access Journals (Sweden)

    Benjamin H. Rotstein PhD

    2016-08-01

    Full Text Available Activation of retinoid X receptors (RXRs has been proposed as a therapeutic mechanism for the treatment of neurodegeneration, including Alzheimer's and Parkinson's diseases. We previously reported radiolabeling of a Food and Drug Administration-approved RXR agonist, bexarotene, by copper-mediated [11C]CO2 fixation and preliminary positron emission tomography (PET neuroimaging that demonstrated brain permeability in nonhuman primate with regional binding distribution consistent with RXRs. In this study, the brain uptake and saturability of [11C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [11C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system.

  15. Effect of tracer metabolism on PET measurement of [[sup 11]C]pyrilamine binding to histamine H[sub 1] receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun (Sungkyunkwan Univ., Seoul (Korea, Republic of). School of Medicine); Szabo, Z.; Seki, Chie; Ravert, H.T.; Scheffel, U.; Dannals, R.F.; Wagner, H.N. Jr.

    1999-04-01

    The present study was carried out to investigate the time course of [[sup 11]C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [[sup 11]C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [[sup 11]C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [[sup 11]C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [[sup 11]C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [[sup 11]C]pyrilamine. Based on the rat data, the contribution of [sup 11]C-labeled metabolites to total [[sup 11]C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [[sup 11]C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [[sup 11]C]pyrilamine by brain tissue itself. Therefore, [[sup 11]C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [[sup 11]C]pyrilamine binding to histamine H[sub 1] receptors. (author)

  16. Effect of tracer metabolism on PET measurement of [{sup 11}C]pyrilamine binding to histamine H{sub 1} receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun [Sungkyunkwan Univ., Seoul (Korea, Republic of). School of Medicine; Szabo, Z.; Seki, Chie; Ravert, H.T.; Scheffel, U.; Dannals, R.F.; Wagner, H.N. Jr.

    1999-04-01

    The present study was carried out to investigate the time course of [{sup 11}C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [{sup 11}C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [{sup 11}C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [{sup 11}C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [{sup 11}C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [{sup 11}C]pyrilamine. Based on the rat data, the contribution of {sup 11}C-labeled metabolites to total [{sup 11}C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [{sup 11}C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [{sup 11}C]pyrilamine by brain tissue itself. Therefore, [{sup 11}C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [{sup 11}C]pyrilamine binding to histamine H{sub 1} receptors. (author)

  17. Palladium-mediated conversion of para-aminoarylboronic esters into para-aminoaryl- 11C-methanes

    DEFF Research Database (Denmark)

    Andersen, Valdemar Lykke; Herth, Matthias Manfred; Lehel, Szabolcs

    2013-01-01

    Cross-couplings are an alternative to conventional 11C-methylations which are generally employed in PET tracer synthesis. Therefore, we set out to develop a general procedure for the synthesis of para-11CH3 labeled aromatic amines from the corresponding para-aminoarylboronic esters in the presence...... of free amines. Aryl boronic esters containing primary, secondary, and tertiary amines were successfully converted into corresponding labeled methyl derivatives in suf¿cient radiochemical yield to apply this method for tracer development. This procedure was applied to the labeling of CIMBI-712...

  18. Could erlotinib treatment lead to acute cardiovascular events in patients with lung adenocarcinoma after chemotherapy failure?

    Directory of Open Access Journals (Sweden)

    Kus T

    2015-06-01

    Full Text Available Tulay Kus, Gokmen Aktas, Alper Sevinc, Mehmet Emin Kalender, Celaletdin Camci Department of Internal Medicine, Division of Medical Oncology, Gaziantep University, Gaziantep, Turkey Abstract: Erlotinib, an epidermal growth factor receptor and tyrosine kinase inhibitor, is a targeted drug that was approved for the treatment of non-small-cell lung cancers and pancreatic cancers. Targeted tyrosine kinase inhibitors are known to have cardiotoxic effects. However, erlotinib does not have a statistically proven effect of increasing acute cardiovascular event (ACE risk. Preclinical studies showed that beta agonist stimulation among rats that were administered erlotinib led to cardiovascular damage. Thus, there would be an aggregate effect of erlotinib on ACE, although it is not thought to be a cardiotoxic drug itself. In this paper, we present two non-small-cell lung cancer cases that developed ACE under erlotinib treatment. Keywords: erlotinib, lung cancer, myocardial infarction, EGFR

  19. Equivalence of arterial and venous blood for [11C]CO2-metabolite analysis following intravenous administration of 1-[11C]acetate and 1-[11C]palmitate.

    Science.gov (United States)

    Ng, Yen; Moberly, Steven P; Mather, Kieren J; Brown-Proctor, Clive; Hutchins, Gary D; Green, Mark A

    2013-04-01

    Sampling of arterial blood for metabolite correction is often required to define a true radiotracer input function in quantitative modeling of PET data. However, arterial puncture for blood sampling is often undesirable. To establish whether venous blood could substitute for arterial blood in metabolite analysis for quantitative PET studies with 1-[(11)C]acetate and 1-[(11)C]palmitate, we compared the results of [(11)C]CO2-metabolite analyses performed on simultaneously collected arterial and venous blood samples. Paired arterial and venous blood samples were drawn from anesthetized pigs at 1, 3, 6, 8, 10, 15, 20, 25 and 30min after i.v. administration of 1-[(11)C]acetate and 1-[(11)C]palmitate. Blood radioactivity present as [(11)C]CO2 was determined employing a validated 10-min gas-purge method. Briefly, total blood (11)C radioactivity was counted in base-treated [(11)C]-blood samples, and non-[(11)C]CO2 radioactivity was counted after the [(11)C]-blood was acidified using 6N HCl and bubbled with air for 10min to quantitatively remove [(11)C]CO2. An excellent correlation was found between concurrent arterial and venous [(11)C]CO2 levels. For the [(11)C]acetate study, the regression equation derived to estimate the venous [(11)C]CO2 from the arterial values was: y=0.994x+0.004 (r(2)=0.97), and for the [(11)C]palmitate: y=0.964x-0.001 (r(2)=0.9). Over the 1-30min period, the fraction of total blood (11)C present as [(11)C]CO2 rose from 4% to 64% for acetate, and 0% to 24% for palmitate. The rate of [(11)C]CO2 appearance in venous blood appears similar for the pig model and humans following i.v. [(11)C]-acetate administration. Venous blood [(11)C]CO2 values appear suitable as substitutes for arterial blood samples in [(11)C]CO2 metabolite analysis after administration of [(11)C]acetate or [(11)C]palmitate Quantitative PET studies employing 1-[(11)C]acetate and 1-[(11)C]palmitate can employ venous blood samples for metabolite correction of an image-derived tracer

  20. Intrasubject correlation between static scan and distribution volume images for [{sup 11}C]flumazenil PET

    Energy Technology Data Exchange (ETDEWEB)

    Mishina, Masahiro [Nippon Medical School, Tokyo (Japan); Senda, Michio; Kimura, Yuichi [and others

    2000-06-01

    Accumulation of [{sup 11}C]flumazenil (FMZ) reflects central nervous system benzodiazepine receptor (BZR). We searched for the optimal time for a static PET scan with FMZ as semi-quantitative imaging of BZR distribution. In 10 normal subjects, a dynamic series of decay-corrected PET scans was performed for 60 minutes, and the arterial blood was sampled during the scan to measure radioactivity and labeled metabolites. We generated 13 kinds of ''static scan'' images from the dynamic scan in each subject, and analyzed the pixel correlation for these images versus distribution volume (DV) images. We also analyzed the time for the [{sup 11}C]FMZ in plasma and tissue to reach the equilibrium. The intra-subject pixel correlation demonstrated that the static scan'' images for the period centering around 30 minutes post-injection had the strongest linear correlation with the DV image. The ratio of radioactivity in the cortex to that in the plasma reached a peak at 40 minutes after injection. Considering the physical decay and patient burden, we conclude that the decay corrected static scan for [{sup 11}C]FMZ PET as semi-quantitative imaging of BZR distribution is to be optimally acquired from 20 to 40 minutes after injection. (author)

  1. Human biodistribution and radiation dosimetry of {sup 11}C-(R)-PK11195, the prototypic PET ligand to image inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Hirvonen, Jussi; Roivainen, Anne; Virta, Jere; Helin, Semi; Naagren, Kjell; Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, P.O. Box 52, Turku (Finland)

    2010-03-15

    The positron emission tomography (PET) radiotracer {sup 11}C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with {sup 11}C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and {sup 11}C-(R)-PK11195 in healthy humans. Five healthy male volunteers were scanned with PET and {sup 11}C-(R)-PK11195, using a dynamic whole-body imaging protocol. An organ-specific method was used to measure accumulated radioactivity in source organs, and residence times were calculated as areas under the curve of time-activity curves expressed as percentage of injected radioactivity. Residence times were used as input for OLINDA/EXM 1.0 software to model the equivalent organ doses and the effective dose for the 70-kg man. After intravenous injection of {sup 11}C-(R)-PK11195, radioactivity accumulated in organs rich in TSPO as well as routes of excretion: the hepatobiliary system and the urine. The mean effective dose was 4.8 {mu}Sv/MBq according to International Commission on Radiological Protection (ICRP) Publication 60 and 5.1 {mu}Sv/MBq according to ICRP Publication 103, and the highest equivalent organ doses were observed in the kidneys (14.0 {mu}Sv/MBq), spleen (12.5 {mu}Sv/MBq) and small intestine (12.2 {mu}Sv/MBq). Imaging of TSPO with PET using {sup 11}C-(R)-PK11195 is associated with modest radiation exposure, similar in magnitude to most other {sup 11}C-labelled PET tracers, suggesting feasibility of {sup 11}C-(R)-PK11195 imaging in clinical human studies involving multiple scans in the same subjects per year. (orig.)

  2. Erlotinib: A successful clinical case and some notes about hepatic toxicity.

    Science.gov (United States)

    Costa, Agostinho

    2008-10-01

    A case of a woman with lung adenocarcinoma in which fifteen-month disease control was achieved with second-line erlotinib treatment is presented. Five months after treatment beginning, isolated grade 3 hyperbilirubinemia occurred and daily dose was reduced to 100mg. Comments on erlotinib hepatic toxicity and the pharmacologic interactions on erlotinib metabolism are given. Rev Port Pneumol 2008; XIV (Supl 3): S29-S34. © 2008 Sociedade Portuguesa de Pneumologia/SPP.

  3. Resolution of (/sup 11/C)DL-leucine and (/sup 11/C)DL-trytophan by high-performance liquid chromatography

    Energy Technology Data Exchange (ETDEWEB)

    Washburn, L.E.; Sun, T.T.; Byrd, B.L. (Oak Ridge Associated Universities, Inc., TN (USA). Medical and Health Science Div.); Callahan, A.P. (Oak Ridge National Lab., TN (USA))

    1985-02-01

    High-performance liquid chromatographic (HPLC) resolution of (/sup 11/C)DL-leucine and (/sup 11/C)DL-tryptophan, using modifications of a previously developed technique for resolution of (/sup 11/C)DL-valine, was used to produce (/sup 11/C)L-leucine and (/sup 11/C)L-tryptophan. The technique employs commercially available reverse phase HPLC columns and chiral mobile phases containing cupric acetate and L-proline.

  4. Epidermal growth factor receptor inhibition with erlotinib partially prevents cisplatin-induced nephrotoxicity in rats.

    Directory of Open Access Journals (Sweden)

    Yukihiro Wada

    Full Text Available The effects of blocking the epidermal growth factor receptor (EGFR in acute kidney injury (AKI are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP-nephrotoxicity (CP-N. In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2. Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.

  5. Erlotinib-Induced Episcleritis in a Patient with Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Armin Shahrokni

    2008-03-01

    Full Text Available Context Erlotinib is a relatively new anilinoquinazoline indicated for treatment of pancreatic cancer in combination with gemcitabine. It is a tyrosine kinase inhibitor that specifically targets epidermal growth factor receptor (EGFR, which is commonly overexpressed and/or mutated in solid tumors. Active competitive inhibition of adenosine triphosphate, inhibits downstream signal transduction of ligand dependent EGFR activation. EGFR kinase inhibitors are less toxic than conventional chemotherapy as they are relatively specific for tumor cells. Common side effects include acneiform (papulopustular rash, diarrhea, edema, pruritus, dry skin and alopecia. Case report This article reports the case of a 55-year-old Caucasian female with recurrent pancreatic cancer who developed episcleritis after seventeen days of treatment with erlotinib. Symptoms completely resolved four weeks after drug discontinuation. Conclusions To our knowledge, erlotinibinduced episcleritis has not been previously described.

  6. Comparative Evaluation of the Translocator Protein Radioligands {sup 11}C-DPA-713, {sup 18}F-DPA- 714, and {sup 11}C-PK11195 in a Rat Model of Acute Neuro-inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Chauveau, F.; Van Camp, N.; Dolle, F.; Kuhnast, B.; Hinnen, F.; Damont, A.; Boutin, H.; Tavitian, B. [CEA, DSV, I2BM, LIME, Orsay (France); Chauveau, F.; Van Camp, N.; Boutin, H; Tavitian, B. [INSERM, U803, Orsay (France); Chauveau, F. [CREATIS-LRMN, CNRS, UMR 5220, and INSERM, U630, Bron (France); Boutin, H. [Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester (GB); James, M. [Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales (Australia); Kassiou, M. [Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New SouthWales (Australia); Kassiou, M. [School of Chemistry, University of Sydney, Sydney, New SouthWales (Australia)

    2009-07-01

    Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (micro-glia and macrophages) during neuro-inflammation. Radiolabeling of TSPO ligands enables the detection of neuro-inflammatory lesions by PET. Two new radioligands, {sup 11}C-labeled N, N-diethyl-2-[2-(4- methoxy-phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl] acetamide (DPA-713) and {sup 18}F-labeled N, N-diethyl-2-(2-(4-(2- fluoroethoxy)phenyl)-5, 7-dimethylpyrazolo[1, 5-a]pyrimidin-3-yl) acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuro-inflammation. Methods: {sup 11}C-DPA-713 and {sup 18}F-DPA-714, as well as the classic radioligand {sup 11}C-labeled (R)-N-methyl- N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intra-striatal injection of (R, S)-a-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuro-inflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions. Results: {sup 11}C-DPA-713 and {sup 18}F-DPA-714 could specifically localize the neuro-inflammatory site with a similar signal-to-noise ratio in vitro. In vivo, {sup 18}F-DPA-714 performed better than {sup 11}C-DPA-713 and {sup 11}C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential. Conclusion: {sup 18}F-DPA-714 appears to be an attractive alternative to {sup 11}C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with {sup 18}F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. {sup 18}F-DPA-714 will be further evaluated in longitudinal studies of neuro

  7. Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

    Directory of Open Access Journals (Sweden)

    Cavazzoni Andrea

    2012-12-01

    Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

  8. Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

    2013-04-15

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  9. Synthesis of PET probe O(6)-[(3-[(11)C]methyl)benzyl]guanine by Pd(0)-mediated rapid C-[(11)C]methylation toward imaging DNA repair protein O(6)-methylguanine-DNA methyltransferase in glioblastoma.

    Science.gov (United States)

    Koyama, Hiroko; Ikenuma, Hiroshi; Toda, Hiroshi; Kondo, Goro; Hirano, Masaki; Kato, Masaya; Abe, Junichiro; Yamada, Takashi; Wakabayashi, Toshihiko; Ito, Kengo; Natsume, Atsushi; Suzuki, Masaaki

    2017-03-18

    O(6)-Benzylguanine (O(6)-BG) is a substrate of O(6)-methylguanine-DNA methyltransferase (MGMT), which is involved in drug resistance of chemotherapy in the majority of glioblastoma multiform. For clinical diagnosis, it is hoped that the MGMT expression level could be determined by a noninvasive method to understand the detailed biological properties of MGMT-specific tumors. We synthesized (11)C-labeled O(6)-[(3-methyl)benzyl]guanine ([(11)C]mMeBG) as a positron emission tomography probe. Thus, a mixed amine-protected stannyl precursor, N(9)-(tert-butoxycarbonyl)-O(6)-[3-(tributylstannyl)benzyl]-N(2)-(trifluoroacetyl)guanine, was subjected to rapid C-[(11)C]methylation under [(11)C]CH3I/[Pd2(dba)3]/P(o-CH3C6H4)3/CuCl/K2CO3 in NMP, followed by quick deprotection with LiOH/H2O, giving [(11)C]mMeBG with total radioactivity of 1.34GBq and ≥99% radiochemical and chemical purities.

  10. Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging.

    Science.gov (United States)

    Syvänen, Stina; Eriksson, Jonas; Genchel, Tove; Lindhe, Orjan; Antoni, Gunnar; Långström, Bengt

    2007-07-30

    The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171. [1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/mumol and 270 GBq/mumol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171. All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171. The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).

  11. Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

    Directory of Open Access Journals (Sweden)

    Genchel Tove

    2007-07-01

    Full Text Available Abstract Background The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171. Methods [1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl-4H-1,2,4-triazol-4-ylphenylethyl-2-phenylpiperidin-3-amine (I and (2S,3S-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl-4H-1,2,4-triazol-4-ylphenylethylpiperidin-3-amine (II was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171. Results All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II had no specific binding in striatum. Ligand (I had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171. Conclusion The propyl-analogue (II cannot be used for detecting changes in NK1-ligand levels, while further studies should be

  12. Syntheses and pharmacological evaluation of two potent antagonists for dopamine D{sub 4} receptors: [{sup 11}C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-1-yl]ethyl]-3-[{sup 11}C]methoxybenzamide

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Mingrong E-mail: zhang@nirs.go.jp; Haradahira, Terushi; Maeda, Jun; Okauchi, Takashi; Kawabe, Kouichi; Noguchi, Junko; Kida, Takayo; Suzuki, Kazutoshi; Suhara, Tetsuya

    2002-02-01

    Two benzamide derivatives as dopamine D{sub 4} receptor antagonists, YM-50001(4) and N- [2-[4-(4-chlorophenyl]piperizin-1-yl]ethyl]-3-methoxybenzamide (9), were labeled by positron-emitter ({sup 11}C), and their pharmacological specificities to dopamine D{sub 4} receptors were examined by quantitative autoradiography and positron emission tomography (PET). Radiosyntheses were accomplished by O-methylation of corresponding phenol precursors (5 and 10) with [{sup 11}C]CH{sub 3}I followed by HPLC purifications. In vitro binding on rat brain slices showed different distribution patterns and pharmacological properties between the two radioligands. The [{sup 11}C]4 showed the highest binding in the striatum, which was inhibited not only by 10 {mu}M 4 but also by 10 {mu}M raclopride, a selective dopamine D{sub 2} receptor antagonist. In contrast, [{sup 11}C]9 showed the highest binding in the cerebral cortex, which was inhibited by several D{sub 4} receptor antagonists (9, RBI-254, L-745,870), but not by any other receptor ligands (D{sub 1}/D{sub 5}, D{sub 2}/D{sub 3}, 5-HT{sub 1A}, 5-HT{sub 2A}, {sigma}{sub 1} and {alpha}{sub 1}) tested. In vivo brain distribution of [{sup 11}C]9 in rat showed the highest uptake in the frontal cortex, a region that has a high density of D{sub 4} receptors. These results indicate that the pharmacological property of [{sup 11}C]9 matches the rat brain D{sub 4} receptors, but that of [{sup 11}C]4 rather appears to match the rat brain D{sub 2} receptors. The results for the benzamide [{sup 11}C]9 prompted us to further evaluate its potential as a PET radioligand for D{sub 4} receptors by employing PET on monkey brain. Unfortunately, in contrast to rats, neither specific binding nor differences in regional uptake of radioactivity were observed in monkey brain after intravenous {sup 11}C]9 injection. Based on that specific activities of radioligands might be critical in mapping the neurotransmitter receptors if they are only faintly expressed

  13. Erlotinib pretreatment improves photodynamic therapy of non-small cell lung carcinoma xenografts via multiple mechanisms

    Science.gov (United States)

    Gallagher-Colombo, Shannon M.; Miller, Joann; Cengel, Keith A.; Putt, Mary E.; Vinogradov, Sergei A.; Busch, Theresa M.

    2015-01-01

    Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, and ovarian cancer. While EGFR is currently a favorite molecular target for treatment of these cancers, inhibition of the receptor with small molecule inhibitors (i.e.- erlotinib) or monoclonal antibodies (i.e.- cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared to 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT. PMID:26054596

  14. Erlotinib Pretreatment Improves Photodynamic Therapy of Non-Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms.

    Science.gov (United States)

    Gallagher-Colombo, Shannon M; Miller, Joann; Cengel, Keith A; Putt, Mary E; Vinogradov, Sergei A; Busch, Theresa M

    2015-08-01

    Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers, including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, and ovarian cancer. Although EGFR is currently a favorite molecular target for the treatment of these cancers, inhibition of the receptor with small-molecule inhibitors (i.e., erlotinib) or monoclonal antibodies (i.e., cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared with 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT.

  15. Rapid reductive-carboxylation of secondary amines, one pot synthesis of N'-(4-/sup 11/C-methyl)imipramine

    Energy Technology Data Exchange (ETDEWEB)

    Ram, Siya; Ehrenkaufer, R.E.; Jewett, D.M.

    1986-01-01

    A new rapid high yield synthesis of radiolabeled N'-(4-/sup 11/C-methyl)imipramine has been developed using a reductive-carboxylation approach, in which /sup 11/CO/sub 2/ is reacted with either N'-trimethylsilyldesimipramine or N'-lithium derivative of desimipramine, followed by lithium aluminium hydride reduction, to give no carrier added or carrier added /sup 11/C-labeled imipramine respectively. The final product is characterized by chromatographic and spectroscopic methods.

  16. 4-(11)C-Methoxy N-(2-Diethylaminoethyl) Benzamide: A Novel Probe to Selectively Target Melanoma.

    Science.gov (United States)

    Garg, Pradeep K; Nazih, Rachid; Wu, Yanjun; Singh, Ravi; Garg, Sudha

    2017-05-01

    We report the synthesis and preclinical evaluation of a (11)C-labeled probe to target melanoma using PET. Methods: The target compound 4-(11)C-methoxy N-(2-diethylaminoethyl) benzamide (4-(11)C-MBZA) was prepared via the (11)C-methylation of 4-hydroxy N-(2-diethylaminoethyl) benzamide (4-HBZA). The in vitro binding was performed using B16F1 (melanoma cells), MCF-10A (breast epithelial cells), and MDA-MB 231 (breast cancer cells). The internalization studies were conducted using B16F1 cells. In vivo biodistribution and small-animal PET imaging were performed in mice bearing B16F1 melanoma tumor xenografts. Results: The target compound 4-(11)C-MBZA was prepared in 46% ± 7% radiochemical yields by reacting (11)C-methyltriflate with 4-HBZA followed by high-performance liquid chromatography purification. The specific activity of this compound was 853 ± 29.6 GBq/μmol (23 ± 0.8 Ci/μmol). The binding of 4-(11)C-MBZA to B16F1, MCF-10A, and MDA-MB-231 cells was 6.41% ± 1.28%, 1.51% ± 0.17%, and 0.30% ± 0.17%, respectively. Internalization studies using B16F1 melanoma cells show 60.7% of the cell-bound activity was internalized. Results from biodistribution studies show a rapid and high uptake of radioactivity in the tumor, with uptake levels reaching 5.85 ± 0.79 and 8.13 ± 1.46 percentage injected dose per gram at 10 and 60 min, respectively. Low uptake in normal tissues in conjunction with high tumor uptake resulted in high tumor-to-tissue ratios. On small-animal PET images, the tumor was clearly delineated soon after 4-(11)C-MBZA injection and tumor uptake reached 4.2 percentage injected dose per gram by 20 min. These preclinical evaluations show a high propensity of 4-(11)C-MBZA toward melanoma tumor. Conclusion: We successfully developed 4-(11)C-MBZA as a PET imaging probe, displaying properties advantageous over those for its (18)F analogs. These preclinical evaluation results demonstrate the clinical potential of this probe to selectively target melanoma.

  17. Clinical aspects and perspectives of erlotinib in the treatment of patients with biliary tract cancer

    DEFF Research Database (Denmark)

    Jensen, Lars Henrik

    2016-01-01

    INTRODUCTION: Patients with non-resectable biliary tract cancer have a poor prognosis even if treated with systemic chemotherapy. One hope for improving treatment is through molecular biology and the characterization of specific cancer driving alterations followed by the design of targeted drugs....... The epidermal growth factor receptor system is upregulated in many cancers and can be targeted by the protein kinase inhibitor erlotinib. Erlotinib has demonstrated a clinically applicable effect in pancreatic and lung cancer Areas covered: In this review, the author presents the published clinical data about...... erlotinib in biliary tract cancer. The data is interpreted with respect to its clinical value and in regards to its future development. EXPERT OPINION: Erlotinib has low activity as a monotherapy, but has shown synergistic effects when combined with bevacizumab. The only phase III trial with erlotinib...

  18. Could erlotinib treatment lead to acute cardiovascular events in patients with lung adenocarcinoma after chemotherapy failure?

    Science.gov (United States)

    Kus, Tulay; Aktas, Gokmen; Sevinc, Alper; Kalender, Mehmet Emin; Camci, Celaletdin

    2015-01-01

    Erlotinib, an epidermal growth factor receptor and tyrosine kinase inhibitor, is a targeted drug that was approved for the treatment of non-small-cell lung cancers and pancreatic cancers. Targeted tyrosine kinase inhibitors are known to have cardiotoxic effects. However, erlotinib does not have a statistically proven effect of increasing acute cardiovascular event (ACE) risk. Preclinical studies showed that beta agonist stimulation among rats that were administered erlotinib led to cardiovascular damage. Thus, there would be an aggregate effect of erlotinib on ACE, although it is not thought to be a cardiotoxic drug itself. In this paper, we present two non-small-cell lung cancer cases that developed ACE under erlotinib treatment. PMID:26150726

  19. Imaging of I{sub 2}-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-{sup 11}C]tolyl)-4,5-dihydro-1H-imidazole ([{sup 11}C]FTIMD)

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Kazunori, E-mail: kawamur@nirs.go.j [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Naganawa, Mika [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Konno, Fujiko; Yui, Joji [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Wakizaka, Hidekatsu [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Yamasaki, Tomoteru; Yanamoto, Kazuhiko; Hatori, Akiko [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Takei, Makoto [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Tokyo Nuclear Services Co., Ltd., Tokyo 110-0016 (Japan); Yoshida, Yuichiro [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); SHI Accelerator Service Ltd., Tokyo 141-0032 (Japan); Sakaguchi, Kazuya [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Fukumura, Toshimitsu [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Kimura, Yuichi [Department of Biophysics, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Zhang, Ming-Rong [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)

    2010-07-15

    Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I{sub 1}R and I{sub 2}R). I{sub 2}Rs are associated with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomography (PET) probes for I{sub 2}Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I{sub 2}Rs by PET. We labeled a selective I{sub 2}R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with {sup 11}C and performed the first imaging of I{sub 2}Rs by PET using 2-(3-fluoro-[4-{sup 11}C]tolyl)-4,5-dihydro-1H-imidazole ([{sup 11}C]FTIMD). Methods: [{sup 11}C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [{sup 11}C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [{sup 11}C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated. Results: [{sup 11}C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant reduction in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite analysis, unchanged [{sup 11}C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were observed in regions with a high density of I{sub 2}R. The radioactivity levels and V{sub T} values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control. Conclusion: [{sup 11}C]FTIMD showed specific binding to I{sub 2}Rs in rat brains with a high density of I{sub 2}R.

  20. Pharmacokinetic analysis of [11C]PBR28 in the rat model of herpes encephalitis: comparison with (R)-[11C]PK11195 for pre-clinical imaging

    NARCIS (Netherlands)

    Kopschina Feltes, Paula; Parente, Andrea; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina; Dierckx, Rudi; de Vries, Erik; Doorduin, Janine

    2015-01-01

    Aim: [11C]PBR28 is a second generation translocator protein (TSPO) ligand with supposedly better imaging characteristics than the most commonly used tracer [11C]PK11195. Surprisingly, only limited studies have evaluated the pharmacokinetic and binding profile of [11C]PBR28 in neuroinflammatory model

  1. Pharmacokinetic analysis of 11C-PBR28 in the rat model of herpes encephalitis (HSE): comparison with (R)-11C-PK11195

    NARCIS (Netherlands)

    Parente, Andrea; Kopschina Feltes, Paula; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina M; Dierckx, Rudi; de Vries, Erik F; Doorduin, Janine

    2016-01-01

    11C-PBR28 is a second generation TSPO tracer with supposedly superior characteristics than the most commonly used tracer for neuroinflammation, (R)-11C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of 11C-PBR28 in rodent models of ne

  2. PET measurements of cAMP-mediated phosphodiesterase-4 with (R)-[11C]rolipram.

    Science.gov (United States)

    Kenk, Miran; Thomas, Adam; Lortie, Mireille; Dekemp, Rob; Beanlands, Rob S; Dasilva, Jean N

    2011-01-01

    Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.

  3. PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [{sup 11}C]MeDAS, [{sup 11}C]CIC and [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Paula Faria, Daniele de [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen (Netherlands); University of Sao Paulo Medical School, Center of Nuclear Medicine, Sao Paulo (Brazil); Copray, Sjef [University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen (Netherlands); Sijbesma, Jurgen W.A.; Willemsen, Antoon T.M.; Dierckx, Rudi A.J.O.; Vries, Erik F.J. de [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Buchpiguel, Carlos A. [University of Sao Paulo Medical School, Center of Nuclear Medicine, Sao Paulo (Brazil)

    2014-05-15

    In this study, we compared the ability of [{sup 11}C]CIC, [{sup 11}C]MeDAS and [{sup 11}C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake. Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group). The kinetics of [{sup 11}C]CIC, [{sup 11}C]MeDAS and [{sup 11}C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [{sup 11}C]CIC make this tracer less suitable for in vivo PET imaging. [{sup 11}C]PIB showed good uptake in the white matter in the cerebrum, but [{sup 11}C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [{sup 11}C]MeDAS distribution correlated well with myelin density in different brain regions. This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [{sup 11}C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [{sup 11}C]CIC and [{sup 11}C]PIB. (orig.)

  4. [{sup 11}C]NNC 22-0215, a metabolically stable dopamine D{sub 1} radioligand for PET

    Energy Technology Data Exchange (ETDEWEB)

    Foged, Christian; Halldin, Christer; Swahn, Carl-Gunnar; Ginovart, Nathalie; Karlsson, Per; Lundkvist, Camilla; Farde, Lars

    1998-07-01

    NNC 22-0215 has been found to be a metabolically stable dopamine D{sub 1} antagonist with high affinity and selectivity for D{sub 1} receptors in vitro. We prepared [{sup 11}C]NNC 22-0215 with a specific radioactivity of about 50 GBq/{mu}mol at time of administration. In PET experiments with [{sup 11}C]NNC 22-0215 there was a rapid uptake of radioactivity in the cynomolgus monkey brain (1.8% of total radioactivity injected). Radioactivity accumulated most markedly in the striatum and the neocortex. The striatum to cerebellum ratio was about 4, with specific binding that remained at a plateau level from 50 min to 100 min after injection. Binding in the striatum and neocortex was markedly displaced by SCH 23390, whereas binding in the cerebellum was not reduced. Metabolite studies showed that about 80% of the radioactivity in the monkey plasma represented unchanged radioligand 30 min after injection. The rate of metabolism in monkey plasma in vivo was also determined for a series of structurally related {sup 11}C-labelled benzazepines, previously used as dopamine D{sub 1} receptor ligands for PET. Results indicate a significantly slower rate of metabolism for [{sup 11}C]NNC 22-0215 than for any of the previously labelled benzazepines. Thus [{sup 11}C]NNC 22-0215 has potential for imaging of selective binding to the dopamine D{sub 1} receptors in the human brain with high count rates at time of equilibrium.

  5. Different sensitivities to competitive inhibition of benzodiazepine receptor binding of {sup 11}C-iomazenil and {sup 11}C-flumazenil in rhesus monkey brain

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Osamu; Hosoi, Rie; Kobayashi, Kaoru [Osaka Univ., Suita (Japan). Medical School; Itoh, Takashi; Gee, A.; Suzuki, Kazutoshi

    2001-04-01

    The in vivo binding kinetics of {sup 11}C-iomazenil were compared with those of {sup 11}C-flumazenil binding in rhesus monkey brain. The monkey was anesthetized with ketamine and intravenously injected with either {sup 11}C-iomazenil or {sup 11}C-flumazenil in combination with the coadministration of different doses of non-radioactive flumazenil (0, 5 and 20 {mu}g/kg). The regional distribution of {sup 11}C-iomazenil in the brain was similar to that of {sup 11}C-flumazenil, but the sensitivity of {sup 11}C-iomazenil binding to competitive inhibition by non-radioactive flumazenil was much less than that of {sup 11}C-flumazenil binding. A significant reduction in {sup 11}C-flumazenil binding in the cerebral cortex was observed with 20 {mu}g/kg of flumazenil, whereas a relatively smaller inhibition of {sup 11}C-iomazenil binding in the same region was observed with the same dose of flumazenil. These results suggest that {sup 11}C-flumazenil may be a superior radiotracer for estimating benzodiazepine receptor occupancy in the intact brain. (author)

  6. Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression.

    Science.gov (United States)

    Suárez-Arroyo, Ivette J; Rios-Fuller, Tiffany J; Feliz-Mosquea, Yismeilin R; Lacourt-Ventura, Mercedes; Leal-Alviarez, Daniel J; Maldonado-Martinez, Gerónimo; Cubano, Luis A; Martínez-Montemayor, Michelle M

    2016-01-01

    The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors.

  7. [{sup 11}C]-MeJDTic: a novel radioligand for {kappa}-opioid receptor positron emission tomography imaging

    Energy Technology Data Exchange (ETDEWEB)

    Poisnel, Geraldine; Oueslati, Farhana; Dhilly, Martine; Delamare, Jerome [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France); Perrio, Cecile [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)], E-mail: perrio@cyceron.fr; Debruyne, Daniele [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)], E-mail: debruyne@cyceron.fr; Barre, Louisa [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)

    2008-07-15

    Introduction: Radiopharmaceuticals that can bind selectively the {kappa}-opioid receptor may present opportunities for staging clinical brain disorders and evaluating the efficiency of new therapies related to stroke, neurodegenerative diseases or opiate addiction. The N-methylated derivative of JDTic (named MeJDTic), which has been recently described as a potent and selective antagonist of {kappa}-opioid receptor in vitro, was labeled with carbon-11 and evaluated for in vivo imaging the {kappa}-opioid receptor in mice. Methods: [{sup 11}C]-MeJDTic was prepared by methylation of JDTic with [{sup 11}C]-methyl triflate. The binding of [{sup 11}C]-MeJDTic to {kappa}-opioid receptor was investigated ex vivo by biodistribution and competition studies using nonfasted male CD1 mice. Results: [{sup 11}C]-MeJDTic exhibited a high and rapid distribution in peripheral organs. The uptake was maximal in lung where the {kappa} receptor is largely expressed. [{sup 11}C]-MeJDTic rapidly crossed the blood-brain barrier and accumulated in the brain regions of interest (hypothalamus). The parent ligand remained the major radioactive compound in brain during the experiment. Chase studies with U50,488 (a {kappa} referring agonist), morphine (a {mu} agonist) and naltrindole (a {delta} antagonist) demonstrated that this uptake was the result of specific binding to the {kappa}-opioid receptor. Conclusion: These findings suggested that [{sup 11}C]-MeJDTic appeared to be a promising selective 'lead' radioligand for {kappa}-opioid receptor PET imaging.

  8. A Convenient Radiolabeling of [{sup 11}C](R)-PK11195 Using Loop Method in Automatic Synthesis Module

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hak Jeong; Jeong, Jae Min; Lee, Yun Sang; Kim, Hyung Woo; Choi, Jae Yeon; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2009-08-15

    ((R)-1-(2-chlorophenyl)-N-1-[[{sup 11}C]methyl-N-(1-propyl)-3-isoquinoline carboxamide ((R)-PK11195) is a specific ligand for the peripheral type benzodiazepine receptor and a marker of activated microglia, used to measure inflammation in neurologic disorders. We report here that a direct and simple radiosynthesis of [[{sup 11}C](R)-PK11195 in mild condition using NaH suspension in DMF and one-step loop method. (R)-NDesmethyl- PK11195 (1 mg) in DMSO (0.1 mL) and NaH suspension in DMF (0.1 mL) were injected into a semi-prep HPLC loop. [{sup 11}C]methyl iodide was passed through HPLC loop at room temperature. Purification was performed using semi-preparative HPLC. Aliquots eluted at 11.3 min were collected and analyzed by analytical HPLC and mass spectrometer. The labeling efficiency of [[{sup 11}C](R)-PK11195 was 71.8{+-}8.5%. The specific activity was 11.8{+-}6.4 GBq/{mu}mol and radiochemical purity was higher than 99.2%. The mass spectrum of the product eluted at 11.3 min showed m/z peaks at 353.1 (M+1), indicating the mass and structure of (R)-PK11195. By the one-step loop method with the [[{sup 11}C]CH3I automated synthesis module, [[{sup 11}C](R)-PK11195 could be easily prepared in high radiochemical yield using NaH suspension in DMF.

  9. Metabolites of (18)F-FDG and 3-O-(11)C-methylglucose in pig liver

    DEFF Research Database (Denmark)

    Bender, D; Munk, O L; Feng, H Q

    2001-01-01

    of metabolites was determined in successive liver tissue biopsies. Freeze-clamped liver tissue samples were subjected to extraction by acetonitrile at -5 degrees C to -10 degrees C, and extracts were analyzed by radio-high-performance liquid chromatography (radio-HPLC). The findings were identified by means...... the metabolic pathways of FDG and 3-O-(11)C-methylglucose (MG) in liver tissue in vivo. It is usually assumed that MG is not metabolized and FDG is converted to (18)F-FDG-6-phosphate (FDG-6-P). METHODS: The study was performed on 6 anesthetized 40-kg pigs that were given the 2 tracers intravenously. The content...... of radio-HLPC measurements of the products of in vitro enzymatic reactions. RESULTS: The applied extraction technique provided almost quantitative recovery of the radioactivity from tissue. After MG injection, only MG was detectable in the liver tissue; no labeled metabolites were found. After FDG...

  10. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study.

    Science.gov (United States)

    Boehrer, Simone; Adès, Lionel; Braun, Thorsten; Galluzzi, Lorenzo; Grosjean, Jennifer; Fabre, Claire; Le Roux, Génèviève; Gardin, Claude; Martin, Antoine; de Botton, Stéphane; Fenaux, Pierre; Kroemer, Guido

    2008-02-15

    Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14(ARF). Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34(+) bone marrow blasts from MDS and AML patients while sparing normal CD34(+) progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14(ARF). One patient afflicted with both MDS and non-small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.

  11. Comparative PET studies of the distribution of ( - )-3,4-methylenedioxy-N-[{sup 11}C]methamphetamine and ( - )-[{sup 11}C]methamphetamine in a monkey brain

    Energy Technology Data Exchange (ETDEWEB)

    Shiue Chyngyann; Shiue, Grace G.; Cornish, Kurtis G.; O' Rourke, Maria F

    1995-04-01

    Carbon-11 labeled ( - )-methamphetamine and ( - )-3,4-methylenedioxy-N-methamphetamine were synthesized by methylation of the corresponding desmethyl precursors with [{sup 11}C]H{sub 3}I in 40-60% yield in a synthesis time of 30 min from EOB with a specific activity of 0.5-1.2 Ci/{mu}M. PET studies in a Rhesus monkey revealed that the uptakes of both compounds in different brain regions were similar, and the retention of radioactivity in these brain regions remained constant throughout the study for the former while it was washed out slowly for the latter. The half-life of ( - )-3,4-methylenedioxy-N-methamphetamine in monkey brain was approximately 70 min. Analyses of arterial plasma by HPLC revealed that 50% of radioactivity in the plasma remained as ( - )-methamphetamine while only 3% remained as ( - )-3,4-methylenedioxy-N-methamphetamine at 60 min post-injection. These results suggest that the uptakes of both compounds in monkey brain are probably not receptor mediated. Rather, blood flow, lipophilicity of the compounds or other transport mechanisms may play a role in their uptakes.

  12. Optimization of the Radiosynthesis of the 2-(4-N-[11 C] methylaminophenyl)-6-hydroxybenzothiazole for AD%AD显像剂11C-PIB合成效率的影响因素

    Institute of Scientific and Technical Information of China (English)

    孙慧萍; 周卫华; 张锦明; 张晓军; 陈英茂; 田嘉禾

    2012-01-01

    11C-PIB was the standard PET radiopharmaceuticals for Alzheimer's disease(AD) imaging targeting beta-amyloid plaques. The optimization for high synthesis yield and specific activity was designed with 11CH3-Triflate as methylation agent for 11C-PIB. Synthesis for 11C-PIB were studied with home made carbon-11 synthesis module. The results showed that the amount of precursor, the temperature and pH could effect the labeling yield. The optimum reaction conditions were as fllows: with 5 g/L of precursor, pH = 7. 0, at room temperature, a yield of 65. 2% ±4. 7% (n = 8) and a specific activity of 70. 6 GBq/g (18. 0 TBq/mmol) were achieved, and radiochemical purity was over 99%. It took 30 min from 11CO2 to 11C-PIB. Single synthesis yielding was 3. 7 GBq of 11C-PIB. The quantity and quality of 11C-PIB were suitable for clinical use after optimization.%11C-PIB是诊断阿尔茨海默病(AD)的特征靶Aβ斑块的正电子放射性药物,本工作系统研究了以11CH3-Triflate为甲基化试剂合成11 C-PIB合成的影响因素.在国产碳多功能合成仪上,研究前体量、溶剂、反应温度及体系的pH等对11C-PIB效率的影响,并对合成条件进行优化.结果显示:前体量、溶剂、反应温度及体系的pH均明显影响合成效率.优化后的合成条件为:丙酮为溶剂,前体浓度为5 g/L,反应温度为常温,pH为中性.在此条件下,11C-PIB的合成效率为65.2%±4.7%(n=8,校正效率),产品的放化纯度大于99%,比活度为70.6 GBq/g(18.0 TBq/mmoL).从11 CO2到11 C-PIB的合成时间为30 min,单次合成的产量为3.7 GBq.以上结果表明,通过优化合成条件,可以稳定、高质量地合成11C-PIB,以满足临床需要.

  13. Erlotinib in the trentment of Advanced Non-small-cell Lung Cancer: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Yanming TANG

    2009-12-01

    Full Text Available Background and objective Erlotinib is a new and efficient anti-tumor targeted therapy drug, and it has been used in China for non-small cell lung cancer since 2006. The aim of this study is to review the effectiveness and safety of erlotinib for treating advanced non-small cell lung cancer. Methods Authors searched the Cochrane Library, Pubmed, Embase, CBM, CNKI and Wanfang Date. The randomized controlled trials (RCTs were analyzed by RevMan 4.2 software. Authors also included retrospective case report published in Chinese journals. Results Four RCTs and 8 uncontrolled case reports were analyzed. The results of the RCTs showed that erlotinib was significantly better than placebo on progression-free survival, median survival time, response rate (OR=10.21, 95%CI: 2.44-42.73 and 1-yr survival rate (OR=1.67, 95%CI: 1.13-2.46; Erlotinib was superior than paclitaxel+carboplatin on median survival time (HR=1.73, 95%CI: 1.09-2.73; P=0.018, the other efficacy were similar; The efficacy of erlotinib combined chemotherapy was close to chemotherapy alone. The main side effects caused by erlotinib were rash and diarrhea, and the tolerance was well. The overall uncontrolled clinical studies showed that the response rate was 27.27%, and the 1-yr survival rate was 56.1%. Conclusion Erlotinib is effect for non-small cell lung cancer, and maybe better for never smokers, female, Asia and adenocarcima. The clinical favor from erlotinib combined chemotherapy remains uncertain. But the effect of erlotinib being used in clinical settings needs to be confirmed by further large and multicenter.

  14. Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Shi, Weiji [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Riely, Gregory J. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Beal, Kathryn [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Yu, Helena A. [Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Chan, Timothy A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Wu, Abraham J., E-mail: wua@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2014-06-01

    Purpose/Objectives: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). Conclusions: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

  15. Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer

    Science.gov (United States)

    Ramalingam, Suresh S.; Blackhall, Fiona; Krzakowski, Maciej; Barrios, Carlos H.; Park, Keunchil; Bover, Isabel; Seog Heo, Dae; Rosell, Rafael; Talbot, Denis C.; Frank, Richard; Letrent, Stephen P.; Ruiz-Garcia, Ana; Taylor, Ian; Liang, Jane Q.; Campbell, Alicyn K.; O'Connell, Joseph; Boyer, Michael

    2012-01-01

    Purpose This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. Conclusion Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants

  16. Characterization of hepatic tumors using [11C]metomidate through positron emission tomography

    DEFF Research Database (Denmark)

    Roivainen, Anne; Naum, Alexandru; Nuutinen, Heikki

    2013-01-01

    ABSTRACT: BACKGROUND: Using positron emission tomography (PET), we compared two tracers, [11C]metomidate ([11C]MTO) and [11C]acetate ([11C]ACE), for the characterization of hepatic tumors. METHODS: Thirty-three patients underwent PET with [11C]MTO and [11C]ACE and magnetic resonance imaging (MRI......). Based on the histology of the tumor biopsy, 14 patients had hepatocellular carcinoma (HCC), 9 patients had focal nodular hyperplasia (FNH), and 10 patients had other types of hepatic tumors. Tumor uptake was evaluated by calculating the maximum and mean standardized uptake value and tumor-to-liver ratio....... RESULTS: Altogether, 120 hepatic lesions (59 HCC, 18 FNH, 30 metastases of different primaries, 9 adenomas, and 4 regenerating nodules of liver cirrhosis) were detected by MRI. The overall tumor detection rate was slightly higher for [11C]MTO (39%) than for [11C]ACE (33%). [11C]ACE was more sensitive...

  17. Synthesis of [{sup 11}C]salicylic acid and related compounds and their biodistribution in mice

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Toru; Ishii, Shin-Ichi; Senda, Michio [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Nakacho, Itabashi, Tokyo (Japan); Ogawa, Koji [Radiological Technology Course, Faculty of Medical Engineering and Technology, School of Allied Health Sciences, Kitasato University, Kanagawa (Japan)

    1999-05-01

    For in vivo measurement of the hydroxyl radical ({sup %s{center_dot}}OH), we synthesized [{sup 11}C]salicylic acid, [{sup 11}C]O-acetylsalicylic acid and [{sup 11}C]2-methoxybenzoic acid by carboxylation of 2-bromomagnesiumanisol using [{sup 11}C]CO{sub 2}. The radiochemical yield of [{sup 11}C]salicylic acid, [{sup 11}C]O-acetylsalicylic acid and [{sup 11}C]2-methoxybenzoic acid calculated from trapped [{sup 11}C]CO{sub 2} in a liquid argon cooled stainless tube was 7.3{+-}1.6, 5.2 and 10.2{+-}1.7% (decay corrected), respectively. The uptake of {sup 11}C tracers by mouse brain was 0.46, 0.32 and 0.46% dose/g tissue, respectively, at 10 min post injection and presented washout patterns thereafter.

  18. Radiosynthesis and in vivo evaluation of a series of substituted {sup 11}C-phenethylamines as 5-HT{sub 2A} agonist PET tracers

    Energy Technology Data Exchange (ETDEWEB)

    Ettrup, Anders; Santini, Martin A.; Palner, Mikael; Knudsen, Gitte M. [Copenhagen University Hospital, Neurobiology Research Unit, Copenhagen (Denmark); Copenhagen University Hospital, Rigshospitalet, Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen (Denmark); Hansen, Martin; Paine, James; Kristensen, Jesper; Begtrup, Mikael [University of Copenhagen, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Copenhagen (Denmark); Copenhagen University Hospital, Rigshospitalet, Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen (Denmark); Gillings, Nic; Herth, Matthias M.; Madsen, Jacob [Copenhagen University Hospital, Rigshospitalet, PET and Cyclotron Unit, Copenhagen (Denmark); Copenhagen University Hospital, Rigshospitalet, Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen (Denmark); Lehel, Szabolcs [Copenhagen University Hospital, Rigshospitalet, PET and Cyclotron Unit, Copenhagen (Denmark)

    2011-04-15

    Positron emission tomography (PET) imaging of serotonin 2A (5-HT{sub 2A}) receptors with agonist tracers holds promise for the selective labelling of 5-HT{sub 2A} receptors in their high-affinity state. We have previously validated [{sup 11}C]Cimbi-5 and found that it is a 5-HT{sub 2A} receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [{sup 11}C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT{sub 2A} receptor agonist PET tracers in the pig brain. Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT{sub 2A} receptor binding, cortical nondisplaceable binding potentials (BP{sub ND}) were calculated using the simplified reference tissue model with the cerebellum as a reference region. After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT{sub 2A} receptor distribution. The largest target-to-background binding ratio was found for [{sup 11}C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [{sup 11}C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT{sub 2A} receptor selectivity in vivo. [{sup 11}C]Cimbi-82 and [{sup 11}C]Cimbi-21 showed lower cortical BP{sub ND}, while [{sup 11}C]Cimbi-27, [{sup 11}C]Cimbi-29, [{sup 11}C]Cimbi-31 and [{sup 11}C]Cimbi-88 gave rise to cortical BP{sub ND} similar to that of [{sup 11}C]Cimbi-5. [{sup 11}C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT{sub 2A} receptor agonist binding in the living human brain with PET. (orig.)

  19. Are [O-methyl-{sup 11}C]derivatives of ICI 89,406 {beta}{sub 1}-adrenoceptor selective radioligands suitable for PET?

    Energy Technology Data Exchange (ETDEWEB)

    Law, Marilyn P.; Wagner, Stefan; Kopka, Klaus; Schober, Otmar; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Pike, Victor W. [National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States)

    2008-01-15

    Radioligand binding studies show that {beta}{sub 1}-adrenoceptor ({beta}{sub 1}-AR) density may be reduced in heart disease without down regulation of {beta}{sub 2}-ARs. Radioligands are available for measuring total {beta}-AR density non-invasively with clinical positron emission tomography (PET) but none are selective for {beta}{sub 1}- or {beta}{sub 2}-ARs. The aim was to evaluate ICI 89,406, a {beta}{sub 1}-AR-selective antagonist amenable to labelling with positron emitters, for PET. The S-enantiomer of an [O-methyl-{sup 11}C] derivative of ICI 89,406 ((S)-[{sup 11}C]ICI-OMe) was synthesised. Tissue radioactivity after i.v. injection of (S)-[{sup 11}C]ICI-OMe (< 2 nmol.kg{sup -1}) into adult Wistar rats was assessed by small animal PET and post mortem dissection. Metabolism was assessed by HPLC of extracts prepared from plasma and tissues and by measuring [{sup 11}C]CO{sub 2} in exhaled air. The heart was visualised by PET after injection of (S)-[{sup 11}C]ICI-OMe but neither unlabelled (S)-ICI-OMe nor propranolol (non-selective {beta}-AR antagonist) injected 15 min after (S)-[{sup 11}C]ICI-OMe affected myocardial radioactivity. Ex vivo dissection showed that injecting unlabelled (S)-ICI-OMe, propranolol or CGP 20712A ({beta}{sub 1}-selective AR antagonist) at high dose (> 2 {mu}mol.kg{sup -1}) before (S)-[{sup 11}C]ICI-OMe had a small effect on myocardial radioactivity. HPLC demonstrated that radioactivity in myocardium was due to unmetabolised (S)-[{sup 11}C]ICI-OMe although {sup 11}C-labelled metabolites rapidly appeared in plasma and liver and [{sup 11}C]CO{sub 2} was detected in exhaled air. Myocardial uptake of (S)-[{sup 11}C]ICI-OMe after i.v. injection was low, possibly due to rapid metabolism in other tissues. Injection of unlabelled ligand or {beta}-AR antagonists had little effect indicating that binding was mainly to non-specific myocardial sites, thus precluding the use of (S)-[{sup 11}C]ICI-OMe to assess {beta}{sub 1}-ARs with PET. (orig.)

  20. [{sup 11}C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl] -1-piperazinecarboxylate ([{sup 11}C]GR89696): synthesis and in vivo binding to kappa opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Ravert, Hayden T.; Mathews, William B.; Musachio, John L.; Scheffel, Ursula; Finley, Paige; Dannals, Robert F

    1999-10-01

    GR89696, racemic methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl] -1-piperazinecarboxylate, a kappa opioid receptor ligand, was labeled with [{sup 11}C]methyl chloroformate. The radiochemical yield was 20% with an observed specific radioactivity of 75.5 GBq/{mu}mol at end of synthesis (2,040 mCi/{mu}mol). Five minutes after intravenous administration, 5.4% of the injected dose accumulated in mouse whole brain. Brain region to cerebellar ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The uptake of [{sup 11}C]GR89696 correlated with known kappa opioid receptor densities and was inhibited by kappa opioid selective drugs.

  1. A comparative small-animal PET evaluation of [{sup 11}C]tariquidar, [{sup 11}C]elacridar and (R)-[{sup 11}C]verapamil for detection of P-glycoprotein-expressing murine breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wanek, Thomas; Kuntner, Claudia; Sauberer, Michael [AIT Austrian Institute of Technology GmbH, Health and Environment Department, Molecular Medicine, Seibersdorf (Austria); Bankstahl, Jens P.; Bankstahl, Marion; Loescher, Wolfgang [University of Veterinary Medicine Hannover, Department of Pharmacology, Toxicology and Pharmacy, Hannover (Germany); Stanek, Johann; Langer, Oliver [AIT Austrian Institute of Technology GmbH, Health and Environment Department, Molecular Medicine, Seibersdorf (Austria); Medical University of Vienna, Department of Clinical Pharmacology, Vienna (Austria); Mairinger, Severin [AIT Austrian Institute of Technology GmbH, Health and Environment Department, Molecular Medicine, Seibersdorf (Austria); Medical University of Vienna, Department of Clinical Pharmacology, Vienna (Austria); University of Vienna, Department of Medicinal Chemistry, Vienna (Austria); Strommer, Sabine; Wacheck, Volker; Mueller, Markus [Medical University of Vienna, Department of Clinical Pharmacology, Vienna (Austria); Erker, Thomas [University of Vienna, Department of Medicinal Chemistry, Vienna (Austria)

    2012-01-15

    One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [{sup 11}C]tariquidar and [{sup 11}C]elacridar with the Pgp substrate radiotracer (R)-[{sup 11}C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [{sup 11}C]tariquidar (n = 7), [{sup 11}C]elacridar (n = 6) and (R)-[{sup 11}C]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. [{sup 11}C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean {+-} SD areas under the time-activity curves in scan 1 from time 0 to 60 min (AUC{sub 0-60}) were 38.8 {+-} 2.2 min and 25.0 {+-} 5.3 min (p = 0.016, Wilcoxon matched pairs test). [{sup 11}C]Elacridar and (R)-[{sup 11}C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [{sup 11}C]tariquidar, [{sup 11}C]elacridar and (R)-[{sup 11}C]verapamil. Among the tested radiotracers, [{sup 11}C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [{sup 11}C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. (orig.)

  2. Reinvestigation of the synthesis and evaluation of [N-methyl-{sup 11}C]vorozole, a radiotracer targeting cytochrome P450 aromatase

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)], E-mail: swkim@bnl.gov; Biegon, Anat; Katsamanis, Zachary E. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Ehrlich, Carolin W. [Johannes-Gutenberg Universitaet Mainz, Institut fuer Organische Chemie, Duesbergweg 10-14, Mainz (Germany); Hooker, Jacob M.; Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [National Institute on Alcoholism and Alcohol Abuse, Bethesda, MD (United States); Xu Youwen; King, Payton; Carter, Pauline; Alexoff, David L. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY (United States)

    2009-04-15

    Introduction: We reinvestigated the synthesis of [N-methyl-{sup 11}C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-{sup 11}C]vorozole. Methods: Norvorozole was alkylated with [{sup 11}C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ({sup 13}C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-{sup 11}C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-{sup 11}C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-{sup 11}C]vorozole binds to aromatase. [N-methyl-{sup 11}C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-{sup 11}C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

  3. In vivo imaging of neuroinflammation: a comparative study between [{sup 18}F]PBR111, [{sup 11}C]CLINME and [{sup 11}C]PK11195 in an acute rodent model

    Energy Technology Data Exchange (ETDEWEB)

    Van Camp, Nadja [CEA, I2BM, SHFJ, Laboratoire d' Imagerie Moleculaire Experimentale (LIME), Orsay (France); INSERM U803, Orsay (France); University of Antwerp, Bio-Imaging Lab, Antwerp (Belgium); Boisgard, Raphael; Theze, Benoit; Viel, Thomas; Tavitian, Bertrand [CEA, I2BM, SHFJ, Laboratoire d' Imagerie Moleculaire Experimentale (LIME), Orsay (France); INSERM U803, Orsay (France); Kuhnast, Bertrand; Dolle, Frederic [CEA, I2BM, SHFJ, Laboratoire d' Imagerie Moleculaire Experimentale (LIME), Orsay (France); Gregoire, Marie-Claude; Katsifis, Andrew [ANSTO, Radiopharmaceutical Research Institute, Lucas Heights (Australia); Chauveau, Fabien [CEA, I2BM, SHFJ, Laboratoire d' Imagerie Moleculaire Experimentale (LIME), Orsay (France); INSERM U803, Orsay (France); CREATIS-LRMN, CNRS, UMR 5220, Lyon (France); INSERM U630, Lyon (France); Boutin, Herve [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom)

    2010-05-15

    The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [{sup 18}F]PBR111 in a rodent model of acute inflammation and compare it with [{sup 11}C]CLINME, an {sup 11}C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [{sup 11}C]PK11195. We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging. We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [{sup 18}F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [{sup 18}F]PBR111 administration, induces a rapid and complete displacement of [{sup 18}F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [{sup 11}C]PK11195. [{sup 18}F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of {sup 18}F over {sup 11}C, these results support [{sup 18}F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging. (orig.)

  4. Opioid receptor imaging and displacement studies with [6-O-[{sup 11}C]methyl]buprenorphine in baboon brain

    Energy Technology Data Exchange (ETDEWEB)

    Galynker, Igor; Schlyer, David J.; Dewey, Stephen L.; Fowler, Joanna S.; Logan, Jean; Gatley, S. John; MacGregor, Robert R.; Ferrieri, Richard A.; Holland, M. J.; Brodie, Jonathan; Simon, Eric; Wolf, Alfred P

    1996-04-01

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[{sup 11}C]methyl]buprenorphine ([{sup 11}C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% {+-} 2.2% and 43% {+-} 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [{sup 11}C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [{sup 11}C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

  5. Radiation recall gastritis secondary to erlotinib in a patient with pancreatic cancer.

    Science.gov (United States)

    Graziani, Casey; Hegde, Sanjay; Saif, Muhammad Wasif

    2014-12-01

    Radiation recall refers to chemotherapy-triggered inflammation in healthy areas previously exposed to irradiation. Chemotherapeutics known to be associated with radiation recall phenomenon include anthracyclines, taxanes and antimetabolites, such as gemcitabine and capecitabine. Case reports detailing radiation recall dermatitis and pneumonitis associated with erlotinib have been previously described in the literature, however, there are no reported cases describing radiation gastritis associated with erlotinib. We report a patient with pancreatic cancer who developed gastrointestinal bleeding secondary to radiation recall gastritis related to erlotinib exposure. A 57-year-old Hispanic male with pancreatic cancer initially received 7 cycles of FOLFIRINOX followed by capecitabine with radiation therapy for 28 fractions for a total of 5,040 cGy. Re-staging with computed tomography demonstrated stable disease. The patient was then treated with erlotinib and capecitabine for approximately two months before restaging demonstrated progressive disease. Shortly after discontinuing erlotinib and capecitabine, the patient reported maroon colored stools. Laboratory studies demonstrated a precipitous drop in hemoglobin and hematocrit from pre-treatment baseline, ultimately requiring transfusion with packed red blood cells. Subsequent esophagogastroduodenoscopy demonstrated findings consistent with radiation gastritis, with oozing in the gastric body and antrum, which was treated therapeutically with argon plasma coagulation. The patient's gastrointestinal bleed was difficult to control. Over the course of a two-month period - the patient required multiple admissions, repeat therapeutic esophagogastroduodenoscopies and transfusions. Radiation recall from erlotinib is rare but can potentially arise in any site that has been previously irradiated. There may be an association between the pathogenesis of radiation recall and erlotinib's up-regulation of the angiogenic growth factor

  6. Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer

    Institute of Scientific and Technical Information of China (English)

    Alexander Huether; Michael H(o)pfner; Andreas P Sutter; Viola Baradari; Detlef Schuppan; Hans Scherübl

    2006-01-01

    AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC).METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology;changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS: Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptoticfactors like Bcl-2, Bcl-XL or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/Go-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib's inhibitory effects on the receptor-receptor cross talk. CONCLUSION: Our study sheds light on the understanding of the mechanisms of action of EGFR-TKinhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.

  7. Impact of [{sup 11}C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

    Energy Technology Data Exchange (ETDEWEB)

    Matsuo, Masayuki, E-mail: matsuo@kizawa-memorial-hospital.jp [Department of Radiation Oncology, Kizawa Memorial Hospital, Minokamo (Japan); Miwa, Kazuhiro [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Tanaka, Osamu [Department of Radiation Oncology, Kizawa Memorial Hospital, Minokamo (Japan); Shinoda, Jun [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Nishibori, Hironori; Tsuge, Yusuke [Department of Radiology, Kizawa Memorial Hospital, Minokamo (Japan); Yano, Hirohito; Iwama, Toru [Department of Neurosurgery, Gifu University School of Medicine, Gifu (Japan); Hayashi, Shinya; Hoshi, Hiroaki [Department of Radiology, Gifu University School of Medicine, Gifu (Japan); Yamada, Jitsuhiro [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Kanematsu, Masayuki [Department of Radiology, Gifu University School of Medicine, Gifu (Japan); Aoyama, Hidefumi [Department of Radiology, Niigata University School of Medicine, Niigata (Japan)

    2012-01-01

    Purpose: The purpose of this work was to define the optimal margins for gadolinium-enhanced T{sub 1}-weighted magnetic resonance imaging (Gd-MRI) and T{sub 2}-weighted MRI (T{sub 2}-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([{sup 11}C]MET-PET) findings. Methods and Materials: Computed tomography (CT), MRI, and [{sup 11}C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T{sub 2}-MRI of the CTV (CTV-T{sub 2}) were compared with the extent of [{sup 11}C]MET-PET (CTV--[{sup 11}C]MET-PET) uptake by using CT--MRI or CT--[{sup 11}C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T{sub 2} (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T{sub 2}, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [{sup 11}C]MET-PET and the relationship between CTV-T{sub 2} (x mm) and CTV-- [{sup 11}C]MET-PET. Results: The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T{sub 2} (20 mm) (96.4%) was significantly higher than that of the other CTV-T{sub 2} (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T{sub 2} (x = 20 mm). Conclusions: It is necessary to use a margin of at least 2 cm for CTV-T{sub 2} for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T{sub 2}-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

  8. {sup 18}F fluoroethylations: different strategies for the rapid translation of {sup 11}C-methylated radiotracers

    Energy Technology Data Exchange (ETDEWEB)

    Wadsak, Wolfgang [Department of Nuclear Medicine, Medical University of Vienna, Vienna A-1090 (Austria); Department of Inorganic Chemistry, University of Vienna, Vienna A-1090 (Austria); Mien, Leonhard-Key [Department of Nuclear Medicine, Medical University of Vienna, Vienna A-1090 (Austria); Department of Psychiatry, Medical University of Vienna, Vienna A-1090 (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna A-1090 (Austria); Ettlinger, Dagmar E.; Eidherr, Harald; Haeusler, Daniela; Sindelar, Karoline-Maria [Department of Nuclear Medicine, Medical University of Vienna, Vienna A-1090 (Austria); Keppler, Bernhard K. [Department of Inorganic Chemistry, University of Vienna, Vienna A-1090 (Austria); Dudczak, Robert; Kletter, Kurt [Department of Nuclear Medicine, Medical University of Vienna, Vienna A-1090 (Austria); Mitterhauser, Markus [Department of Nuclear Medicine, Medical University of Vienna, Vienna A-1090 (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna A-1090 (Austria); Hospital Pharmacy, General Hospital of Vienna, Vienna A-1090 (Austria)], E-mail: markus.mitterhauser@meduniwien.ac.at

    2007-11-15

    Introduction: The translation of {sup 11}C-labeled compounds into their respective {sup 18}F-labeled derivatives is an important tool in the rapid development of positron emission tomography (PET) tracers. Thus, our aim was the development of a general method for the preparation of {sup 18}F-fluoroethylated compounds that (a) is applicable to a variety of precursors, (b) can be performed in a fully automated commercially available synthesizer and (c) enables this rapid translation of {sup 11}C-methylated tracers into their {sup 18}F-fluoroethylated analogs sharing the same precursor molecules. Methods: Ten methods for the preparation and purification of different {sup 18}F-fluoroethylating agents were compared. Subsequently, five {sup 18}F-labeled PET tracers were synthesized under fully automated conditions. Results: Radiochemical yields ranged from 34.4% to 60.8%, and time consumption ranged from 20 to 55 min for all methods. Use of 1-bromo-2-[{sup 18}F]fluoroethane and distillation evinced as the method of choice. Conclusions: We were able to develop a general method for the preparation of a variety of {sup 18}F-fluoroethylated molecules. The provided tool is solely based on commercially available resources and has the potential to simplify and accelerate innovative PET tracer development in the future.

  9. First studies of the (8)B(alpha,p)(11)C reaction

    NARCIS (Netherlands)

    Rehm, KE; Jiang, CL; Greene, JP; Henderson, D; Janssens, RVF; Moore, EF; Mukherjee, G; Pardo, RC; Pennington, T; Schiffer, JP; Sinha, S; Tang, XD; Siemssen, RH; Jisonna, L; Segel, RE; Wuosmaa, AH

    2004-01-01

    The (8)B(alpha,p)(11)C reaction is part of the network that can bypass the triple a process leading to the production of (12)C. We have measured the astrophysical reaction rate for this reaction by studying the inverse (11)C(p,alpha)(8)B process. The radioactive (11)C beam was produced via the p((11

  10. The progress in clinical application of11 C-PIB PET%11C-PIB PET显像临床应用进展

    Institute of Scientific and Technical Information of China (English)

    华逢春

    2010-01-01

    @@ [N-甲基-11C]2-[41-(甲氨基)苯基]6-羟基苯并噻唑(IN-methyl-11C]2-(41-methylamino-pheny1)-6-hydroxybenzothiazole),即11C-6-OH-BTA-1(11C-PIB,俗称匹茨堡化合物B),属于硫磺素衍生物类,可与淀粉样蛋白特异性结合的分子探针,已成为阿尔茨海默病(Alzheimer diseas,AD)研究的热点,并向其他类疾病的鉴别诊断发展,本文就11C-PIB在不同人群和疾病中的分布及其临床应用前景作一综述.

  11. Characterisation of [11C]PR04.MZ in Papio anubis baboon: A selective high-affinity radioligand for quantitative imaging of the dopamine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Riss P. J.; Fowler J.; Riss, P.J.; Hooker, J.M.; Shea, C.; Xu, Y.; Carter, P.; Warner, D.; Ferrari V.; Kim, S.W.; Aigbirhio, F.I.; Fowler, J.S.; Roesch, F.

    2011-10-25

    N-(4-fluorobut-2-yn-1-yl)-2{beta}-carbomethoxy-3{beta}-(4{prime}-tolyl)nortropane (PR04.MZ, 1) is a PET radioligand for the non-invasive exploration of the function of the cerebral dopamine transporter (DAT). A reliable automated process for routine production of the carbon-11 labelled analogue [{sup 11}C]PR04.MZ ([{sup 11}C]-1) has been developed using GMP compliant equipment. An adult female Papioanubis baboon was studied using a test-retest protocol with [{sup 11}C]-1 in order to assess test-retest reliability, metabolism and CNS distribution profile of the tracer in non-human primates. Blood sampling was performed throughout the studies for determination of the free fraction in plasma (fP), plasma input functions and metabolic degradation of the radiotracer [{sup 11}C]-1. Time-activity curves were derived for the putamen, the caudate nucleus, the ventral striatum, the midbrain and the cerebellum. Distribution volumes (VT) and non-displaceable binding potentials (BPND) for various brain regions and the blood were obtained from kinetic modelling. [{sup 11}C]-1 shows promising results as aselective marker of the presynaptic dopamine transporter. With the reliable visualisation of the extra-striatal dopaminergic neurons and no indication on labelled metabolites, the tracer provides excellent potential for translation into man.

  12. Radiosynthesis and in vivo evaluation of N-[{sup 11}C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sekimata, Katsuhiko [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan); Hatano, Kentaro [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan)], E-mail: hatanok@nils.go.jp; Ogawa, Mikako [Photon Medical Research Center, Hamamatsu University School of Medicine, Shizuoka 431-3192 Japan (Japan); Abe, Junichiro [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu University School of Medicine, Shizuoka 431-3192 Japan (Japan); Biggio, Giovanni; Serra, Mariangela [Department of Experimental Biology, University of Cagliari, Cagliari 09100 (Italy); Laquintana, Valentino; Denora, Nunzio; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano [Pharmaco-Chemistry Department, University of Bari, Bari 70125 (Italy); Ito, Kengo [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan)

    2008-04-15

    Imidazopyridineacetoamide 5-8, a series of novel and potentially selective peripheral benzodiazepine receptor (PBR) ligands with affinities comparable to those of known PBR ligands, was investigated. Radiosyntheses of [{sup 11}C]5, 6, 7 or 8 was accomplished by N-methylation of the corresponding desmethyl precursors with [{sup 11}C]methyl iodide in the presence of NaH in dimethylformamide (DMF), resulting in 25% to 77% radiochemical yield and specific activitiy of 20 to 150 MBq/nmol. Each of the labeled compounds was injected in ddY mice, and the radioactivity and weight of dissected peripheral organs and brain regions were measured. Organ distribution of [{sup 11}C]7 was consistent with the known PBR distribution. Moreover, [{sup 11}C]7 showed the best combination of brain uptake and PBR binding, leading to its high retention in the olfactory bulb and cerebellum, areas where PBR density is high in mouse brain. Coinjection of PK11195 or unlabeled 7 significantly reduced the brain uptake of [{sup 11}C]7. These results suggest that [{sup 11}C]7 could be a useful radioligand for positron emission tomography imaging of PBRs.

  13. A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions.

    Science.gov (United States)

    Lingford-Hughes, Anne; Reid, Alastair G; Myers, James; Feeney, Adrian; Hammers, Alexander; Taylor, Lindsay G; Rosso, Lula; Turkheimer, Federico; Brooks, David J; Grasby, Paul; Nutt, David J

    2012-02-01

    Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [(11)C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [(11)C]Ro15 4513 PET scan. We report [(11)C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [(11)C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [(11)C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.

  14. PET-Guided Surgery - High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours.

    Science.gov (United States)

    Orlefors, Håkan; Sundin, Anders; Eriksson, Barbro; Skogseid, Britt; Oberg, Kjell; Akerström, Göran; Hellman, Per

    2012-02-08

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

  15. PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours

    Science.gov (United States)

    Örlefors, Håkan; Sundin, Anders; Eriksson, Barbro; Skogseid, Britt; Öberg, Kjell; Åkerström, Göran; Hellman, Per

    2012-01-01

    Positron emission tomography (PET) with 11C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower. PMID:24213229

  16. Synthesis and evaluation of [11C]Cimbi-806 as a potential PET ligand for 5-HT7 receptor imaging

    DEFF Research Database (Denmark)

    Herth, Matthias Manfred; Hansen, Hanne Demant; Ettrup, Anders Janusz;

    2012-01-01

    2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl......)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300 GBq......L/cm(3) in the cerebellum to 12 mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence...

  17. PET-Guided Surgery — High Correlation between Positron Emission Tomography with 11C-5-Hydroxytryptophane (5-HTP and Surgical Findings in Abdominal Neuroendocrine Tumours

    Directory of Open Access Journals (Sweden)

    Barbro Eriksson

    2012-02-01

    Full Text Available Positron emission tomography (PET with 11C-labeled 5-hydroxytryptophane (5-HTP is a sensitive technique to visualize neuroendocrine tumours (NETs, due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent 11C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. 11C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients 11C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by 11C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that 11C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

  18. Characterization of a radioactive {sup 11}C beam by means of the associated particle technique

    Energy Technology Data Exchange (ETDEWEB)

    Varela, A.; Policroniades, R.; Murillo, G.; Moreno, E. [ININ, Laboratorio del Acelerador Tandem, Carretera Mexico-Toluca s/n, Ocoyoacac 52750, Estado de Mexico (Mexico); Huerta, A.; Chavez, E.; Ortiz, M. E.; Barron, L.; Curiel, Q. [UNAM, Instituto de Fisica, Circuito Exterior, Ciudad Universitaria, 04510 Mexico D. F. (Mexico); Aguilar, C.; Coello, E. A.; Juarez, M. A.; Martinez, J. N. [UNAM, Facultad de Ciencias, Circuito Exterior, Ciudad Universitaria, 04510 Mexico D. F. (Mexico)

    2010-02-15

    This paper describes the results obtained for the production and characterization of a radioactive {sup 11}C beam, by means of the in flight technique and the tandem laboratory of the National Institute of Nuclear Research, Mexico. The {sup 11}C production technique described here, uses the well known associated particle technique with the reaction {sup 2}H({sup 10}B, {sup 11}C)n, in order to obtain a bi univocal correspondence between the radioactive {sup 11}C particles and the associated neutrons. A discussion concerning the possible use of this {sup 11}C beam in the study of the elastic scattering of protons is introduced. (Author)

  19. Potential of [{sup 11}C]DASB for measuring endogenous serotonin with PET: binding studies

    Energy Technology Data Exchange (ETDEWEB)

    Lundquist, Pinelopi [Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, SE-751 24 Uppsala (Sweden) and Hospital Pharmacy, University Hospital, SE-751 85 Uppsala (Sweden)]. E-mail: pinelopi.lundquist@farmbio.uu.se; Wilking, Helena [Uppsala Imanet, SE-751 09 Uppsala (Sweden); Hoeglund, A. Urban [Uppsala Imanet, SE-751 09 Uppsala (Sweden); Sandell, Johan [Uppsala Imanet, SE-751 09 Uppsala (Sweden); Bergstroem, Mats [Uppsala Imanet, SE-751 09 Uppsala (Sweden); Hartvig, Per [Hospital Pharmacy, University Hospital, SE-751 85 Uppsala (Sweden); Langstroem, Bengt [Uppsala Imanet, SE-751 09 Uppsala (Sweden)

    2005-02-01

    The serotonin transporter radioligand [{sup 11}C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [{sup 11}C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [{sup 11}C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [{sup 11}C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [{sup 11}C]DASB for transporter binding.

  20. Optimisation of [11C]Raclopride production using a Synthra GPextent system.

    Science.gov (United States)

    Perkins, Gary; Sheth, Rajeev; Greguric, Ivan; Pascali, Giancarlo

    2014-01-01

    The dopamine D2 receptor radiotracer [(11)C]Raclopride is used extensively in clinical and preclinical imaging. Currently, a wide range of methods to produce [(11)C]Raclopride have been developed using traditional vessel reactions as well as cartridge or captive solvent. This work reports the optimisation of the production of [(11)C]Raclopride using a Synthra GPextent, comparing various methods. With optimised conditions, we were able to obtain 4±2% (ndc) yield of [(11)C]Raclopride (100 GBq [(11)C]CO2, n = 42) in 25 min. The radiochemical purity was >95% with specific activities of 135±41 MBq/nmol at end of synthesis.

  1. Synthesis of L-[{beta}-{sup 11}C]amino acids using immobilized enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Ikemoto, M.; Yada, T. [Ikeda Food Research Corporation, Minooki-cho, Fukuyama-shi, Hiroshima (Japan); Sasaki, M. [Sumitomo Heavy Industries, Kitashinagawa, Shinagawa-ku, Tokyo (Japan); Haradahira, T. [Division of Advanced Technology for Medical Imaging, National Institute of Radiological Sciences, Chiba (Japan); Omura, H.; Furuya, Y.; Watanabe, Y.; Suzuki, K. [Subfemtomole Biorecognition Project, Japan Science and Technology Corporation, Osaka (Japan)

    1999-04-01

    L-[{beta}-{sup 11}C]-3,4-dihydroxyphenylalanine(L-[{beta}-{sup 11}C]DOPA) and L-[{beta}-{sup 11}C]-5-hydroxytryptophan(L-[{beta}-{sup 11}C]-5-HTP) were synthesized in one step with immobilized thermostable enzymes (alanine racemase, D-amino acid oxidase, and {beta}-tyrosinase or tryptophanase) on an aminopropyl-CPG carrier in a single column and by passing D,L-[3-{sup 11}C]alanine through the column with coenzymes and other substrates. L-[{beta}-{sup 11}C]DOPA and L-[{beta}-{sup 11}C]-5-HTP could be obtained at yields of 53% and 60%, respectively, by optimizing the amounts and the ratios of the enzymes used, the reaction temperature, the pH, and the flow rate. Moreover, the same immobilized enzyme column could be used repeatedly.

  2. In vivo evaluation of [{sup 11}C]-3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole- 2-carboxylic acid ([{sup 11}C]3MPICA) as a PET radiotracer for the glycine site of the NMDA ion channel

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. E-mail: rnw7@columbia.edu; Sultana, Abida; Laruelle, M

    2002-11-01

    Alterations in normal NMDA receptor composition, densities and function have been implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. In our first effort to provide PET ligands for the NMDA/glycine site, we reported the synthesis of a novel high affinity glycine site ligand, 3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2 -carboxylic acid ((3MPICA), Ki=4.8{+-}0.9 nM) and the corresponding carbon-11 labeled PET ligand, [{sup 11}C]3MPICA. We report here the in vivo evaluation of [{sup 11}C]3MPICA in rats. Biodistribution analysis revealed that [{sup 11}C]3MPICA exhibited low degree of brain penetration and high blood concentration. The average uptake at two minutes was highest in the cerebellum (0.19{+-}0.04 %ID/g) and thalamus (0.18{+-}0.05 %ID/g) and lower in the hippocampus (0.13{+-}0.03) and frontal cortex (0.11{+-}0.04 %ID/g). The radioactivity cleared quickly from all brain regions examined. Administration of unlabeled 3MPICA (1 mg/kg, i.v.) revealed at 60 minutes a small general reduction in regional brain radioactivity concentrations in treated animals versus controls, however, the blood radioactivity concentration was also lowered, confounding the assessment of the degree of saturable binding. Warfarin co-administration (100 mg/kg, i.v.) significantly lowered blood activity at 5 minutes post-injection (-27%, P<0.01) but failed to significantly increase the brain uptake of the radiotracer. In view of these results, and especially considering the low brain penetration of this tracer, [{sup 11}C]3MPICA does not appear to be a promising PET radiotracer for in vivo use.

  3. Evaluation of (+)-p-[{sup 11}C]methylvesamicol for mapping sigma{sub 1} receptors: a comparison with [{sup 11}C]SA4503

    Energy Technology Data Exchange (ETDEWEB)

    Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan)]. E-mail: ishiwata@pet.tmig.or.jp; Kawamura, Kazunori [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan); SHI Accelerator Service Ltd., Tokyo 141-0032 (Japan); Yajima, Kazuyoshi [The Medical and Pharmacological Research Center Foundation, Hakui 920-0631 (Japan); QingGeLeTu [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan); Mori, Hirofumi [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan); Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan)

    2006-05-15

    Vesamicol is a leading compound for positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers for mapping the vesicular acetylcholine transporter (VAChT). Recently, we found that (+)-p-methylvesamicol ((+)-PMV) has low affinity for VAChT (K {sub i}=199 nM), but has moderate to high affinity for sigma receptors: K {sub i}=3.0 nM for sigma{sub 1} and K {sub i}=40.7 nM for sigma{sub 2}, and that sigma{sub 1}-selective SA4503 (K {sub i}=4.4 nM for sigma{sub 1} and K {sub i}=242 nM for sigma{sub 2}) has moderate affinity for VAChT (K {sub i}=50.2 nM). In the present study, we examined the potential of (+)-[{sup 11}C]PMV as a PET radioligand for mapping sigma{sub 1} receptors as compared with [{sup 11}C]SA4503. In rat brain, similar regional distribution patterns of (+)-[{sup 11}C]PMV and [{sup 11}C]SA4503 were shown by tissue dissection and by ex vivo autoradiography. Blocking experiments using ({+-})-PMV (-)-vesamicol, SA4503, haloperidol and ({+-})-pentazocine showed that the two tracers specifically bound to sigma{sub 1} receptors, and that [{sup 11}C]SA4503 exhibited greater specific binding than (+)-[{sup 11}C]PMV. No sign of VAChT-specific binding by [{sup 11}C]SA4503 was observed in the striatum, which is rich in VAChT sites. In conclusion, (+)-[{sup 11}C]PMV specifically bound to sigma{sub 1} receptors in the brain, but to a lesser extent than [{sup 11}C]SA4503, suggesting that (+)-[{sup 11}C]PMV is a less preferable PET ligand than [{sup 11}C]SA4503. On the other hand, the moderate affinity of [{sup 11}C]SA4503 for VAChT is negligible in vivo.

  4. Do androgens control the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in human prostate cancer cell lines?

    Energy Technology Data Exchange (ETDEWEB)

    Emonds, Kimy M.; Nuyts, Johan; Mortelmans, Luc [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Swinnen, Johannes V.; Vanderhoydonc, Frank [K.U. Leuven, Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Leuven (Belgium); Weerden, Wytske M. van [Erasmus University Rotterdam, Department of Experimental Urology, Josephine Nefkens Institute, Rotterdam (Netherlands); Mottaghy, Felix M. [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Maastricht University Medical Center, Department of Nuclear Medicine, Maastricht (Netherlands)

    2011-10-15

    The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines - reflecting different stages of the disease - on {sup 18}F-fluorodeoxyglucose (FDG), {sup 11}C-choline and {sup 11}C-acetate uptake. Uptake experiments were performed in androgen-sensitive (LNCaP, PC346C) and independent cell lines (22Rv1, PC346DCC, PC-3) as well as in a benign prostatic hyperplasia (BPH-1) cell line. Tracer uptake was assessed under androgen ablation. Results of the cancer cell lines were normalized to those of BPH-1. To evaluate the effect of androgen on the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in PCa cell lines, 10{sup -8}M R1881, 10{sup -10}M R1881, the combination of 10{sup -10}M R1881 plus 10{sup -6}M Casodex or 10{sup -6}M Casodex alone were added in parallel cell cultures 1 day before uptake experiments. Uptake in androgen-supplemented cell cultures was compared to the uptake under androgen deprivation. Uptake was corrected for cell number using protein content. Compared to BPH-1, a higher {sup 18}F-FDG uptake was observed only in PC346C cells, whereas a higher {sup 11}C-choline and markedly increased {sup 11}C-acetate uptake was seen in all cancer cell lines. Androgens significantly modulated the uptake of {sup 18}F-FDG in LNCaP, PC346C and 22Rv1 cells, and of {sup 11}C-choline in the PC346C and 22Rv1 cell line. No androgenic effect on {sup 11}C-choline and {sup 18}F-FDG uptake was observed in PC-3 and PC346DCC cells. {sup 11}C-Acetate uptake was independent of androgen status in all PCa cell lines studied. {sup 18}F-FDG uptake in PCa cell lines showed the highest variability and strongest androgen effect, suggesting its poor potential for metabolic imaging of advanced PCa. In contrast to {sup 18}F-FDG and {sup 11}C-choline, {sup 11}C-acetate uptake was unaffected by androgens and thus {sup 11}C-acetate seems best for monitoring PCa progression. (orig.)

  5. Synthesis and biodistribution of [{sup 11}C]procaterol, a {beta}{sub 2}-adrenoceptor agonist for positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Visser, Ton J.; Wouden, Els A. van der; Waarde, Aren van E-mail: a.van.waarde@pet.azg.nl; Doze, Petra; Elsinga, Philip H.; Vaalburg, Willem

    2000-04-01

    The potent, subtype-selective radioligand ({+-})-erythro-5-(1-hydroxy-2-[{sup 11}C]isopropyl-aminobutyl)-8-hydroxycarbostyri= l ([{sup 11}C]procaterol) was synthesized and evaluated for visualization of pulmonary {beta}{sub 2}-adrenoceptors with positron emission tomography (PET). Procaterol was labelled by reductive alkylation of the desisopropyl precursor with [{sup 11}C]acetone under the influence of NaCNBH{sub 3} and acetic acid. Synthesis and HPLC purification were performed in 34 min. Specific activities ranged from 26.5-39.3 TBq (about 700-1000 Ci)/mmol and the radiochemical yield was 2.4-8.6% (corrected for decay). Biodistribution studies were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride ({beta}-adrenoceptor antagonist, 2.5 mg/kg), ICI 118551 ({beta}{sub 2}-adrenoceptor antagonist, 0.15 mg/kg), CGP 20712A ({beta}{sub 1}-adrenoceptor antagonist, 0.15 mg/kg) or isoprenaline ({beta}-adrenoceptor agonist, 15 mg/kg). Specific binding was observed in lungs, spleen and red blood cells, tissues known to contain {beta}{sub 2}-adrenoceptors. Pulmonary binding was blocked by propranolol, ICI 118551 and isoprenaline, but not by CGP 20712A. This binding pattern is consistent with the {beta}{sub 2} selectivity of the adioligand. The clearance of [{sup 11}C]procaterol was biphasic, with a rapid distribution phase (t{sub 1/2} 0.17 min) representing 90% of the injected dose followed by an elimination phase (t{sub 1/2} 18.1 min). About 45% of the plasma radioactivity was unmetabolized procaterol at 15 min postinjection. In a dynamic PET-study, the lungs of untreated control rats could barely be detected and total/non-specific binding ratios rose to only 1.2 at 20 min postinjection. Although labelling and administration of (-) erythro-procaterol, the most active of 4 stereoisomers, may produce better results, [{sup 11}C]procaterol seems unsuitable for {beta}-adrenoceptor imaging.

  6. Radiosynthesis of 11C-meta- (-) Hydroxyephedrine and Micro PET Imaging%11C-(-)间羟基麻黄素的合成及Micro PET显像

    Institute of Scientific and Technical Information of China (English)

    尹大一; 刘健; 张晓军; 徐白萱; 田嘉禾; 张锦明

    2012-01-01

    11C标记(-)间羟基麻黄素(11C-(-)HED,11C-HED)是一种交感神经系统显像剂,可用于心肌和肾上腺肿瘤的显像.碘代甲烷与(-)间羟胺直接甲基化反应,生成11C-HED,经HPLC梯度淋洗纯化;通过动物实验研究在11C-HED中添加前体后对心肌摄取的影响.结果表明,用碘代甲烷作甲基化试剂可减少副反应,分别用含3%乙醇和10%乙醇的0.24 mol/L磷酸二氢钠溶液梯度淋洗,能有效去除前体间羟胺,同时放化纯度从93.2%提高到98%.11 C-HED在动物体内的生物分布表明,注射含2 mg/kg前体间羟胺的11 C-HED后,30 min时心肌摄取明显降低,而肾上腺摄取增高.Micro PET显像证实,注射11C-HED后正常心肌显像,但加入前体后心肌摄取降低,清除加快.以上结果提示,分别用含3%和10%乙醇的0.24 mol/L磷酸二氢钠溶液梯度淋洗可提高产品化学纯度和放化纯度;在11C-HED中加入前体间羟胺后对心肌摄取明显降低,而肾上腺摄取增高.%11C-meta-(-)Hydroxyephedrine(11C-(-) HED, 11C-HED) is a radiotracer suitable for mapping human sympathetic nervous system for heart failure, heart transplantation, arrhythmia and diabetic autonomic neuropathy and imaging tumors of the adrenal marrow. 11C-HED was synthesized by direct N-methylation of metaraminol with the 11C-methy-iodine and purified by semi-preparative reversed-phase HPLC(Semi-HPLC). The uptake of myocardium was studied by co-injection of 11C-(-)HED with metaraminol in mice. The results showed that the by-products can be reduced with 11C-methy-iodine as the N-methylation a-gents. HPLC purification was started with 3% EthOH in 0. 24 moL/L NaH2PO4, and then switched to 10% EthOH in 0. 24 moL/L NaH2PO4 after 10 min, through this process theprecursor was speparated from 11C-HED. Results of biodistribution showed that the uptake of 11C-HED in heard was blocked by co-injection of the metaraminol at 2 mg/kg, but the ID/'o/g of adrenals was increased. Micro PET

  7. Synthesis and PET studies of [11C-cyano]letrozole (Femara®), an aromatase inhibitor drug

    Science.gov (United States)

    Kil, Kun-Eek; Biegon, Anat; Ding, Yu-Shin; Fischer, Andre; Ferrieri, Richard A.; Kim, Sung Won; Pareto, Deborah; Schueller, Michael J.; Fowler, Joanna S.

    2011-01-01

    Introduction Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara®) is a high affinity aromatase inhibitor (Ki=11.5 nM) which has FDA approval for breast cancer treatment. Here we report the synthesis of carbon-11 labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [11C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [11C-cyano]letrozole fraction in the arterial plasma were also measured. Results [11C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79–80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance followed by slow clearance of carbon-11 from the brain with no difference between brain regions. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. Conclusion [11C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [11C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase as revealed by the absence of regional specificity and saturability in brain regions, such as amygdala, which are known to contain

  8. Erlotinib: a new therapeutic approach for non-small cell lung cancer.

    Science.gov (United States)

    Bonomi, Philip

    2003-08-01

    Although treatment with cytotoxic agents has produced modest survival improvement in patients with stage III and IV non-small cell lung cancer (NSCLC), it appears that a plateau has been reached with currently available chemotherapeutic regimens. Increasing knowledge regarding the properties of malignant neoplasms has identified a number of potential therapeutic targets. The epidermal growth factor receptor (EGFR) is one of these targets. Preclinical models have revealed that tumour growth can be inhibited by monoclonal antibodies directed against EGFR and EGFR-specific tyrosine kinase inhibitors. Erlotinib (Tarceva trade mark; OSI Pharmaceuticals, Genentech and Roche), a quinazoline derivative with good oral absorption, is one of several EGFR tyrosine kinases that has been studied in clinical trials. In a Phase I study, mild diarrhoea and mild rash were the most common toxicities. At a dose of 200 mg/day, diarrhoea was the dose-limiting toxicity. The observation that EGFR overexpression is relatively common in NSCLC led to a Phase II trial of erlotinib at the maximum-tolerated dose (150 mg/day) in previously treated NSCLC patients. Erlotinib produced a 12% response rate and there was no apparent relationship between response and tumour EGFR levels. More recent reports suggest that patients who develop a rash have higher responses. Based on its single agent activity, erlotinib has been evaluated in two Phase III trials which compared erlotinib plus chemotherapy to chemotherapy alone in previously untreated NSCLC patients. Erlotinib has also been compared to placebo in a Phase III trial which was limited to advanced stage NSCLC patients whose disease had progressed after two previous chemotherapy regimens. The optimum use of erlotinib in NSCLC will be determined by the results of the completed and future Phase III trials.

  9. Synthesis and preclinical evaluation of [{sup 11}C]PAQ as a PET imaging tracer for VEGFR-2

    Energy Technology Data Exchange (ETDEWEB)

    Samen, Erik; Stone-Elander, Sharon [Karolinska University Hospital Solna, Karolinska Pharmacy, Stockholm (Sweden); Karolinska Institutet, Clinical Neurosciences, Stockholm (Sweden); Thorell, Jan-Olov [Karolinska University Hospital Solna, Karolinska Pharmacy, Stockholm (Sweden); Lu, Li [Karolinska Institutet, Clinical Neurosciences, Stockholm (Sweden); Tegnebratt, Tetyana; Holmgren, Lars [Karolinska Institutet, Cancer Center Karolinska, Oncology-Pathology, Stockholm (Sweden)

    2009-08-15

    (R,S)-N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolinamine (PAQ) is a tyrosine kinase inhibitor with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR-2), which plays an important role in tumour angiogenesis. The aim of this work was to develop and evaluate in mice the {sup 11}C-labelled analogue as an in vivo tracer for VEGFR-2 expression in solid tumours. [{sup 11}C]PAQ was synthesized by an N-methylation of desmethyl-PAQ using [{sup 11}C]methyl iodide. The tracer's pharmacokinetic properties and its distribution in both subcutaneous and intraperitoneal tumour models were evaluated with positron emission tomography (PET). [{sup 18}F]FDG was used as a reference tracer for tumour growth. PET results were corroborated by ex vivo and in vitro phosphor imaging and immunohistochemical analyses. In vitro assays and PET in healthy animals revealed low tracer metabolism, limited excretion over 60 min and a saturable and irreversible binding. Radiotracer uptake in subcutaneous tumour masses was low, while focal areas of high uptake (up to 8% ID/g) were observed in regions connecting the tumour to the host. Uptake was similarly high but more distributed in tumours growing within the peritoneum. The pattern of radiotracer uptake was generally different from that of the metabolic tracer [{sup 18}F]FDG and correlated well with variations in VEGFR-2 expression determined ex vivo by immunohistochemical analysis. These results suggest that [{sup 11}C]PAQ has potential as a noninvasive PET tracer for in vivo imaging of VEGFR-2 expression in angiogenic ''hot spots''. (orig.)

  10. [{sup 11}C]diclofenac sodium: synthesis and PET assessment of transdermal penetration

    Energy Technology Data Exchange (ETDEWEB)

    Petroni, Debora, E-mail: debora.petroni@ifc.cnr.i [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy); Menichetti, Luca; Sorace, Oreste; Poli, Michela [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy); Vanasia, Massimo [Gienne Pharma, Via Lorenteggio 270/A, 20152 Milan (Italy); Salvadori, Piero A. [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy)

    2011-02-15

    The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. {sup 11}C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.

  11. Erlotinib dosing-to-rash: A phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer

    NARCIS (Netherlands)

    A. mita (Alain); K. Papadopoulos (K.); M.J.A. de Jonge (Maja); G. Schwartz (G.); J. Verweij (Jaap); A. Ricart (A.); Q.S.C. Chu (Q. S C); A.W. Tolcher (A. W.); L. Wood (Lori); S.W. McCarthy (Stanley); M. Hamilton; K.K. Iwata (Kenneth); B. Wacker; K. de Witte (Karel); E.K. Rowinsky (Eric Keith)

    2011-01-01

    textabstractBackground: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacok

  12. Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), β-amyloid PET imaging tracer for Alzheimer's disease diagnosis.

    Science.gov (United States)

    Coliva, A; Monterisi, C; Apollaro, A; Gatti, D; Penso, M; Gianolli, L; Perani, D; Gilardi, M C; Carpinelli, A

    2015-11-01

    [11C]PIB is the most used amyloid plaques-specific positron-emitting radiotracers. The radiosynthesis of this compound, carried out by methylation of its precursor with [11C]methyl triflate in 2-butanone, has been improved optimizing the initial concentration and the purification method. Two HPLC methods were compared: good radiochemical yields, specific activities, and chemical purity above 98% were achieved by using as eluant acetonitrile/citrate and formulation in 10% ethanol.

  13. Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

    Science.gov (United States)

    Collier, Thomas Lee; Normandin, Marc D.; Stephenson, Nickeisha A.; Livni, Eli; Liang, Steven H.; Wooten, Dustin W.; Esfahani, Shadi A.; Stabin, Michael G.; Mahmood, Umar; Chen, Jianqing; Wang, Wei; Maresca, Kevin; Waterhouse, Rikki N.; El Fakhri, Georges; Richardson, Paul; Vasdev, Neil

    2017-06-01

    Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

  14. [{sup 18}F]{beta}-CIT-FP is superior to [{sup 11}C]{beta}-CIT-FP for quantitation of the dopamine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Lundkvist, Camilla; Halldin, Christer; Ginovart, Nathalie; Swahn, Carl-Gunnar; Farde, Lars

    1997-10-01

    {beta}-CIT-FP [N-(3-fluoropropyl)-2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)nortropane] is a cocaine analogue with high affinity for the dopamine transporter. Positron emission tomography (PET) studies with [O-methyl-{sup 11}C]{beta}-CIT-FP ([{sup 11}C]{beta}-CIT-FP) has shown that equilibrium conditions were approached but, however, not reached at the end of measurement. Moreover, metabolite studies of [{sup 11}C]{beta}-CIT-FP in monkey plasma demonstrated a lipophilic-labelled metabolite that may enter the brain. We therefore labelled {beta}-CIT-FP with fluorine-18 in a position that may avoid the formation of labelled lipophilic metabolites. The more long-lived radionuclide ({sup 18}F) was used to allow for measurements over longer time. [N-fluoropropyl-{sup 18}F]{beta}-CIT-FP ([{sup 18}F]{beta}-CIT-FP) was prepared by N-alkylation of nor-{beta}-CIT with [{sup 18}F]fluoropropyl bromide. PET studies were performed in cynomolgus monkeys. [{sup 18}F]{beta}-CIT-FP entered the brain rapidly. There was a high concentration of radioactivity in the striatum and much lower in the thalamus, neocortex, and cerebellum. The striatum-to-cerebellum ratio was about 5 at time of transient equilibrium, which occurred after 60 to 100 min. After pretreatment with GBR 12909, radioactivity in the striatum was markedly reduced, thus indicating specific [{sup 18}F]{beta}-CIT-FP binding to the dopamine transporter. The fraction of unchanged [{sup 18}F]{beta}-CIT-FP determined by HPLC was 10-15% after 140 min. No lipophilic labelled metabolites were detected. The absence of measurable lipophilic labelled metabolites and the occurrence of transient equilibrium within the time of the PET measurement indicate that [{sup 18}F]{beta}-CIT-FP is superior to [{sup 11}C]{beta}-CIT-FP as a PET radioligand for quantification of the dopamine transporter in the human brain.

  15. Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

    Institute of Scientific and Technical Information of China (English)

    Pei-pei DONG; Chang-xiao LIU; Ling YANG; Zhong-ze FANG; Yan-yan ZHANG; Guang-bo GE; Yu-xi MAO; Liang-liang ZHU; Yan-qing QU; Wei Li; Li-ming WANG

    2011-01-01

    Aim: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo.Methods:The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.Results: The activity of CYP2C8 was inhibited with an IC50 value of 6.17±2.0μmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substratedependent: the IC50 values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K1 and k1nack were 6.3μmol/L and 0.035 min-1 for midazolam; 9.0μmol/L and 0.045 min-1 for testosterone; and 10.1μmol/L and 0.058 min-1 for nifedipine.Conclusion: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrateindependent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.

  16. Bevacizumab and erlotinib: a promising new approach to the treatment of advanced NSCLC.

    Science.gov (United States)

    Herbst, Roy S; Sandler, Alan

    2008-11-01

    Biologic agents that target molecules involved in tumor growth, progression, and pathological angiogenesis--such as the human epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)--have demonstrated efficacy in patients with non-small cell lung cancer (NSCLC). Erlotinib (Tarceva); OSI Pharmaceuticals, Inc., Melville, NY, Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a highly selective tyrosine kinase inhibitor that inhibits EGFR, and bevacizumab (Avastin); Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a VEGF-targeted recombinant humanized monoclonal antibody, have displayed very encouraging activity in a randomized phase II trial in patients with previously treated NSCLC. Because erlotinib and bevacizumab act on two different pathways critical to tumor growth and dissemination, administering these drugs concomitantly may confer additional clinical benefits to cancer patients with advanced disease, by virtue of their complementary (or additive) antitumor activity. The combination of bevacizumab plus erlotinib may prove to be a viable second-line alternative to chemotherapy or erlotinib monotherapy in patients with NSCLC. The benefits of the combination may be further enhanced by selecting for patients who are likely to respond to this therapy. While a number of potential predictive markers have been identified for erlotinib, their value remains to be confirmed in prospective trials. In addition, the application of such personalized therapy will also depend on the availability of validated screening methods.

  17. Clinical Observation of Erlotinib in the Treatment of Advanced Non-small Cell Lung Cancer: A Report of 92 Eases

    Directory of Open Access Journals (Sweden)

    Baohui HAN

    2009-12-01

    Full Text Available Background and objective Erlotinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved effective in local advanced or metastatic non-small cell lung cancer (NSCLC. The aim of this study was to evaluate the efficacy and safety of erlotinib for the treatment of advanced NSCLC. Methods Ninety-two patients with advanced NSCLC who had failed or not tolerated or refused chemotherapy received 150 mg oral doses of erlotinib once daily until the disease progression or intolerable toxicity. Results Among the 92 NSCLC patients, 2 patient got complete response (2.2%, 22 partial response (23.9%, 48 stable disease (52.2% and 20 progressive disease (21.7%. The overall response rate and the disease controlled rate of erlotinib was 26.1% (24/92 and 78.3% (72/92, respectively. The response rate of erlotinib were significantly higher in rash and ECOG 0-1 than no rash and ECOG ≥ 2. The disease controlled rate of erlotinib was significantly higher in female and non-smokers than male and smokers (P < 0.05. The response rate of erlotinib did not show significant differences within pathological type or previous treatment. The most common side effects were rash and diarrhea with 84.8% and 31.5%, respectively, but usually were mild. Conclusion Erlotinib is effective and safe in the treatment of advanced NSCLC patients.

  18. The potential of (-)-o-[11C]methylvesamicol for diagnosing cholinergic deficit dementia.

    Science.gov (United States)

    Shiba, Kazuhiro; Nishiyama, Shingo; Tsukada, Hideo; Ishiwata, Kiichi; Kawamura, Kazunori; Ogawa, Kazuma; Mori, Hirofumi

    2009-02-01

    (-)-o-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for a vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM), and (-)-o-[(11)C]methylvesamicol [(-)-[(11)C]OMV] exhibited appropriate kinetics and bound mainly to VAChTs in the rat brain. In this study, the in vivo distribution and kinetics of (-)-[(11)C]OMV were evaluated in comparison with [(11)C]SA4503 in disability model monkeys produced by selectively destroying the p75NTR-positive cells in the right hemisphere of the brain using positron emission tomography. Time-activity curves of (-)-[(11)C]OMV showed peaks within 20 min in regions rich in acetylcholine transporters (AchT). (-)-[(11)C]OMV binding in the ipsilateral cortex to the lesion was significantly reduced by 22.0% +/- 6.7% when compared with that in the contralateral region. The decrease (19.3% +/- 2.2%) in (-)-[(11)C]OMV binding in the ipsilateral temporal cortex to the lesion was greater than that (7.4% +/- 4.6%) of [(11)C]SA4503. These results suggested that (-)-[(11)C]OMV may be useful in the study of dementia characterized by degeneration of the cholinergic neurotransmitter system. 2008 Wiley-Liss, Inc.

  19. Reproducibility of automated simplified voxel-based analysis of PET amyloid ligand [{sup 11}C]PIB uptake using 30-min scanning data

    Energy Technology Data Exchange (ETDEWEB)

    Aalto, Sargo [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Aabo Akademi University, Department of Psychology, Turku (Finland); University of Turku, Turku PET Centre, P.O. Box 52, Turku (Finland); Scheinin, Noora M.; Naagren, Kjell; Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Kemppainen, Nina M. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Department of Neurology, Turku (Finland); Kailajaervi, Marita [University of Turku, Department of Pharmacology and Clinical Research Services Turku (CRST), Turku (Finland); GE Healthcare, Turku Imanet, Turku (Finland); Leinonen, Mika [4-Pharma Ltd, Turku (Finland); Scheinin, Mika [University of Turku, Department of Pharmacology and Clinical Research Services Turku (CRST), Turku (Finland)

    2009-10-15

    Positron emission tomography (PET) with {sup 11}C-labelled Pittsburgh compound B ([{sup 11}C]PIB) enables the quantitation of {beta}-amyloid accumulation in the brain of patients with Alzheimer's disease (AD). Voxel-based image analysis techniques conducted in a standard brain space provide an objective, rapid and fully automated method to analyze [{sup 11}C]PIB PET data. The purpose of this study was to evaluate both region- and voxel-level reproducibility of automated and simplified [{sup 11}C]PIB quantitation when using only 30 min of imaging data. Six AD patients and four healthy controls were scanned twice with an average interval of 6 weeks. To evaluate the feasibility of short scanning (convenient for AD patients), [{sup 11}C]PIB uptake was quantitated using 30 min of imaging data (60 to 90 min after tracer injection) for region-to-cerebellum ratio calculations. To evaluate the reproducibility, a test-retest design was used to derive absolute variability (VAR) estimates and intraclass correlation coefficients at both region-of-interest (ROI) and voxel level. The reproducibility both at the region level (VAR 0.9-5.5%) and at the voxel level (VAR 4.2-6.4%) was good to excellent. Based on the variability estimates obtained, power calculations indicated that 90% power to obtain statistically significant difference can be achieved using a sample size of five subjects per group when a 15% change from baseline (increase or decrease) in [{sup 11}C]PIB accumulation in the frontal cortex is anticipated in one group compared to no change in another group. Our results showed that an automated analysis method based on an efficient scanning protocol provides reproducible results for [{sup 11}C]PIB uptake and appears suitable for PET studies aiming at the quantitation of amyloid accumulation in the brain of AD patients for the evaluation of progression and treatment effects. (orig.)

  20. [{sup 11}C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zessin, Joerg [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)]. E-mail: j.zessin@fz-rossendorf.de; Deuther-Conrad, Winnie [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Kretzschmar, Marion [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Wuest, Frank [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Pawelke, Beate [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany); Brust, Peter [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Steinbach, Joerg [Institut fuer Interdisziplinaere Isotopenforschung, 04318 Leipzig (Germany); Bergmann, Ralf [Institut fuer Bioanorganische und Radiopharmazeutische Chemie, Forschungszentrum Rossendorf, 01314 Dresden (Germany)

    2006-01-15

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (S Me-Adam, 1) is a highly potent and selective inhibitor of the serotonin transporter (SPERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [{sup 11}C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [{sup 11}C]S Me-Adam. The radiochemical yield was 27{+-}5%, and the specific radioactivity was 26-40 GBq/{mu}mol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SPERT, such as the thalamus/hypothalamus region (3.59{+-}0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74{+-}0.95 at 60 min postinjection. The [{sup 11}C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38{+-}11% of the control value. Furthermore, no metabolites of [{sup 11}C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [{sup 11}C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  1. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats.

    Science.gov (United States)

    Zessin, Jörg; Deuther-Conrad, Winnie; Kretzschmar, Marion; Wüst, Frank; Pawelke, Beate; Brust, Peter; Steinbach, Jörg; Bergmann, Ralf

    2006-01-01

    N,N-Dimethyl-2-(2-amino-4-methylthiophenylthio)benzylamine (SMe-ADAM, 1) is a highly potent and selective inhibitor of the serotonin transporter (SERT). This compound was labeled with carbon-11 by methylation of the S-desmethyl precursor 10 with [(11)C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [(11)C]SMe-ADAM. The radiochemical yield was 27 +/- 5%, and the specific radioactivity was 26-40 GBq/micromol at the end of synthesis. Ex vivo and in vivo biodistribution experiments in rats demonstrated a rapid accumulation of the radiotracer in brain regions known to be rich in SERT, such as the thalamus/hypothalamus region (3.59 +/- 0.41%ID/g at 5 min after injection). The specific uptake reached a thalamus to cerebellum ratio of 6.74 +/- 0.95 at 60 min postinjection. The [(11)C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38 +/- 11% of the control value. Furthermore, no metabolites of [(11)C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [(11)C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain.

  2. [{sup 11}C]Choline as pharmacodynamic marker for therapy response assessment in a prostate cancer xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Krause, Bernd J.; Souvatzoglou, Michael; Herrmann, Ken; Weber, Axel W.; Buck, Andreas K.; Wester, Hans-Juergen; Ziegler, Sibylle I.; Senekowitsch-Schmidtke, Reingard; Schwaiger, Markus [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar (Germany); Schuster, Tibor [Technische Universitaet Muenchen, Department of Statistics (Germany); Nawroth, Roman; Treiber, Uwe [Technische Universitaet Muenchen, Department of Urology (Germany); Weirich, Gregor [Technische Universitaet Muenchen, Institute of Pathology (Germany)

    2010-10-15

    ; -1.08{+-}0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M{sub dyn} ratios (mean change 0.085{+-}0.39, p=0.83, after 1 week; 0.31{+-}0.48, p=0.52, after 2 weeks; 0.11{+-}0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy. Our results demonstrate that [{sup 11}C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer. (orig.)

  3. Synthesis and positron emission tomographic (PET) baboon studies of [{sup 11}C]methadone and R-(-)-[{sup 11}C]methandone

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Fowler, J.S.; Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1996-05-01

    Methadone (MET) maintenance has been used successfully for many years in the rehabilitation of heroin addicts. MET, a typical m{mu}-opioid receptor agonist, exists as two enantiomers and is used clinically as the racemic mixture. However, R-(-)-MET has a 10-fold higher affinity for m{mu} receptors than S-(+)-MET (IC{sub 50}: 3.0 nM and 26.4 nM, respectively) and R-(-)-MET is almost entirely responsible for the therapeutic actions of the racemate. In order to examine the pharmacokinetics and stereoselectivity of the drug, we have synthesized both [{sup 11}C]MET and R-(-)-[{sup 11}C]MET. Preparing the precursor by one-step approach to the N-demethylated methadone was precluded as other investigators cited problems with intramolecular cyclization. Therefore, a four-step synthesis using MET (or R-(-)-MET) as starting material was required to obtain the precursor, followed by a two-step radiolabeling synthesis (N-methylation followed by oxidation) to obtain [{sup 11}C]MET (or R-(-)-[{sup 11}C]MET). Comparative PET studies in the same baboon showed peak striatal uptake was 0.022%/cc at 5 minutes with a half time of clearance from peak of 100 minutes for R-(-)-[{sup 11}C]MET and a peak uptake of 0.013%/cc with a half time of 90 min for [{sup 11}C]MET. R-(-)-[{sup 11}C]MET also showed a slower disappearance in plasma. Both tracers showed higher C-11 in basal ganglia (BG), thalamus and midbrain relative to the cerebellum (CB) and occipital cortex (OC) but the BG/OC ratio was higher for R-(-)-[{sup 11}C]MET (1.3 vs 1.1). Pretreatment with naloxone (1 mg/kg, iv) increased R-(-)-[{sup 11}C]MET uptake in all brain regions whereas unlabeled MET slightly increased C-11 clearance in BG, OC and CB. These initial results show higher brain concentration and specificity of the pharmacologically active enantiomer of methadone along with significant non-specific binding.

  4. NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Sobhakumari, Arya [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Pathology, The University of Iowa, Iowa City, IA (United States); Schickling, Brandon M. [Department of Internal Medicine, The University of Iowa, Iowa City, IA (United States); Love-Homan, Laurie; Raeburn, Ayanna [Department of Pathology, The University of Iowa, Iowa City, IA (United States); Fletcher, Elise V.M. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Pathology, The University of Iowa, Iowa City, IA (United States); Case, Adam J. [Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Domann, Frederick E. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Pathology, The University of Iowa, Iowa City, IA (United States); Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics (UIHC), Iowa City, IA (United States); Miller, Francis J. [Department of Internal Medicine, The University of Iowa, Iowa City, IA (United States); Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA (United States); Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics (UIHC), Iowa City, IA (United States); and others

    2013-11-01

    Most head and neck squamous cell carcinomas (HNSCCs) overexpress epidermal growth factor receptor (EGFR) and EGFR inhibitors are routinely used in the treatment of HNSCC. However, many HNSCC tumors do not respond or become refractory to EGFR inhibitors. Autophagy, which is a stress-induced cellular self-degradation process, has been reported to reduce the efficacy of chemotherapy in various disease models. The purpose of this study is to determine if the efficacy of the EGFR inhibitor erlotinib is reduced by activation of autophagy via NOX4-mediated oxidative stress in HNSCC cells. Erlotinib induced the expression of the autophagy marker LC3B-II and autophagosome formation in FaDu and Cal-27 cells. Inhibition of autophagy by chloroquine and knockdown of autophagy pathway genes Beclin-1 and Atg5 sensitized both cell lines to erlotinib-induced cytotoxicity, suggesting that autophagy may serve as a protective mechanism. Treatment with catalase (CAT) and diphenylene iodonium (DPI) in the presence of erlotinib suppressed the increase in LC3B-II expression in FaDu and Cal-27 cells. Erlotinib increased NOX4 mRNA and protein expression by increasing its promoter activity and mRNA stability in FaDu cells. Knockdown of NOX4 using adenoviral siNOX4 partially suppressed erlotinib-induced LC3B-II expression, while overexpression of NOX4 increased expression of LC3B-II. These studies suggest that erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect. - Highlights: • Erlotinib increased LC3B-II and autophagosome formation in HNSCC cells. • Inhibition of autophagy sensitized HNSCC cells to erlotinib. • Erlotinib increased NOX4 promoter and 3′UTR luciferase activity. • Manipulating NOX4 decreases or increases autophagy.

  5. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

    DEFF Research Database (Denmark)

    Ettrup, Anders; Hansen, Martin; Santini, Martin A;

    2011-01-01

    Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer....... In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig...

  6. EGFR CA repeat polymorphism predict clinical outcome in EGFR mutation positive NSCLC patients treated with erlotinib

    DEFF Research Database (Denmark)

    Winther Larsen, Anne; Nissen, Peter Henrik; Meldgaard, Peter;

    2014-01-01

    OBJECTIVES: Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription...... of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib.MATERIALS AND METHODS: Number of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC...... patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA≤16 in any allele) or long alleles (CA>16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based...

  7. Soil pH regulates the abundance and diversity of Group 1.1c Crenarchaeota.

    Science.gov (United States)

    Lehtovirta, Laura E; Prosser, James I; Nicol, Graeme W

    2009-12-01

    Archaeal communities in many acidic forest soil systems are dominated by a distinct crenarchaeal lineage Group 1.1c. In addition, they are found consistently in other acidic soils including grassland pasture, moorland and alpine soils. To determine whether soil pH is a major factor in determining their presence and abundance, Group 1.1c community size and composition were investigated across a pH gradient from 4.5 to 7.5 that has been maintained for > 40 years. The abundances of Group 1.1c Crenarchaeota, total Crenarchaeota and total bacteria were assessed by quantitative PCR (qPCR) targeting 16S rRNA genes and the diversity of Group 1.1c crenarchaeal community was investigated by denaturing gradient gel electrophoresis (DGGE) and phylogenetic analysis. The abundance of Group 1.1c Crenarchaeota declined as the pH increased, whereas total Crenarchaeota and Bacteria showed no clear trend. Community diversity of Group 1.1c Crenarchaeota was also influenced with different DGGE bands dominating at different pH. Group 1.1c Crenarchaeota were also quantified in 13 other soils representing a range of habitats, soil types and pH. These results exhibited the same trend as that shown across the pH gradient with Group 1.1c Crenarchaeota representing a greater proportion of total Crenarchaeota in the most acidic soils.

  8. In vivo visualization of amyloid deposits in the heart with 11C-PIB and PET

    DEFF Research Database (Denmark)

    Antoni, Gunnar; Lubberink, Mark; Estrada, Sergio

    2013-01-01

    UNLABELLED: Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-(11)C]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole ((11)C-PIB) PET is used in the eval......UNLABELLED: Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-(11)C]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole ((11)C-PIB) PET is used...... in the evaluation of brain amyloidosis. We evaluated the potential use of (11)C-PIB PET in systemic amyloidosis affecting the heart. METHODS: Patients (n = 10) diagnosed with systemic amyloidosis-including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type......-and healthy volunteers (n = 5) were investigated with PET/CT using (11)C-PIB to study cardiac amyloid deposits and with (11)C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention. RESULTS: Myocardial (11)C-PIB uptake was visually evident in all...

  9. PET Imaging of CRF1 with [{sup 11}C]R121920 and [{sup 11}C]DMP696: is the target of sufficient density?

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Gregory M. [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States)]. E-mail: gms11@columbia.edu; Parsey, Ramin V. [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Kumar, J.S. Dileep [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Arango, Victoria [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Kassir, Suham A. [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Huang, Yung-yu [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Simpson, Norman R. [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Van Heertum, Ronald L. [Department of Radiology, Columbia University, New York, NY 10032 (United States); Mann, J. John [Division of Neuroscience, Department of Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY 10032 (United States); Department of Radiology, Columbia University, New York, NY 10032 (United States)

    2007-05-15

    Aim: Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [{sup 11}C]R121920 and [{sup 11}C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1. Methods: PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET. Results: Both [{sup 11}C]R121920 and [{sup 11}C]DMP696 distributed rapidly and uniformly throughout the brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [{sup 125}I]Tyr{sup 0}-sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding (B {sub max}) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded B {sub max} of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants (K {sub D}) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore, B {sub max} and K {sub D} were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. Conclusion: Neither [{sup 11}C]R121920 nor [{sup 11}C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

  10. Further characterization of the epidermal growth factor receptor ligand 11C-PD153035

    Institute of Scientific and Technical Information of China (English)

    WANG Hui; YU Jin-ming; YANG Guo-ren; SONG Xian-rang; SUN Xiao-rong; ZHAO Shu-qiang; WANG Xing-wu; ZHAO Wei

    2007-01-01

    Background 11C-4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (11C-PD153035) has been reported as a tracer for imaging human tumors that overexpress epidermal growth factor receptor (EGFR). However it is still unclear whether 11C-PD153035 uptake correlates with EGFR expression levels. The objective of this study was to investigate the relationship between 11C-PD153035 accumulation and EGFR expression levels.Methods Synthesis of 11C-PD153035 was performed in the Tracerlab FXc system. Accumulation of 11C-PD153035 by MDA-MB-468, A549 and MDA-MB-231 cells was measured in vitro. There were six tumor-bearing mice in each group.11C-PD153035 uptake in tumors was determined by positron emission tomography/computed tomography (PET/CT).Tumor/normal muscle tissue (T/NT) analysis in PET images was applied to quantify the PET data. Sixty minutes after PET/CT scanning, the nude mice were sacrificed and the tumors were excised. The 11C-PD153035 accumulation in different tumors was determined by a gamma counter.Results Close correlation existed between the uptake and the level of EGFR expression both in vitro and ex vivo (r2=0.72, P<0.001; r2=0.63, P=0.003). When the static T/NT analysis method was applied to analyze the PET data, the observed correlation was again excellent (r2=0.70, P=0.001).Conclusions The uptake of PET tracer 11C-PD153035 closely correlates with the EGFR expression levels in tumor cells. 11C-PD153035 has the potential to yield useful information for both cancer diagnosis and therapy.

  11. Patterns of 11C-PIB cerebral retention in mild cognitive impairment patients.

    Science.gov (United States)

    Banzo, I; Jiménez-Bonilla, J F; Martínez-Rodríguez, I; Quirce, R; de Arcocha-Torres, M; Bravo-Ferrer, Z; Lavado-Pérez, C; Sánchez-Juan, P; Rodríguez, E; Jiménez-Alonso, M; López-Defilló, J; Carril, J M

    2016-01-01

    To evaluate the patterns of cerebral cortical distribution of (11)C-PIB in patients with mild cognitive impairment (MCI). The study included 69 patients (37 male, age range 42-79 years) with MCI, sub-classified as 53 with amnestic-MCI (A-MCI), and 16 with non-amnestic-MCI (NA-MCI). Patients underwent (11)C-PIB PET/CT scan 60min after intravenous injection of the radiotracer. A visual analysis of the images was performed by 2 experienced physicians. (11)C-PIB-positive studies were considered when gray matter uptake was equal to or greater than white matter. According to the regions involved, (11)C-PIB-positive studies were classified into A-pattern (predominant retention in frontal, anterior cingulate, lateral temporal, and basal ganglia) and B-pattern (generalized retention). Thirty-nine of the 69 (56%) patients with MCI showed (11)C-PIB retention. Of the 53 A-MCI patients, 36 (68%) showed (11)C-PIB retention. Eleven out of 36 (30%) positive scans in A-MCI patients showed A-pattern, and 25 out of 36 (70%) patients had a B-pattern. Positive (11)C-PIB was observed in 3 out of 16 (19%) patients with NA-MCI. Regional distribution in these 3 patients showed A-pattern in 1, and B-pattern in 2 patients. Cortical retention of (11)C-PIB was more frequent in A-MCI than in NA-MCI patients, and also B-pattern than A-pattern in the (11)C-PIB positive group. The recognition of (11)C-PIB distribution patterns allows MCI patients to be classified, and the A-pattern may offer a therapeutic window for potential future treatments. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  12. [11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings.

    Science.gov (United States)

    Hennings, Joakim; Lindhe, Orjan; Bergström, Mats; Långström, Bengt; Sundin, Anders; Hellman, Per

    2006-04-01

    Adrenal incidentalomas are common findings necessitating extensive laboratory work-up and repetitive radiological examinations. Positron emission tomography (PET) using (11)C-labeled metomidate (MTO) has previously been described as a tool for specific adrenocortical imaging. We evaluated 212 MTO-PET examinations in 173 patients to identify its role in the management of adrenal tumors. Seventy-five histopathological examinations from 73 patients were retrospectively analyzed. All examinations were performed at a referral center. Patients who were operated or biopsied due to adrenal tumors had histopathological diagnoses of adrenocortical adenoma (n = 26), adrenocortical cancer (ACC; n = 13), adrenocortical hyperplasia (n = 8), pheochromocytoma (n = 6), metastasis (n = 3), and tumors of nonadrenal origin (n = 19). The main outcome measures were statistical analyses and findings while scrutinizing images. The hypothesis that MTO-PET is of value in the management of adrenal tumors, especially incidentaloma, was stated before data collection. Sensitivity was 0.89 and specificity was 0.96 for MTO-PET in proving adrenocortical origin of the lesions. Pheochromocytomas, metastases to the adrenal gland, and nonadrenal masses were all MTO negative. PET measurements using standardized uptake values (SUV) in pathological adrenocortical tissue could differentiate lesions larger than 1-1.5 cm from normal adrenocortical tissue. SUV was higher in aldosterone-hypersecreting adenomas, and the SUV ratio between the tumor and the contralateral gland was significantly higher in all hormonally hypersecreting adenomas as well as in ACC. MTO-PET is a specific and sensitive method for diagnosing adrenocortical tumors. MTO-PET is useful in the imaging work-up of adrenal incidentalomas and may be beneficial for the examination of patients with primary aldosteronism or ACC.

  13. β淀粉样蛋白PET显像剂11C-DPOD的制备及其在动物体内的分布%Synthesis and Biological Evaluation of 11C-DPOD for PET Imaging Agent of Amyloid-β in Mouse Brain

    Institute of Scientific and Technical Information of China (English)

    王新艳; 张政伟; 蒋雨平; 孔艳艳; 桂媛; 胡名扬; 华逢春; 管一晖

    2013-01-01

    Aim To study the synthesis of 11C-labeled PET amyloid-P (Ap) imaging agent titled DPOD, a new series of 11C-6-OH-BTA-1 derivatives, and biological evaluation of 11C-DPOD for detecting amyloid-P plaques in mouse brain. Methods 11C-triflate-CH3 was bubbled into 2 mg precursor DPOD, which was dissolved in 0.1 mg methyl ethyl ketone, to generate 11C-DPOD in a V-tube at high temperature (about 80℃). The radiolabelled products were purified by HPLC. Then the image of radioactive concentration of transgenic, senile mice and rhesus monkey was made by using PET/CT. All data were analyzed by Stata 10.0 software (P<0.05). Results 11C-DPOD was a kind of colorless transparent liquid with ethyl alcohol about 10%, pH7.0. The radiochemical purity was over 95% and the average radiolabeling yield was from 10% to 15%. 11C-DPOD had the same effect as 11C-PIB in pharmacokinetics of transgenic and senile mice. Conclusion 11C-DPOD radioactivity of brain was synthesized by ourselves and washed out quickly thereafter in both transgenic mice and monkey.%目的 研究脑内β淀粉样蛋白(Aβ)的PET显像剂11C-DPOD即[N-甲基-11C]-3,5-二苯基-1,2,4-苯并噻唑的制备路线和在动物体内的分布情况.方法 使用11C-三氟甲基磺酰甲烷(11C-triflate-CH3)和2 mg自制DPOD前体(溶于0.1 mL丁酮中,摇匀后装于3mL的特制密闭反应瓶中,置-20℃)反应,在80℃水浴中对前体进行甲基化反应并完成11C标记.反应后的液体加入5mL注射用水稀释,过活化的固相C18柱除去杂质,再用乙醇0.5 mL洗脱保留在柱上的产品.经无菌注射水稀释和0.22 μm的微孔无菌滤膜过滤,得到澄清11C-DPOD乙醇水溶液.经尾静脉注射于转基因型阿尔茨海默病(AD)小鼠(AD小鼠)、正常C57老龄小鼠(正常老龄小鼠,作为对照);经肘静脉注射猕猴,进行动态显像.结果 11C-DPOD注射液为无色澄清透明液体(pH 7.0),含10%的乙醇,放射性化学纯度>98%,产率为10%~15%.在AD小鼠和正常

  14. Radiosynthesis and autoradiographic evaluation of [{sup 11}C]NAD-299, a radioligand for visualization of the 5-HT{sub 1A} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Sandell, Johan E-mail: Johan.Sandell@psyk.ks.se; Halldin, Christer; Hall, Haakan; Thorberg, Seth-Olov; Werner, Tom; Sohn, Daniel; Sedvall, Goeran; Farde, Lars

    1999-02-01

    The selective 5-HT{sub 1A} receptor antagonist NAD-299 ([R]-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide) was labeled with the positron emitting radionucldie carbon-11. The radioligand was synthesized from NAD-195 ([R]-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethylsulfonyloxy-3, 4-dihydro-2H-1-benzopyran) in two radiochemical steps. A palladium-catalyzed reaction of NAD-195 and [{sup 11}C]cyanide was followed by hydrolysis of the carbon-11-labeled nitrile intermediate with basic hydrogen peroxide. The total radiochemical yield, based on [{sup 11}C]CO{sub 2} and corrected for decay, was 20-40%. The specific radioactivity was 24 GBq/{mu}mol (900 Ci/mmol) at end of synthesis, with a radiochemical purity better than 99% and a total synthesis time of 40-45 min. Autoradiographic examination of [{sup 11}C]NAD-299 binding in human brain postmortem demonstrated high binding in hippocampus, raphe nuclei, and neocortex. The binding in the hippocampus was higher than in the neocortex. Within the hippocampus, the densest binding was observed in the CA1 region. [{sup 11}C]NAD-299 binding was inhibited by addition of the 5-HT{sub 1A} receptor ligands WAY-100635, pindolol, ({+-})-8-OH-DPAT, 5-HT, and buspirone, leaving a low background of nonspecific binding. The results indicate that [{sup 11}C]NAD-299 binds specifically to 5-HT{sub 1A} receptors in the human brain in vitro and is a potential radioligand for positron emission tomography (PET) examination of 5-HT{sub 1A} receptors in vivo.

  15. Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.

    Science.gov (United States)

    Zhang, Liang; Huang, Yi; Zhuo, Wenlei; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2016-01-01

    Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.

  16. Optimization of the radiosynthesis of the Alzheimer tracer 2-(4-N-[{sup 11}C]methylaminophenyl)-6-hydroxybenzothiazole ([{sup 11}C]PIB)

    Energy Technology Data Exchange (ETDEWEB)

    Philippe, C. [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna (Austria); Haeusler, D. [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Mitterhauser, M. [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna (Austria); Ungersboeck, J. [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Department of Inorganic Chemistry, University of Vienna (Austria); Viernstein, H. [Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna (Austria); Dudczak, R. [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Wadsak, W., E-mail: wolfgang.wadsak@meduniwien.ac.at [Department of Nuclear Medicine, Medical University of Vienna, Radiochemistry and Biomarker Development Unit, Waehringer Guertel 18-20, A-1090 Vienna (Austria); Department of Inorganic Chemistry, University of Vienna (Austria)

    2011-09-15

    [{sup 11}C]PIB is still the standard PET compound for Alzheimer imaging targeting beta-amyloid plaques. We aimed to establish a fully-automated procedure for the synthesis and purification of [{sup 11}C]PIB with a high degree of reliability and improved specific activity as well as a suitable and fast quality control assay. The optimum reaction conditions were 75 deg. C, 4 mg/mL precursor yielding at 48.0{+-}2.7% (EOS, based on [{sup 11}C]CH{sub 3}OTf, corrected for decay), 183{+-}14 GBq/{mu}mol specific activity and >99% radiochemical purity. Time consumption was kept to a minimum (40 min from EOB) and overall yields were enough to serve 2 consecutive patients with a single preparation. - Highlights: > Optimized radiosynthesis of [{sup 11}C]PIB in 40 min. > Optimum reaction conditions were 75 deg. C and 4 mg/mL precursor. > Radiochemical yields were 4.2{+-}1.1 GBq. > The specific activity was 183{+-}14 GBq/{mu}mol.

  17. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans.

    Science.gov (United States)

    Endres, Christopher J; Pomper, Martin G; James, Michelle; Uzuner, Ovsev; Hammoud, Dima A; Watkins, Crystal C; Reynolds, Aaron; Hilton, John; Dannals, Robert F; Kassiou, Michael

    2009-08-01

    Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, (11)C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide ((11)C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of (11)C-DPA-713 in human subjects using PET. Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity (11)C-DPA-713. For comparison, 2 additional healthy controls were studied with (11)C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model. In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for (11)C-R-PK11195. Accordingly, dose-normalized time-activity curves showed that (11)C-DPA-713 gives a larger brain signal. Studies in patient populations will help determine whether (11)C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that (11)C-DPA-713 is a promising ligand for evaluating TSPO binding with PET.

  18. Yiqi Formula Enhances the Antitumor Effects of Erlotinib for Treatment of Triple-Negative Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Ming-juan Liao

    2014-01-01

    Full Text Available Yiqi formula (YF, a traditional herbal prescription, has long been used to treat triple-negative breast cancer (TNBC patients. The present study aims to investigate the effects and the related mechanism of YF for treatment of TNBC xenografts. MDA-MB-231 (human TNBC cells were subcutaneously injected into the second mammary fat pad of 40 female nude mice, which were divided into four groups: control, erlotinib (an epidermal growth factor receptor (EGFR tyrosine kinase inhibitor, YF, and combination (YF plus erlotinib. All treatments were administered orally for 30 days. Inhibition rate of tumor weight by erlotinib, YF, and the combination was 26.47%, 17.24%, and 39.15%, respectively. Western blotting showed that YF, erlotinib, and the combination downregulated p-EGFR (P<0.01 and p-Akt1 (pT308 (P<0.05 and upregulated PTEN compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. Similar results were detected by immunohistochemistry. Real-time quantitative PCR showed that YF, erlotinib, and the combination increased PTEN mRNA (P<0.05, P<0.01 compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. In conclusion, YF can regulate the main components of the PI3K/Akt pathway in TNBC xenografts. When YF was used in combination with erlotinib, it enhanced the antitumor effects of erlotinib on TNBC xenografts. These findings suggest that YF is suitable to use for the treatment of TNBC patients.

  19. High-dose corticosteroid therapy for erlotinib-induced interstitial lung disease in Japanese patient with advanced pancreatic cancer.

    Science.gov (United States)

    Yoshioka, Masato; Watanabe, Go; Uchinami, Hiroshi; Ise, Norihito; Nakagawa, Yasuhiko; Kudoh, Kazuhiro; Morita, Ryo; Andoh, Hideaki; Yamamoto, Yuzo

    2014-11-28

    Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor used as a target therapy against non-small lung cancer and advanced pancreatic cancer. A regimen of erlotinib plus gemcitabine has been proven to prolong overall survival in the patient with advanced pancreatic cancer. In addition to common adverse effects, such as diarrhea, mucositis and skin rash (acne form eruptions), acute interstitial lung disease (ILD) has been reported as an infrequent but potentially fatal complication. We here report a case of a Japanese patient with erlotinib-induced ILD in whom high-dose corticosteroid therapy was successful. A fifty-five-year-old male with cancer of the head of the pancreas with multiple liver metastases started treatment with gemcitabine plus erlotinib. On the 13th day of erlotinib treatment, he had high fever. Chest computed tomography (CT) scan showed a diffuse ground-glass like infiltration of both lungs. He was diagnosed with ILD, and high-dose corticosteroid therapy was started. Two weeks after the introduction of steroid therapy, the reticular shadow faded away on CT. He was successfully treated with corticosteroid for erlotinib-induced acute ILD although he died 6 months after the initiation of chemotherapy owing to disease progression. we showed a case of a successfully treated Japanese patient of erlotinib-induced ILD. Because erlotinib-induced ILD would frequently occur in Japanese patients, closer attention to ILD should be paid for Japanese patients than in Western populations. If erlotinib-induced ILD occurs, a high-dose corticosteroid therapy would be a useful option of treatment.

  20. Lack of age-dependent decrease in dopamine D3 receptor availability: a [11C]-(+)-PHNO and [11C]-raclopride positron emission tomography study

    Science.gov (United States)

    Nakajima, Shinichiro; Caravaggio, Fernando; Boileau, Isabelle; Chung, Jun K; Plitman, Eric; Gerretsen, Philip; Wilson, Alan A; Houle, Sylvain; Mamo, David C; Graff-Guerrero, Ariel

    2015-01-01

    Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [11C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [11C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D3R to the [11C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [11C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=−0.32, P=0.005). No correlations were observed in the other regions. With [11C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=−0.50, P<0.001), putamen (r(68)=−0.41, P<0.001), and ventral striatum (r(68)=−0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age. PMID:26058690

  1. Lack of age-dependent decrease in dopamine D3 receptor availability: a [(11)C]-(+)-PHNO and [(11)C]-raclopride positron emission tomography study.

    Science.gov (United States)

    Nakajima, Shinichiro; Caravaggio, Fernando; Boileau, Isabelle; Chung, Jun K; Plitman, Eric; Gerretsen, Philip; Wilson, Alan A; Houle, Sylvain; Mamo, David C; Graff-Guerrero, Ariel

    2015-11-01

    Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [(11)C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [(11)C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D3R to the [(11)C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [(11)C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=-0.32, P=0.005). No correlations were observed in the other regions. With [(11)C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=-0.50, P<0.001), putamen (r(68)=-0.41, P<0.001), and ventral striatum (r(68)=-0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age.

  2. Automated radiosynthesis of [{sup 11}C]morphine for clinical investigation

    Energy Technology Data Exchange (ETDEWEB)

    Fan Jinda [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Meissner, Konrad [Department of Anesthesiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Gaehle, Gregory G.; Li Shihong [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Kharasch, Evan D. [Department of Anesthesiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Mach, Robert H. [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States); Tu Zhude, E-mail: tuz@mir.wustl.ed [Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd. St. Louis, MO 63110 (United States)

    2011-02-15

    To meet a multiple-dose clinical evaluation of the P-gp modulation of [{sup 11}C]morphine delivery into the human brain, radiosynthesis of [{sup 11}C]morphine was accomplished on an automated system by N-methylation of normorphine with [{sup 11}C]CH{sub 3}I. A methodology employing optimized solid phase extraction of the HPLC eluent was developed. Radiosynthesis took 45 min with a radiochemical yield ranging from 45% to 50% and specific activity ranging from 20 to 26 Ci/{mu}mol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28).

  3. Preparation of [11C]formaldehyde using a hollow fiber membrane bioreactor.

    Science.gov (United States)

    Hughes, J A; Jay, M

    1995-01-01

    A bioreactor consisting of the enzymes alcohol oxidase and catalase immobilized onto a hollow fiber membrane was used to convert [11C]methanol to [11C]formaldehyde. Using an alcohol oxidase:catalase ratio of 1:500 U, conversion yields of 90-95% were obtained allowing the production of up to 7400 MBq (200 mCi) of [11C]formaldehyde in 5 min. The hollow fiber bioreactor allowed for a convenient, rapid synthesis with yields significantly higher than the standard chemical procedures, has demonstrable advantages over glass bead immobilized systems (primarily due to convective flow), and was amenable to hot cell conditions.

  4. Biomarkers in tissue from patients with upper gastrointestinal cancers treated with erlotinib and bevacizumab

    DEFF Research Database (Denmark)

    Rohrberg, Kristoffer Staal; Pappot, Helle; Lassen, Ulrik;

    2011-01-01

    Malignancies in the upper gastrointestinal (UGI) tract are amongst the most aggressive cancers and only few treatment options exist. We have recently analysed data from a phase II trial where patients with UGI cancers were treated with erlotinib and bevacizumab. The combination therapy could...

  5. Development and Application of an HPLC Method for Erlotinib Protein Binding Studies

    Directory of Open Access Journals (Sweden)

    Soheila Bolandnazar

    2013-08-01

    Full Text Available Purpose: The aim of the present study was to develop a simple and rapid reversed-phase high performance liquid chromatographic method with UV detection for erlotinib hydrochloride quantification, which is applicable for protein binding studies. Methods: Ultrafilteration method was used for protein binding study of erlotinib hydrochloride. For sample analysis a simple and rapid reversed-phase high performance liquid chromatographic method with UV detection at 332 nm was developed. The mobile phase was a mixture of methanol, acetonitril and potassium dihydrogen phosphate buffer (15:45:40 %v/v set at flow rate of 1.3 ml/min. Results: The run time for erlotinib hydrochloride was approximately 6 minutes. The calibration curve was linear over the range of 320-20000 ng/ml with acceptable intra- and inter-day precision and accuracy. The intra-day and inter-day precisions were less than 10% and the accuracies of intra and inter-day assays were within the range of 97.20-104.83% and 98.8-102.2% respectively. Conclusion: Based on the obtained results, a simple, accurate and precise reversed-phase isocratic HPLC method with UV detection has been optimized and validated for the determination of erlotinib hydrochloride in biological samples.

  6. PET imaging of hepatocellular carcinoma with {sup 18}F-fluoroethylcholine and {sup 11}C-choline

    Energy Technology Data Exchange (ETDEWEB)

    Kolthammer, Jeffrey A.; Tenley, Nathan [Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH (United States); Corn, David J.; Wu, Chunying; Tian, Haibin; Wang, Yanming [University Hospitals Case Medical Center, Nuclear Medicine Division, Department of Radiology, Cleveland, OH (United States); Lee, Zhenghong [Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH (United States); University Hospitals Case Medical Center, Nuclear Medicine Division, Department of Radiology, Cleveland, OH (United States)

    2011-07-15

    Choline-based radiotracers have been studied for PET imaging of hepatocellular carcinoma (HCC). Using an {sup 18}F-labeled choline analog, instead of the {sup 11}C-labeled native choline, would facilitate its widespread use in the clinic. In this study, PET with {sup 18}F-fluoroethylcholine (FEC) and {sup 11}C-choline (CHOL) were compared using an animal model of HCC. The effects of fasting on the performance of choline-based tracers were also investigated. A woodchuck model of HCC was used to compare the two tracers, which were administered and imaged in sequence during the same imaging session. Dynamic PET images were generated spanning 50 min starting from tracer injection. Time-activity curves and tracer contrast were calculated in liver regions with tracer accumulation, and the contrast at a late time-point with the two tracers, and between fasted and nonfasted states, were compared. Foci of HCC with increased uptake ranged in size from 1.0 to 1.6 cm, with mean tumor-to-background contrast of 1.3 with FEC and 1.5 with CHOL at 50 min after injection. The tracers show similar patterns of uptake immediately following administration, and both activities plateaued at 10 min after injection. No significant differences in uptake dynamics or final contrast were observed between the fasted and nonfasted states. PET imaging of HCC is possible with both CHOL and FEC. Fasting was not found to affect accumulation of either tracer. These results encourage further investigation into the clinical utility of FEC for HCC imaging. (orig.)

  7. Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC

    Directory of Open Access Journals (Sweden)

    Fadi Kayali

    2011-02-01

    Full Text Available Fadi Kayali, Muhamad A Janjua, Damian A Laber, Donald Miller, Goetz H KloeckerUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY, USABackground: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC, with a response rate (RR of 10%. This study's hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP in NSCLC.Methods: Patients with progressive disease (PD after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group score from 0 to 2 and good organ function. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred.Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78, 14 were female, 17 had prior radiation (not involving the target lesions, 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were

  8. Insights into erlotinib action in pancreatic cancer cells using a combined experimental and mathematical approach

    Institute of Scientific and Technical Information of China (English)

    Falko Lange; Katja Rateitschak; Christina Kossow; Olaf Wolkenhauer; Robert Jaster

    2012-01-01

    AIM:To gain insights into the molecular action of erlotinib in pancreatic cancer (PC) cells.METHODS:Two PC cell lines,BxPC-3 and Capan-1,were treated with various concentrations of erlotinib,the specific mitogen-activated protein kinase kinase (MEK) inhibitor U0126,and protein kinase B (AKT) inhibitor XIV.DNA synthesis was measured by 5-bromo2'-deoxyuridine (BrdU) assays.Expression and phosphorylation of the epidermal growth factor receptor (EGFR) and downstream signaling molecules were quantified by Western blot analysis.The data were processed to calibrate a mathematical model,based on ordinary differential equations,describing the EGFRmediated signal transduction.RESULTS:Erlotinib significantly inhibited BrdU incorporation in BxPC-3 cells at a concentration of 1 μmol/L,whereas Capan-1 cells were much more resistant.In both cell lines,MEK inhibitor U0126 and erlotinib attenuated DNA synthesis in a cumulative manner,whereas the AKT pathway-specific inhibitor did not enhance the effects of erlotinib.While basal phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) did not differ much between the two cell lines,BxPC-3 cells displayed a more than five-times higher basal phospho-AKT level than Capan-1 cells.Epidermal growth factor (EGF) at 10 ng/mL induced the phosphorylation of EGFR,AKT and ERK in both cell lines with similar kinetics.In BxPC-3 cells,higher levels of phospho-AKT and phospho-ERK (normalized to the total protein levels) were observed.Independent of the cell line,erlotinib efficiently inhibited phosphorylation of EGFR,AKT and ERK.The mathematical model successfully simulated the experimental findings and provided predictions regarding phosphoprotein levels that could be verified experimentally.CONCLUSION:Our data suggest basal AKT phosphorylation and the degree of EGF-induced activation of AKT and ERK as molecular determinants of erlotinib efficiency in PC cells.

  9. [{sup 11}C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Alan A., E-mail: alan.wilson@camhpet.c [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Garcia, Armando; Parkes, Jun [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Houle, Sylvain [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Tong, Junchao [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 (Canada); Vasdev, Neil [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada)

    2011-02-15

    Introduction: Fatty acid amide hydrolase (FAAH) is the enzyme responsible for metabolising the endogenous cannabinoid, anandamide, and thus represents an important target for molecular imaging. To date, no radiotracer has been shown to be useful for imaging of FAAH using either positron emission tomography (PET) or single photon emission computed tomography (SPECT). We here determine the suitability of a novel carbon-11-labeled inhibitor of FAAH via ex vivo biodistribution studies in rat brain in conjunction with pharmacological challenges. Methods: A potent irreversible inhibitor of FAAH, URB694, radiolabeled with carbon-11 in the carbonyl position ([{sup 11}C]CURB), was administered to male rats via tail-vein injection. Rats were sacrificed at various time points postinjection, and tissue samples were dissected, counted and weighed. Specific binding to FAAH was investigated by pretreatment of animals with URB694 or URB597. For metabolism and mechanism of binding studies, whole brains were excised post-radiotracer injection, homogenised and extracted exhaustively with 80% aq. acetonitrile to determine the time course and fraction of radioactivity that was irreversibly bound to brain parenchyma. Results: Upon intravenous injection into rats, [{sup 11}C]CURB showed high brain uptake [standard uptake value (SUV) of 1.6-2.4 at 5 min] with little washout over time, which is characteristic of irreversible binding. Highest uptake of radioactivity was seen in the cortex, intermediate in the cerebellum and lowest in the hypothalamus, reflecting the reported distribution of FAAH. Brain uptake of radioactivity was decreased in a dose-dependent manner by pretreatment with increasing amounts of URB694, demonstrating that binding was saturable. Pretreatment with the well-characterised FAAH inhibitor, URB597, reduced binding in all brain regions by 70-80%. Homogenised brain extraction experiments demonstrated unequivocally that [{sup 11}C]CURB was irreversibly bound to FAAH

  10. Washout allometric reference method (WARM) for parametric analysis of [(11)C]PIB in human brains

    DEFF Research Database (Denmark)

    Rodell, Anders; Aanerud, Joel Fredrik Astrup; Brændgaard, Hans

    2013-01-01

    Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB......) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects...... reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P

  11. Synthesis of ethyl 8-fluoro-5,6-dihydro-5-(/sup 11/C)methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylate (RO 15. 1788-/sup 11/C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Maziere, M.; Hantraye, P.; Prenant, C.; Sastre, J.; Comar, D. (CEA, 91 - Orsay (France). Service Hospitalier Frederic Joliot)

    1984-10-01

    A method of labelling ethyl 8-fluoro-5,6-dihydro-5-(/sup 11/C) methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylate (RO 15.1788 /sup 11/C), a benzodiazepine antagonist with carbon-11 has been developed. RO 15.1788-/sup 11/C was prepared by methylation of the nor derivative by I/sup 11/CH/sub 3/. About 100 mCi (maximum 153 mCi, 5.66 GBq) of the chemically and radiochemically pure labelled product were obtained within 25 min with a specific activity on average of 1100 mCi/..mu.. mol (maximum 1740 mCi/..mu..mol-64.4 GBq/..mu..mol). Preliminary results obtained after i.v. administration in the baboon have shown RO 15.1788-/sup 11/C to be of interest as a benzodiazepine radioligand for the in vivo study of benzodiazepine receptors by positron emission tomography.

  12. Erlotinib preserves renal function and prevents salt retention in doxorubicin treated nephrotic rats.

    Directory of Open Access Journals (Sweden)

    Raed N Bou Matar

    Full Text Available Nephrotic syndrome is associated with up-regulation of the heparin-binding epidermal growth factor (HB-EGF. Erlotinib blocks the activation of the epidermal growth factor receptor (EGFR in response to HB-EGF. This study investigates the effect of Erlotinib on the progression of proteinuria, renal dysfunction, and salt retention in doxorubicin treated nephrotic rats. Male rats were divided into 3 pair-fed groups (n = 13/group as follows: Control rats (Ctrl; rats receiving intravenous doxorubicin (Dox; and rats receiving intravenous doxorubicin followed by daily oral Erlotinib (Dox + Erl. Upon establishment of high grade proteinuria, urine sodium and creatinine clearance were measured. Kidney tissue was dissected and analyzed for γ-epithelial sodium channel (γENaC, sodium-potassium -chloride co-transporter 2 (NKCC2, sodium chloride co-transporter (NCC, aquaporin 2 (AQP2, and EGFR abundances using western blot. Creatinine clearance was preserved in the Dox + Erl rats as compared to the Dox group (in ml/min: Ctrl: 5.2±.5, Dox: 1.9±0.3, Dox + Erl: 3.6±0.5. Despite a minimal effect on the degree of proteinuria, Erlotinib prevented salt retention (Urinary Na in mEq/d: Ctrl: 2.2±0.2, Dox: 1.8±0.3, Dox + Erl: 2.2±0.2. The cleaved/uncleaved γENaC ratio was increased by 41±16% in the Dox group but unchanged in the Dox + Erl group when compared to Ctrl. The phosphorylated EGFR/total EGFR ratio was reduced by 74±7% in the Dox group and by 77±4% in the Dox + Erl group. In conclusion, Erlotinib preserved renal function and prevented salt retention in nephrotic rats. The observed effects do not appear to be mediated by direct blockade of EGFR.

  13. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

    Science.gov (United States)

    Wakelee, Heather A; Gettinger, Scott; Engelman, Jeffrey; Jänne, Pasi A; West, Howard; Subramaniam, Deepa S; Leach, Joseph; Wax, Michael; Yaron, Yifah; Miles, Dale R; Lara, Primo N

    2017-05-01

    Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

  14. Uptake of inflammatory cell marker [{sup 11}C]PK11195 into mouse atherosclerotic plaques

    Energy Technology Data Exchange (ETDEWEB)

    Laitinen, Iina; Marjamaeki, Paeivi; Naagren, Kjell; Roivainen, Anne; Knuuti, Juhani [University of Turku, Turku PET Centre, Turku (Finland); Laine, V.J.O. [Turku University Hospital, Department of Pathology, Turku (Finland); Wilson, Ian [GE Healthcare Biosciences, Medical Diagnostics, London (United Kingdom); Leppaenen, Pia; Ylae-Herttuala, Seppo [University of Kuopio, A.I. Virtanen Institute, Kuopio (Finland)

    2009-01-15

    The ligand [{sup 11}C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [{sup 11}C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [{sup 11}C]PK11195 in imaging inflammation in the atherosclerotic plaques. The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [{sup 3}H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [{sup 11}C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. The [{sup 3}H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [{sup 11}C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of {sup 11}C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Our results indicate that the uptake of [{sup 11}C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [{sup 11}C]PK11195 in clinical imaging of atherosclerotic plaques. (orig.)

  15. Automated preparation of the dopamine D{sub 2/3} receptor agonist ligand [{sup 11}C]-(+)-PHNO for human PET imaging studies

    Energy Technology Data Exchange (ETDEWEB)

    Plisson, Christophe, E-mail: Christophe.2.plisson@gsk.com [GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London W12 0NN (United Kingdom); Huiban, Mickael; Pampols-Maso, Sabina; Singleton, Goerkem; Hill, Samuel P.; Passchier, Jan [GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London W12 0NN (United Kingdom)

    2012-02-15

    Carbon-11 labelled (+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([{sup 11}C]-(+)-PHNO) is used as a high-affinity state, dopamine D{sub 2/3} receptor ligand in clinical PET studies. To facilitate its use, robust, rapid, efficient and GMP compliant methods are required for the manufacturing and QC testing processes. Additionally, to allow for full quantification of the resulting signal in the CNS, a reliable method is required to establish the parent plasma concentration over the course of the scan. This paper provides high-quality methods to support clinical application of [{sup 11}C]-(+)-PHNO. - Highlights: Black-Right-Pointing-Pointer Fully automated synthesis of [{sup 11}C]-(+)-PHNO. Black-Right-Pointing-Pointer Rapid multi-step synthesis and QC analysis. Black-Right-Pointing-Pointer Reproducible synthesis process typically yielding more than 3 GBq of [{sup 11}C]-(+)-PHNO. Black-Right-Pointing-Pointer Very low failure rate.

  16. Radiosynthesis and Evaluation of [(11)C]3-Hydroxycyclopent-1-enecarboxylic Acid as Potential PET Ligand for the High-Affinity γ-Hydroxybutyric Acid Binding Sites.

    Science.gov (United States)

    Jensen, Claus H; Hansen, Hanne D; Bay, Tina; Vogensen, Stine B; Lehel, Szabolcs; Thiesen, Louise; Bundgaard, Christoffer; Clausen, Rasmus P; Knudsen, Gitte M; Herth, Matthias M; Wellendorph, Petrine; Frølund, Bente

    2017-01-18

    γ-Hydroxybutyric acid (GHB) is an endogenous neuroactive substance and proposed neurotransmitter with affinity for both low- and high-affinity binding sites. A radioligand with high and specific affinity toward the high-affinity GHB binding site would be a unique tool toward a more complete understanding of this population of binding sites. With its high specific affinity and monocarboxylate transporter (MCT1) mediated transport across the blood-brain barrier in pharmacological doses, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) seems like a suitable PET radiotracer candidate. Here, we report the (11)C-labeling and subsequent evaluation of [(11)C]HOCPCA in a domestic pig, as a PET-radioligand for visualization of the high-affinity GHB binding sites in the live pig brain. To investigate the regional binding of HOCPCA in pig brain prior to in vivo PET studies, in vitro quantitative autoradiography on sections of pig brain was performed using [(3)H]HOCPCA. In vivo evaluation of [(11)C]HOCPCA showed no brain uptake, possibly due to a limited uptake of HOCPCA by the MCT1 transporter at tracer doses of [(11)C]HOCPCA.

  17. Optimization for the Synthesis Efficiency of the 11C-Raclopride

    Directory of Open Access Journals (Sweden)

    LI Hai-feng

    2016-02-01

    Full Text Available The synthesis conditions of the 11C-Raclopride with domestic PET-CM-3H-IT-I synthesis module and 11C-Triflate-CH-3I as methylation agent were studied, which included the alkali equivalent, solvents, temperature, the amount of precursor and elution conditions for the product. The optimum condition was 1.5-3.0 g/L of precursor in acetone (0.2 mL, alkali equivalent (0.30-1.25 eq and at room temperature (25 ℃ for synthesis of 11C-Raclopride. It could be got with radiochemical yield of (64.82±4.74% (n=46, EOB of 11C-Triflate-CH3. The radiochemical purity was over 97% and the specific activity was at (423.61±13.43 GBq/g. It took 23 minutes from 11C-CO2 to 11C-Raclopride, and the production radioactivity was (6.9±0.87 GBq (n=46. The synthetic process was reliable and reproducible, and the product synthesized by this process was suitable for clinical use.

  18. Radiosynthesis and evaluation of [{sup 11}C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1

    Energy Technology Data Exchange (ETDEWEB)

    Yanamoto, Kazuhiko; Konno, Fujiko; Odawara, Chika; Yamasaki, Tomoteru; Kawamura, Kazunori; Hatori, Akiko; Yui, Joji; Wakizaka, Hidekatsu [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Nengaki, Nobuki [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); SHI Accelerator Service Co., Ltd., Shinagawa-ku, Tokyo 141-8686 (Japan); Takei, Makoto [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Tokyo Nuclear Service Co., Ltd., Taito-ku, Tokyo 110-0005 (Japan); Zhang Mingrong, E-mail: zhang@nirs.go.j [Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan)

    2010-07-15

    Introduction: Developing positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{l_brace}[N-(2-methoxyethyl)-N-methylamino]methyl{r_brace} -N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K{sub i}=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [{sup 11}C]YM-202074 as a PET ligand for mGluR1 in rodents. Methods: [{sup 11}C]YM-202074 was synthesized by N-[{sup 11}C]methylation of its desmethyl precursor with [{sup 11}C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively. Results: [{sup 11}C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/{mu}mol at the end of synthesis, starting from [{sup 11}C]CO{sub 2} of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [{sup 11}C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain. Conclusions: From these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [{sup 11}C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain.

  19. Dopamine D2 receptor radiotracers [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    McCormick, Patrick N. [Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada)], E-mail: patrick.mccormick@camhpet.ca; Kapur, Shitij [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Seeman, Philip [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Wilson, Alan A. [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada)

    2008-01-15

    Introduction: In vitro, the dopamine D2 receptor exists in two states, with high and low affinity for agonists. The high-affinity state is the physiologically active state thought to be involved in dopaminergic illnesses such as schizophrenia. The positron emission tomography radiotracer [{sup 11}C](+)-PHNO ([{sup 11}C](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4] oxazin-9-o l), being a D2 agonist, should selectively label the high-affinity state at tracer dose and therefore be more susceptible to competition by agonist as compared to the antagonist [{sup 3}H]raclopride, which binds to both affinity states. Methods: We tested this prediction using ex vivo dual-radiotracer experiments in conscious rats. D2 antagonists (haloperidol or clozapine), a partial agonist (aripiprazole), a full agonist [(-)-NPA] or the dopamine-releasing drug amphetamine (AMPH) were administered to rats prior to an intravenous coinjection of [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for {sup 11}C and {sup 3}H. The specific binding ratio {l_brace}SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum){r_brace} was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs responded indistinguishably in terms of both ED{sub 50} and Hill slope (e.g., (-)-NPA ED{sub 50} values are 0.027 and 0.023 mg/kg for [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride, respectively). In response to AMPH challenge, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [{sup 11}C](+)-PHNO- and [{sup 3}H]raclopride do not differ in their response to agonist challenge. These results do not support predictions of the in vivo binding behavior of a D2 agonist radiotracer and cast some doubt on the in vivo

  20. Synthesis and characterization in monkey of [{sup 11}C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Simeon, Fabrice G.; Liow, Jeih-San; Zhang, Yi; Hong, Jinsoo; Gladding, Robert L.; Zoghbi, Sami S.; Innis, Robert B.; Pike, Victor W. [National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD (United States)

    2012-12-15

    [{sup 18}F]SP203 (3-fluoro-5-(2-(2-([{sup 18}F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived {sup 11}C (t{sub 1/2} = 20.4 min) and to characterize its behavior as a radioligand with PET in the monkey. Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [{sup 11}C]cyanide ion rapidly gave [{sup 11}C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [{sup 11}C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [{sup 11}C]SP203 in human blood in vitro was also measured. The iodo precursor gave [{sup 11}C]SP203 in higher radiochemical yield (>98 %) than the bromo precursor (20-52 %). After intravenous administration of [{sup 11}C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5 min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [{sup 11}C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [{sup 11}C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites

  1. Radiosynthesis and biodistribution of a histamine H{sub 3} receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[{sup 11}C]benzyl]-morpholine: evaluation of a potential PET ligand

    Energy Technology Data Exchange (ETDEWEB)

    Airaksinen, Anu J. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Jablonowski, Jill A. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Mey, Margreet van der [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Barbier, Ann J. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Klok, Rob P. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Verbeek, Joost [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Schuit, Robert [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Herscheid, Jacobus D.M. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Leysen, Josee E. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Carruthers, Nicholas I. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Lammertsma, Adriaan A. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Windhorst, Albert D. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands)]. E-mail: bwindhorst@rnc.vu.nl

    2006-08-15

    The potent histamine H{sub 3} receptor antagonist JNJ-10181457 () was successfully labeled with {sup 11}C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28{+-}8%) and high specific radioactivity (56{+-}26 GBq/{mu}mol). The binding of [{sup 11}C] to H{sub 3} receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [{sup 11}C] in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H{sub 3} antagonists, JNJ-5207852 () and unlabeled Compound (), in a concentration-dependent manner. The biodistribution of [{sup 11}C] in rats was measured at 5, 10, 30 and 60 min. The uptake of [{sup 11}C] in regions rich in H{sub 3} receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [{sup 11}C] in the rat brain could not be blocked by pretreatment with either Compound () (30 min or 24 h pretreatment) or cold Compound () (30-min pretreatment). The biodistribution of [{sup 11}C] in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H{sub 3}(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [{sup 11}C] could not specifically label H{sub 3} receptors in rodent brain in vivo. Possible causes are discussed.

  2. [{sup 11}C]GR103545: novel one-pot radiosynthesis with high specific activity

    Energy Technology Data Exchange (ETDEWEB)

    Nabulsi, Nabeel B., E-mail: nabeel.nabulsi@yale.ed [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States); Zheng Mingqiang; Ropchan, Jim; Labaree, David; Ding Yushin [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States); Blumberg, Laura [Pfizer Global R and D, Groton, CT 06340 (United States); Huang Yiyun [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States)

    2011-02-15

    Introduction: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [{sup 11}C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [{sup 11}C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [{sup 11}C]GR103545 with higher SA and radiochemical yields. Methods: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [{sup 11}C]methyl trifluoromethanesulfonate to give [{sup 11}C]GR103545. Results: This novel synthesis produced [{sup 11}C]GR103545 with {>=}90% chemical and radiochemical purities and an SA of 290.45{+-}99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961{+-}814 GBq/{mu}mol with 43 min of average synthesis time from the end of beam. Conclusion: We have developed a practical one-pot method for the routine production of [{sup 11}C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.

  3. 11C-acetate PET imaging in patients with multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Kazushiro Takata

    Full Text Available BACKGROUND: Activation of glial cells is a cardinal feature in multiple sclerosis (MS pathology, and acetate has been reported to be selectively uptaken by astrocytes in the CNS. The aim of this study was to investigate the efficacy of PET with (11C-acetate for MS diagnosis. MATERIALS AND METHODS: Six patients with relapsing-remitting MS and 6 healthy volunteers (HV were enrolled. The (11C-acetate brain uptake on PET was measured in patients with MS and HV. Volume-of-interest analysis of cerebral gray and white matter based on the segmentation technique for co-registered MRI and voxel-based statistical parametric analysis were performed. Correlation between 11C-acetate uptake and the lesion number in T1- and T2- weighted MR images were also assessed. RESULTS: The standardized uptake value (SUV of 11C-acetate was increased in both white and gray matter in MS patients compared to HV. Voxel-based statistical analysis revealed a significantly increased SUV relative to that in the bilateral thalami (SUVt in a broad area of white matter, particularly in the subcortical white matter of MS patients. The numbers of T2 lesions and T1 black holes were significantly correlated with SUV of (11C-acetate in white and gray matter. CONCLUSIONS: The 11C-acetate uptake significantly increased in MS patients and correlated to the number of MRI lesions. These preliminary data suggest that (11C-acetate PET can be a useful clinical examination for MS patients.

  4. Afatinib-refractory brain metastases from EGFR-mutant non-small-cell lung cancer successfully controlled with erlotinib: a case report.

    Science.gov (United States)

    Nonagase, Yoshikane; Okamoto, Kunio; Iwasa, Tsutomu; Yoshida, Takeshi; Tanaka, Kaoru; Takeda, Masayuki; Kaneda, Hiroyasu; Shimizu, Toshio; Tsurutani, Junji; Nakagawa, Kazuhiko

    2016-03-01

    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.

  5. Toxic risk of stereotactic body radiotherapy and concurrent helical tomotherapy followed by erlotinib for non-small-cell lung cancer treatment - case report

    Directory of Open Access Journals (Sweden)

    Chen Chien-An

    2010-12-01

    Full Text Available Abstract Background Stereotactic body radiation therapy (SBRT applied by helical tomotherapy (HT is feasible for lung cancer in clinical. Using SBRT concurrently with erlotinib for non-small cell lung cancer (NSCLC is not reported previously. Case Presentation A 77-year-old man with stage III NSCLC, received erlotinib 150 mg/day, combined with image-guided SBRT via HT. A total tumor dose of 54 Gy/9 fractions was delivered to the tumor bed. The tumor responded dramatically and the combined regimen was well tolerated. After concurrent erlotinib-SBRT, erlotinib was continued as maintenance therapy. The patient developed dyspnea three months after the combined therapy and radiation pneumonitis with interstitial lung disease was suspected. Conclusions Combination SBRT, HT, and erlotinib therapy provided effective anti-tumor results. Nonetheless, the potential risks of enhanced adverse effects between radiation and erlotinib should be monitored closely, especially when SBRT is part of the regimen.

  6. Specific activity of [{sup 11}C]CH{sub 3}I synthesized by the 'wet' method: Main sources of non-radioactive carbon

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Vallejo, Vanessa [Institut Alta Tecnologia PRBB-Fundacio Privada, Parc de Recerca Biomedica de Barcelona, C/Dr. Aiguader, 88 08003 Barcelona (Spain); Llop, Jordi [Institut Alta Tecnologia PRBB-Fundacio Privada, Parc de Recerca Biomedica de Barcelona, C/Dr. Aiguader, 88 08003 Barcelona (Spain)], E-mail: jllop@cicbiomagune.es

    2009-01-15

    Positron emission tomography (PET) is a powerful molecular imaging technique based on the administration and detection of radioactive (positron emitting) species. In some applications, the concept of specific activity becomes especially important in order to prevent undesired pharmacological and/or toxic effects after injection of the radiotracer. Problems to obtain high specific activities are found when {sup 11}C-labeled compounds are prepared by methylation following the so called 'wet' method, which consists of a simple route but usually yields radiotracers highly diluted with the stable specie. In the present work, the main sources of contamination by stable carbon in the [{sup 11}C]CH{sub 3}I synthesis following the 'wet' method have been analyzed and their individual contribution has been quantified. The results show that the most relevant contamination of CO{sub 2} is generated during the bombardment process.

  7. Radiosynthesis and Evaluation of [(11)C]3-Hydroxycyclopent-1-enecarboxylic Acid as Potential PET Ligand for the High-Affinity γ-Hydroxybutyric Acid Binding Sites

    DEFF Research Database (Denmark)

    Jensen, Claus H; Hansen, Hanne D; Bay, Tina

    2017-01-01

    the (11)C-labeling and subsequent evaluation of [(11)C]HOCPCA in a domestic pig, as a PET-radioligand for visualization of the high-affinity GHB binding sites in the live pig brain. To investigate the regional binding of HOCPCA in pig brain prior to in vivo PET studies, in vitro quantitative......γ-Hydroxybutyric acid (GHB) is an endogenous neuroactive substance and proposed neurotransmitter with affinity for both low- and high-affinity binding sites. A radioligand with high and specific affinity toward the high-affinity GHB binding site would be a unique tool toward a more complete...... understanding of this population of binding sites. With its high specific affinity and monocarboxylate transporter (MCT1) mediated transport across the blood-brain barrier in pharmacological doses, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) seems like a suitable PET radiotracer candidate. Here, we report...

  8. Combination of erlotinib and EGCG induces apoptosis of head and neck cancers through posttranscriptional regulation of Bim and Bcl-2.

    Science.gov (United States)

    Haque, Abedul; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Saba, Nabil F; Khuri, Fadlo R; Shin, Dong M; Ruhul Amin, A R M

    2015-07-01

    Combinatorial approaches using two or more compounds are gaining increasing attention for cancer therapy. We have previously reported that the combination of the EGFR-TKI erlotinib and epigallocatechin-3-gallate (EGCG) exhibited synergistic chemopreventive effects in head and neck cancers by inducing the expression of Bim, p21, p27, and by inhibiting the phosphorylation of ERK and AKT and expression of Bcl-2. In the current study, we further investigated the mechanism of regulation of Bim, Bcl-2, p21 and p27, and their role in apoptosis. shRNA-mediated silencing of Bim significantly inhibited apoptosis induced by the combination of erlotinib and EGCG (p = 0.005). On the other hand, overexpression of Bcl-2 markedly protected cells from apoptosis (p = 0.003), whereas overexpression of constitutively active AKT only minimally protected cells from apoptosis induced by the combination of the two compounds. Analysis of mRNA expression by RT-PCR revealed that erlotinib, EGCG and their combination had no significant effects on the mRNA expression of Bim, p21, p27 or Bcl-2 suggesting the post-transcriptional regulation of these molecules. Furthermore, we found that erlotinib or the combination of EGCG and erlotinib inhibited the phosphorylation of Bim and stabilized Bim after inhibition of protein translation by cycloheximide. Taken together, our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the posttranscriptional level.

  9. Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases

    Directory of Open Access Journals (Sweden)

    Yukihiro Yano

    2012-01-01

    Full Text Available Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

  10. Long-Term Treatment with Erlotinib for EGFR Wild-Type Non-Small Cell Lung Cancer: A Case Report.

    Science.gov (United States)

    Polychronidou, Genovefa; Papakotoulas, Pavlos

    2013-01-01

    The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are known to have greater efficacy in EGFR mutation-positive non-small cell lung cancer (NSCLC), although erlotinib also has activity in wild-type disease. We report the successful long-term maintenance treatment of a patient with EGFR wild-type NSCLC with gefitinib and later erlotinib. The patient (male; 44 years old; smoker) was diagnosed with EGFR wild-type NSCLC after computer tomography had revealed a mediastinal mass, and histology and mutation testing had identified the tumor as an EGFR wild-type grade 3 adenocarcinoma. The patient received multiple rounds of chemotherapy, followed by gefitinib maintenance (3 years). Later on, he received erlotinib maintenance and developed a persistent rash (grade 1/2) that lasted throughout the treatment. The patient's condition has remained stable on erlotinib for more than 5 years, with no evidence of progression. We describe the patient's disease course and treatment in the context of EGFR TKI therapy and the prognostic factors for long-term clinical outcomes of NSCLC, including the development of erlotinib-induced rash.

  11. Kinetics of [{sup 11}C]choline uptake in prostate cancer: a PET stydy

    Energy Technology Data Exchange (ETDEWEB)

    Sutinen, Eija; Minn, Heikki [Turku PET Centre, Turku University Central Hospital, Turku (Finland); Department of Oncology and Radiotherapy, Turku University Central Hospital, PO Box 52, 20521, Turku (Finland); Nurmi, Martti [Department of Surgery, Turku University Central Hospital, Turku (Finland); Roivainen, Anne; Tolvanen, Tuula; Lehikoinen, Pertti [Turku PET Centre, Turku University Central Hospital, Turku (Finland); Varpula, Matti [Department of Radiology, Turku University Central Hospital, Turku (Finland)

    2004-03-01

    Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [{sup 11}C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [{sup 11}C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [{sup 11}C]choline PET. A mean dose of 430{+-}31 MBq of [{sup 11}C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [{sup 11}C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant (K{sub i}) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [{sup 11}C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K{sub i} of the untreated tumour was 0.205{+-}0.089 min{sup -1} (range 0.128-0.351; n=7) and the mean SUV was 5.6{+-}3.2 (range 1.9-15.5; n=15). K{sub i} values and SUVs correlated closely (r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [{sup 11}C]choline and the histological grade, Gleason score, volume of the prostate or PSA. The mean SUV and the mean K{sub i} of benign hyperplastic prostate were 3.5{+-}1.0 (range 2.0-4.5; n=4) and 0.119{+-}0.076 min{sup -1} (range 0.065-0.173; n=2). In conclusion, a high uptake of [{sup 11}C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [{sup 11}C]choline in the prostate shows a good applicability of the graphical analysis model with an

  12. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8+CD11c+ cells

    Science.gov (United States)

    Zhao, Hai-Mei; Han, Fei; Xu, Rong; Huang, Xiao-Ying; Cheng, Shao-Min; Huang, Min-Fang; Yue, Hai-Yang; Wang, Xin; Zou, Yong; Xu, Han-Lin; Liu, Duan-Yong

    2017-01-01

    AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8+CD11c+ cells. METHODS We evaluated the suppressive effect of Cur on CD8+CD11c+ cells in spleen and Peyer’s patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8+CD11c+ cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-γ and transforming growth factor (TGF)-β1 in spleen and colonic mucosa were determined by ELISA. RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8+CD11c+ cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-γ and TGF-β1 levels were increased compared with those in mice with untreated colitis. CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting CD8+CD11c+ cells. PMID:28348486

  13. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8(+)CD11c(+) cells.

    Science.gov (United States)

    Zhao, Hai-Mei; Han, Fei; Xu, Rong; Huang, Xiao-Ying; Cheng, Shao-Min; Huang, Min-Fang; Yue, Hai-Yang; Wang, Xin; Zou, Yong; Xu, Han-Lin; Liu, Duan-Yong

    2017-03-14

    To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8(+)CD11c(+) cells. We evaluated the suppressive effect of Cur on CD8(+)CD11c(+) cells in spleen and Peyer's patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8(+)CD11c(+) cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-γ and transforming growth factor (TGF)-β1 in spleen and colonic mucosa were determined by ELISA. The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8(+)CD11c(+) cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-γ and TGF-β1 levels were increased compared with those in mice with untreated colitis. Cur can effectively treat experimental colitis, which is realized by inhibiting CD8(+)CD11c(+) cells.

  14. L-(4-/sup 11/C)aspartic acid: enzymatic synthesis, myocardial uptake, and metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Barrio, J.R.; Egbert, J.E.; Henze, E.; Schelbert, H.R.; Baumgartner, F.J.

    1982-01-01

    Sterile, pyrogen-free L-(4-/sup 11/C)aspartic acid was prepared from /sup 11/CO/sub 2/ using phosphoenolpyruvate carboxylase and glutamic/oxaloacetic acid transaminase immobilized on Sepharose supports to determine if it is a useful indicator for in vivo, noninvasive determination of myocardial metabolism. An intracoronary bolus injection of L-(4-/sup 11/C)aspartic acid into dog myocardium showed a triexponential clearance curve with maximal production of /sup 11/CO/sub 2/ 100 s after injection. Inactivation of myocardial transaminase activity modified the tracer clearance and inhibited the production of /sup 11/CO/sub 2/. Positron-computed tomography imaging showed that the /sup 11/C activities retained in rhesus monkey myocardium are higher than those observed in dog heart after intravenous injection of L-(4-/sup 11/C)aspartic acid. These findings demonstrated the rapid incorporation of the carbon skeleton of L-aspartic acid into the tricarboxylic acid cycle after enzymatic transamination in myocardium and suggested that L-(4-/sup 11/C)aspartic acid could be of value for in vivo, noninvasive assessment of local myocardial metabolism.

  15. Ionic interaction of [11C]-N,alpha-dimethylbenzylamine (DMBA) in rodent brain.

    Science.gov (United States)

    Inoue, Osamu; Hosoi, Rie; Momosaki, Sotaro; Kobayashi, Kaoru; Kida, Takayo; Suzuki, Kazutoshi; Gee, Antony

    2003-09-01

    The [S] enantiomer of [11C]-N,alpha-dimethylbenzylamine (DMBA) was synthesized by N-methylation of [S]-alpha-methylbenzylamine, and its biodistribution in mice was measured. [11C]-[S]-DMBA was rapidly distributed into the brain, heart and lungs, and considerable long-term retention in the brain was observed. The radioactive metabolites in the plasma were analyzed by liquid chromatography. Kinetic analysis using unmetabolized [11C]DMBA in the plasma as the input function was performed employing a simplified two-compartment model. The estimated distribution volumes (DV) of [11C]DMBA in the brain and heart were 6.05 and 3.95, respectively. The right striatum of the rat brain was lesioned with ibotenic acid 2 weeks before the tracer experiment. Both in vitro and in vivo autoragiographic studies were performed, and revealed significant reduction of the radioactivity levels in the lesioned striatum. On the other hand, the regional cerebral blood flow, as measured by [14C]iodoantipyrine, was not significantly altered in the lesioned striatum. These results indicate that the ionic binding component for DMBA exists mainly in neural cells rather than in glial cells. [11C]DMBA might be a useful radiotracer for detection of neural cell loss in the brain.

  16. Preclinical evaluation of [{sup 11}C]SA4503. Radiation dosimetry, in vivo selectivity and PET imaging of sigma{sub 1} receptors in the cat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Kazunori; Ishiwata, Kiichi; Shimada, Yuhei; Kimura, Yuichi; Senda, Michio [Tokyo Metropolitan Inst. of Gerontology (Japan). Positron Medical Center; Kobayashi, Tadayuki; Matsuno, Kiyoshi; Homma, Yoshio

    2000-08-01

    Our previous in vivo study with rats has demonstrated that {sup 11}C-labeled 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([{sup 11}C]SA4503) is a potential radioligand for mapping central nervous system (CNS) sigma{sub 1} receptors by positron emission tomography (PET). In the present study, we further characterized this ligand. The radiation absorbed-dose of [{sup 11}C]SA4503 in humans estimated with the tissue distribution in mice, was higher in the liver, kidney and pancreas than in other organs studied, but was low enough for clinical use. The brain uptake of [{sup 11}C]SA4503 in mice was reduced to approximately 60-70% by co-injection of carrier SA4503 and haloperidol, but not by co-injection of any of six ligands for sigma{sub 2} or other receptors, for which SA4503 showed in vitro >100 times weaker affinity than for sigma{sub 1} receptor. In the cat brain, the uptake in the cortex was higher than that in the cerebellum. The radioactivity in the cortex and cerebellum accumulated for the first 10 min and then gradually decreased until 81.5 min in the baseline measurement, but rapidly decreased in the carrier-loading condition. The receptor-mediated uptake was estimated to be approximately 60-65% of the total radioactivity in the cortex and cerebellum at 76 min after tracer injection. We have concluded that [{sup 11}C]SA4503 has the potential for mapping sigma{sub 1} receptor by PET. (author)

  17. Whole-body distribution and radiation dosimetry of the dopamine transporter radioligand [{sup 11}C]PE2I in healthy volunteers

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Maria-Joao [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France)]. E-mail: maria-joao.ribeiro@cea.fr; Ricard, Marcel [Service de Physique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif (France); Lievre, Marie-Angele [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France); Bourgeois, Sandrine [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France); Emond, Patrick [INSERM U316, Laboratoire de Biophysique medicale et pharmaceutique, UFR des Sciences Pharmaceutiques, 37200 Tours (France); Gervais, Philippe [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France); Dolle, Frederic [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France); Syrota, Andre [Service Hospitalier Frederic Joliot, Institut d' Imagerie Biomedicale, Direction des Sciences du Vivant, Commissariat a l' Energie Atomique, F-91406 Orsay (France)

    2007-05-15

    Introduction: This study reports on the biodistribution and radiation dosimetry of a cocaine analog, the (E)-N-(3-iodoprop-2-enyl)-2{beta}-carbomethoxy-3{beta}-(4'-tolyl)nortropane (PE2I), labeled with carbon 11 ([{sup 11}C]PE2I). [{sup 11}C]PE2I is used in positron emission tomography (PET) for examination of the dopamine neuronal transporter (DAT). DAT radioligands are often used to evaluate the progression of Parkinson's disease or the efficiency of neuroprotective therapeutics, and, typically, these studies required several successive PET scans. Methods: In three healthy male volunteers, whole-body scans were performed up to 2 h following intravenous injection of 321{+-}6 MBq of [{sup 11}C]PE2I. For each subject, regions of interest were defined over all visible organs to generate time-activity curves and calculate the percentage of injected activity. Time-activity data were fitted to a monoexponential model, as an uptake phase followed by a mono-exponential washout, or bi-exponential model to obtain residence times. With the use of the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. Results: Blood pressure and ECG findings remained unchanged after radioligand injection. The primary route of clearance was renal. Ten minutes after injection, high activities were observed in the kidneys, urinary-bladder, stomach, liver, salivary glands and brain. The urine bladder wall, stomach and liver received the highest absorbed doses. The average effective dose of [{sup 11}C]PE2I was estimated to be 6.4{+-}0.6 {mu}Sv/MBq. Conclusion: The amount of [{sup 11}C]PE2I required for adequate DAT PET imaging results in an acceptable effective dose equivalent permitting two or three repeated cerebral PET studies, with the injection of 222 MBq for each study.

  18. The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin

    DEFF Research Database (Denmark)

    Rasmussen, Andreas Rosén; Viby, Niels-Erik; Hare, Kristine Juul;

    2010-01-01

    Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined wi...... with the cytostatic, cisplatin, on the gastrointestinal tract and examined whether glucagon-like peptide-2 (GLP-2), an intestinal hormone with potent intestinotrophic properties, might counteract the possible damaging effects of the treatments....

  19. Imaging of amyloid deposition in human brain using positron emission tomography and [{sup 18}F]FACT: comparison with [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Shinotoh, Hitoshi; Shimada, Hitoshi; Miyoshi, Michie; Takano, Harumasa; Takahashi, Hidehiko; Arakawa, Ryosuke; Kodaka, Fumitoshi; Ono, Maiko; Eguchi, Yoko; Higuchi, Makoto; Fukumura, Toshimitsu; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); Yanai, Kazuhiko; Okamura, Nobuyuki [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan)

    2014-04-15

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The {sup 18}F-labeled amyloid tracer, [{sup 18}F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ {sup 11}C ]Pittsburgh compound B (PIB) and [ {sup 18}F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ {sup 11}C ]PIB and [ {sup 18}F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ {sup 18}F ]FACT studies without partial volume correction, while significant differences were observed in [ {sup 11}C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ {sup 18}F ]FACT studies as well as [ {sup 11}C ]PIB. Relatively lower uptakes of [ {sup 11}C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ {sup 18}F ]FACT. Relatively higher uptake of [ {sup 11}C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ {sup 18}F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ {sup 11}C ]PIB and [ {sup 18}F ]FACT might be due to differences

  20. [(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease.

    Science.gov (United States)

    Deters, Kacie D; Risacher, Shannon L; Yoder, Karmen K; Oblak, Adrian L; Unverzagt, Frederick W; Murrell, Jill R; Epperson, Francine; Tallman, Eileen F; Quaid, Kimberly A; Farlow, Martin R; Saykin, Andrew J; Ghetti, Bernardino

    2016-01-01

    Gerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.

  1. Washout allometric reference method (WARM) for parametric analysis of [(11)C]PIB in human brains.

    Science.gov (United States)

    Rodell, Anders; Aanerud, Joel; Braendgaard, Hans; Gjedde, Albert

    2013-01-01

    Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Aβ plaque load discrimination between patients with AD and healthy controls (P = 0.009).

  2. RANTES In1.1C allele polymorphisms in 13 Chinese ethnic populations

    Institute of Scientific and Technical Information of China (English)

    QIAN Yuan; SUN Hao; CHU Jia-you

    2009-01-01

    Background The In1.1C single nucleotide polymorphism (SNP) allele results in reduced RANTES transcription, which is associated with increased frequency of HIV-1 infection, and rapid progression to AIDS among HIV-1-infected individuals. This study aimed to study the mutant frequency and polymorphism of RANTES in Chinese populations.Methods The genotypes of RANTES In1.1C were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with the digestion of restriction endonuclease Mbo Ⅱ.Results Of the 617 individuals, 290 (47%) were carriers of the RANTES In1.1C allele, 52 of whom were homozygotes,whereas 238 were heterozygotes. The frequency of the RANTES In1.1C allele in those tested individuals was 0.2840.The frequencies of Inl.lC allele vaded from 0.07-0.27 in most of the populations in South-west China except for the two Lisu populations, while the frequencies of In1.1C spans from 0.35 to 0.45 in North-west China. The prevalence of the allele varied substantially between the South-west groups and North-west groups (X2=7.838, P=0.006).Conclusions The prevalence of the RANTES In1.1C allele varies substantially between the South-west groups and North-west groups. There is no significant difference between the groups with different languages, which suggests that language relationship is not consistent with the genetic relationship. These results have important implications for the design, assessment, and implementation of HIV-1 vaccines.

  3. GMP compliant radiosynthesis of11C and18F-labeled PET radiopharmaceuticals with a modular disposable cassette system

    NARCIS (Netherlands)

    Hessels-Scheper, J.G.; Maarsingh, P.; Kwizera, C.; Zijlma, R.; Maas, B.; De Vries, A.M.T.; Antunes, I.F.; Lub-de Hooge, M.N.; Boersma, H.H.; Dierckx, R.A.J.O.; De Vries, E.F.J.; Luurtsema, G.; Elsinga, P.H.

    2014-01-01

    Background Many nuclear medicine departments have an extensive radiopharmaceutical portfolio. Consequently, these multiple PET radiopharmaceuticals have to be produced with the same synthesis module. An important consideration in GMP-compliant PET production is to avoid potential

  4. Positron emission tomography in urologic oncology : on the application of 11C-labeled radiopharmaceuticals in prostate and bladder cancer

    NARCIS (Netherlands)

    Jong, Igle Jan de

    2003-01-01

    Prostate cancer is an important disease as it has become the most common diagnosed malignancy in men in an increasing number of countries. Moreover, it is the second cause of cancer death, exceeded by lung cancer only. For the diagnosis of prostate cancer, the serum prostate specific antigen (PSA) i

  5. GMP compliant radiosynthesis of11C and18F-labeled PET radiopharmaceuticals with a modular disposable cassette system

    NARCIS (Netherlands)

    Hessels-Scheper, J.G.; Maarsingh, P.; Kwizera, C.; Zijlma, R.; Maas, B.; De Vries, A.M.T.; Antunes, I.F.; Lub-de Hooge, M.N.; Boersma, H.H.; Dierckx, R.A.J.O.; De Vries, E.F.J.; Luurtsema, G.; Elsinga, P.H.

    2014-01-01

    Background Many nuclear medicine departments have an extensive radiopharmaceutical portfolio. Consequently, these multiple PET radiopharmaceuticals have to be produced with the same synthesis module. An important consideration in GMP-compliant PET production is to avoid potential cross-contamination

  6. Mapping a2 Adrenoceptors of the Human Brain with 11C-Yohimbine

    DEFF Research Database (Denmark)

    Nahimi, Adjmal; Jakobsen, Steen; Munk, Ole

    2015-01-01

    A previous study from this laboratory suggested that 11C-yohimbine, a selective α2-adrenoceptor antagonist, is an appropriate ligand for PET of α2 adrenoceptors that passes readily from blood to brain tissue in pigs but not in rodents. To test usefulness in humans, we determined blood–brain...... adrenoceptors in human brain had the highest values in cortical areas and hippocampus, with moderate values in subcortical structures, as found also in vitro. The results confirm the usefulness of the tracer 11C-yohimbine for mapping α2 adrenoceptors in human brain in vivo....

  7. New developments of {sup 11}C post-accelerated beams for hadron therapy and imaging

    Energy Technology Data Exchange (ETDEWEB)

    Augusto, R.S., E-mail: r.s.augusto@cern.ch [European Organization for Nuclear Research – CERN, 1211 Geneva 23 (Switzerland); Ludwig Maximilians – University of Munich, Munich (Germany); Mendonca, T.M.; Wenander, F. [European Organization for Nuclear Research – CERN, 1211 Geneva 23 (Switzerland); Penescu, L. [MedAustron GmbH, Wiener Neustadt (Austria); Orecchia, R. [CNAO – Centro Nazionale di Adroterapia Oncologica per il trattamento dei tumori, Pavia (Italy); Parodi, K. [Ludwig Maximilians – University of Munich, Munich (Germany); Ferrari, A.; Stora, T. [European Organization for Nuclear Research – CERN, 1211 Geneva 23 (Switzerland)

    2016-06-01

    Hadron therapy was first proposed in 1946 and is by now widespread throughout the world, as witnessed with the design and construction of the CNAO, HIT, PROSCAN and MedAustron treatment centres, among others. The clinical interest in hadron therapy lies in the fact that it delivers precision treatment of tumours, exploiting the characteristic shape (the Bragg peak) of the energy deposition in the tissues for charged hadrons. In particular, carbon ion therapy is found to be biologically more effective, with respect to protons, on certain types of tumours. Following an approach tested at NIRS in Japan [1], carbon ion therapy treatments based on {sup 12}C could be combined or fully replaced with {sup 11}C PET radioactive ions post-accelerated to the same energy. This approach allows providing a beam for treatment and, at the same time, to collect information on the 3D distributions of the implanted ions by PET imaging. The production of {sup 11}C ion beams can be performed using two methods. A first one is based on the production using compact PET cyclotrons with 10–20 MeV protons via {sup 14}N(p,α){sup 11}C reactions following an approach developed at the Lawrence Berkeley National Laboratory [2]. A second route exploits spallation reactions {sup 19}F(p,X){sup 11}C and {sup 23}Na(p,X){sup 11}C on a molten fluoride salt target using the ISOL (isotope separation on-line) technique [3]. This approach can be seriously envisaged at CERN-ISOLDE following recent progresses made on {sup 11}C{sup +} production [4] and proven post-acceleration of pure {sup 10}C{sup 3/6+} beams in the REX-ISOLDE linac [5]. Part of the required components is operational in radioactive ion beam facilities or commercial medical PET cyclotrons. The driver could be a 70 MeV, 1.2 mA proton commercial cyclotron, which would lead to 8.1 × 10{sup 711}C{sup 6+} per spill. This intensity is appropriate using {sup 11}C ions alone for both imaging and treatment. Here we report on the ongoing feasibility

  8. New developments of 11C post-accelerated beams for hadron therapy and imaging

    Science.gov (United States)

    Augusto, R. S.; Mendonca, T. M.; Wenander, F.; Penescu, L.; Orecchia, R.; Parodi, K.; Ferrari, A.; Stora, T.

    2016-06-01

    Hadron therapy was first proposed in 1946 and is by now widespread throughout the world, as witnessed with the design and construction of the CNAO, HIT, PROSCAN and MedAustron treatment centres, among others. The clinical interest in hadron therapy lies in the fact that it delivers precision treatment of tumours, exploiting the characteristic shape (the Bragg peak) of the energy deposition in the tissues for charged hadrons. In particular, carbon ion therapy is found to be biologically more effective, with respect to protons, on certain types of tumours. Following an approach tested at NIRS in Japan [1], carbon ion therapy treatments based on 12C could be combined or fully replaced with 11C PET radioactive ions post-accelerated to the same energy. This approach allows providing a beam for treatment and, at the same time, to collect information on the 3D distributions of the implanted ions by PET imaging. The production of 11C ion beams can be performed using two methods. A first one is based on the production using compact PET cyclotrons with 10-20 MeV protons via 14N(p,α)11C reactions following an approach developed at the Lawrence Berkeley National Laboratory [2]. A second route exploits spallation reactions 19F(p,X)11C and 23Na(p,X)11C on a molten fluoride salt target using the ISOL (isotope separation on-line) technique [3]. This approach can be seriously envisaged at CERN-ISOLDE following recent progresses made on 11C+ production [4] and proven post-acceleration of pure 10C3/6+ beams in the REX-ISOLDE linac [5]. Part of the required components is operational in radioactive ion beam facilities or commercial medical PET cyclotrons. The driver could be a 70 MeV, 1.2 mA proton commercial cyclotron, which would lead to 8.1 × 10711C6+ per spill. This intensity is appropriate using 11C ions alone for both imaging and treatment. Here we report on the ongoing feasibility studies of such approach, using the Monte Carlo particle transport code FLUKA [6,7] to simulate

  9. Automated synthesis of {sup 11}C-acetoacetic acid, a key alternate brain fuel to glucose

    Energy Technology Data Exchange (ETDEWEB)

    Tremblay, Sebastien [Research Center on Aging, Sherbrooke University Geriatric Institute, 1036 Belvedere Street South, Sherbrooke, Quebec, J1H 4C4 (Canada)]. E-mail: Sebastien.Tremblay@USherbrooke.ca; Ouellet, Rene [Sherbrooke Molecular Imaging Centre, Etienne-LeBel Clinical Research Centre, Centre Hospitalier Universitaire de Sherbrooke, Quebec, J1H 5N4 (Canada); Rodrigue, Serge [Sherbrooke Molecular Imaging Centre, Etienne-LeBel Clinical Research Centre, Centre Hospitalier Universitaire de Sherbrooke, Quebec, J1H 5N4 (Canada); Langlois, Rejean [Sherbrooke Molecular Imaging Centre, Etienne-LeBel Clinical Research Centre, Centre Hospitalier Universitaire de Sherbrooke, Quebec, J1H 5N4 (Canada); Department of Nuclear Medicine and Radiobiology, Quebec, J1H 5N4 (Canada); Benard, Francois [Sherbrooke Molecular Imaging Centre, Etienne-LeBel Clinical Research Centre, Centre Hospitalier Universitaire de Sherbrooke, Quebec, J1H 5N4 (Canada); Department of Nuclear Medicine and Radiobiology, Quebec, J1H 5N4 (Canada); Cunnane, Stephen C. [Research Center on Aging, Sherbrooke University Geriatric Institute, 1036 Belvedere Street South, Sherbrooke, Quebec, J1H 4C4 (Canada); Department of Medicine, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, Quebec, J1H 5N4 (Canada)

    2007-08-15

    An automated, one-pot radio-synthesis module for the routine preparation of 1-[{sup 11}C]acetoacetic acid has been developed. The enolate anion of acetone was reacted with [{sup 11}C]CO{sub 2} in tetrahydrofuran (THF), followed by hydrolysis and purification by ion-exchange chromatography. The total synthesis time was 18 min and radiochemical yield was 34% after decay correction. HPLC analysis showed {<=}3% impurities while residual THF ({<=}200 ppm) and ethanol ({<=}500 ppm) were well under the tolerable limits for human studies.

  10. Lack of association between prior depressive episodes and cerebral [(11)C]PiB binding

    DEFF Research Database (Denmark)

    Madsen, K; Hasselbalch, Bo Jacob; Frederiksen, K S

    2012-01-01

    Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-ß (Aß) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondem......Depressive symptoms are frequent in Alzheimer's disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-ß (Aß) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group...

  11. Erlotinib-associated interstitial lung disease in advanced pancreatic carcinoma: a case report and literature review.

    Science.gov (United States)

    Macerelli, Marianna; Mazzer, Micol; Foltran, Luisa; Cardellino, Giovanni Gerardo; Aprile, Giuseppe

    2015-07-24

    The combination of erlotinib and gemcitabine is a recognized option for patients with metastatic pancreatic cancer whose common adverse events such as skin rash, diarrhea, or fatigue are usually easily manageable. Interstitial lung disease (ILD) is a life-threatening toxicity reported in patients with non-small-cell lung cancers treated with epidermal growth factor receptor-tyrosine kinase inhibitors or gemcitabine. This side effect is extremely rare in patients with pancreatic cancer. We report fatal treatment-related ILD that occurred in a 67-year-old patient with metastatic pancreatic cancer. Risk factors and pathophysiology of ILD need further investigation but caution is highly recommended for patients with an underlying pulmonary disease when using erlotinib in monotherapy or combination therapy.

  12. Preoperative Radiation Therapy With Concurrent Capecitabine, Bevacizumab, and Erlotinib for Rectal Cancer: A Phase 1 Trial

    Energy Technology Data Exchange (ETDEWEB)

    Das, Prajnan, E-mail: PrajDas@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Eng, Cathy [Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Rodriguez-Bigas, Miguel A.; Chang, George J.; Skibber, John M.; You, Y. Nancy [Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Maru, Dipen M. [Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Munsell, Mark F. [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Clemons, Marilyn V. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kopetz, Scott E.; Garrett, Christopher R.; Shureiqi, Imad [Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Delclos, Marc E.; Krishnan, Sunil; Crane, Christopher H. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2014-02-01

    Purpose: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer. Methods and Materials: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine. Capecitabine dose was increased from 650 mg/m{sup 2} to 825 mg/m{sup 2} orally twice daily on the days of radiation therapy; erlotinib dose was increased from 50 mg orally daily in weeks 1 to 3, to 50 mg daily in weeks 1 to 6, to 100 mg daily in weeks 1 to 6. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab. Results: A total of 19 patients were enrolled, and 18 patients were considered evaluable. No patient had grade 4 acute toxicity, and 1 patient had grade 3 acute toxicity (hypertension). The MTD was not reached. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 4 patients (22%), posterior pelvic exenteration in 1 (6%), and abdominoperineal resection in 6 (33%). Of the 18 patients, 8 (44%) had pathologic complete response, and 1 had complete response of the primary tumor with positive nodes. Three patients (17%) had grade 3 postoperative complications (ileus, small bowel obstruction, and infection). With a median follow-up of 34 months, 1 patient developed distant metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 94%. Conclusions: The combination of preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib was well tolerated. The pathologic complete response rate appears promising and may warrant further investigation.

  13. {sup 18}F-Choline, {sup 11}C-choline and {sup 11}C-acetate PET/CT: comparative analysis for imaging prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Brogsitter, Claudia; Zoephel, Klaus; Kotzerke, Joerg [Carl Gustav Carus Medical School, University of Dresden, Department of Nuclear Medicine, Dresden (Germany)

    2013-07-15

    Prostate cancer (PCA) is the second most common tumour in men worldwide. Whereas prostate specific antigen (PSA) is an established biochemical marker, the optimal imaging method for all clinical scenarios has not yet been found. With the rising number of PET centres there is an increasing availability and use of {sup 18}F-/{sup 11}C-choline or {sup 11}C-acetate for staging of PCA. However, to date no final conclusion has been reached as to whether acetate or choline tracers should be preferred. In this review we provide an overview of the performance of choline and acetate PET for staging the primary and recurrent disease and lymph nodes in PCA, based on the literature of the last 10 years. Although predominantly choline has been used rather than acetate, both tracers performed in a similar manner in published studies. Choline as well as acetate have insufficient diagnostic accuracy for the staging of the primary tumour, due to a minimum detectable tumour size of 5 mm and inability to differentiate PCA from benign prostate hyperplasia, chronic prostatitis and high-grade intraepithelial neoplasia. Regarding lymph node staging, choline tracers have demonstrated a high specificity. Unfortunately, the sensitivity is only moderate. For staging recurrent disease, sensitivity depends on the level of serum PSA (PSA should be >2 ng/ml). This applies to both choline and acetate. However, despite these limitations, a significant number of patients with recurrent disease can benefit from PET imaging by a change in treatment planning. (orig.)

  14. 18F-Choline, 11C-choline and 11C-acetate PET/CT: comparative analysis for imaging prostate cancer patients.

    Science.gov (United States)

    Brogsitter, Claudia; Zöphel, Klaus; Kotzerke, Jörg

    2013-07-01

    Prostate cancer (PCA) is the second most common tumour in men worldwide. Whereas prostate specific antigen (PSA) is an established biochemical marker, the optimal imaging method for all clinical scenarios has not yet been found. With the rising number of PET centres there is an increasing availability and use of (18)F-/(11)C-choline or (11)C-acetate for staging of PCA. However, to date no final conclusion has been reached as to whether acetate or choline tracers should be preferred. In this review we provide an overview of the performance of choline and acetate PET for staging the primary and recurrent disease and lymph nodes in PCA, based on the literature of the last 10 years. Although predominantly choline has been used rather than acetate, both tracers performed in a similar manner in published studies. Choline as well as acetate have insufficient diagnostic accuracy for the staging of the primary tumour, due to a minimum detectable tumour size of 5 mm and inability to differentiate PCA from benign prostate hyperplasia, chronic prostatitis and high-grade intraepithelial neoplasia. Regarding lymph node staging, choline tracers have demonstrated a high specificity. Unfortunately, the sensitivity is only moderate. For staging recurrent disease, sensitivity depends on the level of serum PSA (PSA should be >2 ng/ml). This applies to both choline and acetate. However, despite these limitations, a significant number of patients with recurrent disease can benefit from PET imaging by a change in treatment planning.

  15. 5-HT(1A) receptor and 5-HTT binding during the menstrual cycle in healthy women examined with [(11)C] WAY100635 and [(11)C] MADAM PET.

    Science.gov (United States)

    Jovanovic, Hristina; Karlsson, Per; Cerin, Asta; Halldin, Christer; Nordström, Anna-Lena

    2009-04-30

    The aim of the present study was to explore the effects of the menstrual cycle phases on 5-HT(1A) receptor and 5-HTT binding potentials (BPs) in healthy women by using positron emission tomography (PET). Women were investigated in the follicular and luteal phase of the menstrual cycle with radioligands [(11)C]WAY10035 (n=13) and [(11)C]MADAM (n=8) to study 5-HT(1A) and 5-HTT BPs. The BPs values were quantified using the simplified reference tissue model. The phases of the menstrual cycle were characterized by transvaginal ultrasound (TSV) and plasma levels of hormones estradiol (E(2)), progesterone (P(4)), follicle stimulating hormone (FSH) and luteinizing hormone (LH).The 5-HT(1A) receptor and 5-HTT BPs did not significantly differ between follicular and luteal phases in any of the investigated regions. There were no significant correlations between the change in E(2) or P(4) values with the change in 5-HT(1A) receptor or 5-HTT BPs. The results provide principally a new in vivo finding in human female biology, suggesting the absence of influence of menstrual cycle phase on 5-HT(1A) receptors or 5-HTT. The finding however does not preclude that gonadal hormones differentially influence central serotonin system inwomen and men, which might contribute to gender differences in serotonin-associated disorders.

  16. PET studies with L-(1- sup 11 C)tyrosine, L-(methyl- sup 11 C)methionine and sup 18 F-fluorodeoxyglucose in relation to bromocryptine treatment

    Energy Technology Data Exchange (ETDEWEB)

    Daemen, B.J.G.; Elsinga, P.H.; Paans, A.M.J.; Vaalburg, W. (Rijksuniversiteit Groningen (Netherlands). Dept. of Nuclear Medicine); Zwertbroek, R.; Doorenbos, H. (Rijksuniversiteit Groningen (Netherlands). Dept. of Endocrinology)

    1991-07-01

    Aspects of metabolism in prolactinomas were investigated by positron emission tomography using L-(1-{sup 11}C)tyrosine, L-(methyl-{sup 11}C)methionine and fluorodeoxyl glucose 18. Using L-(1-{sup 11}C)tyrosine, four patients were monitored prior to and 18 h after an injection of 50 mg bromocryptine. At 18 h after bromocryptine intervention L-(1-{sup 11}C)tyrosine uptake into tumour was reduced with 28% (P<0.07). A correlation analysis of the bromocryptine-induced decrease in L-(1-{sup 11}C)tyrosine uptake and the reduction of serum prolactin levels indicated that the action of bromocryptine on prolactin synthesis and prolactin release is not coupled. In the untreated situation, the four patients were investigated with {sup 18}FDG as well, but the prolactinomas could not be visualized. Three untreated patients were studied with L-(methyl-{sup 11}C)methionine. The tumour-imaging potential of L-(methyl-{sup 11}C)methionine and L-(1-{sup 11}C)tyrosine appeared to be nearly equivalent for prolactinomas. Unlike prolactinoma tissue, the salivary glands showed a pronounced preference for L-(1-{sup 11}C)tyrosine as compared to L-(methyl-{sup 11}C)methionine. L-(1-{sup 11}C)tyrosine is a valuable tool to obtain information on the metabolism and treatment of prolactinomas. (orig.).

  17. Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

    Directory of Open Access Journals (Sweden)

    Jinu Abraham

    2011-01-01

    Full Text Available Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma.

  18. Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI

    Science.gov (United States)

    Ali, Ahmed Atef Ahmed; Hsu, Fei-Ting; Hsieh, Chia-Ling; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Wei, Zung-Hang; Chen, Cheng-Yu; Huang, Hsu-Shan

    2016-11-01

    We designed and synthesized novel theranostic nanoparticles that showed the considerable potential for clinical use in targeted therapy, and non-invasive real-time monitoring of tumors by MRI. Our nanoparticles were ultra-small with superparamagnetic iron oxide cores, conjugated to erlotinib (FeDC-E NPs). Such smart targeted nanoparticles have the preference to release the drug intracellularly rather than into the bloodstream, and specifically recognize and kill cancer cells that overexpress EGFR while being non-toxic to EGFR-negative cells. MRI, transmission electron microscopy and Prussian blue staining results indicated that cellular uptake and intracellular accumulation of FeDC-E NPs in the EGFR overexpressing cells was significantly higher than those of the non-erlotinib-conjugated nanoparticles. FeDC-E NPs inhibited the EGFR-ERK-NF-κB signaling pathways, and subsequently suppressed the migration and invasion capabilities of the highly invasive and migrative CL1-5-F4 cancer cells. In vivo tumor xenograft experiments using BALB/c nude mice showed that FeDC-E NPs could effectively inhibit the growth of tumors. T2-weighted MRI images of the mice showed significant decrease in the normalized signal within the tumor post-treatment with FeDC-E NPs compared to the non-targeted control iron oxide nanoparticles. This is the first study to use erlotinib as a small-molecule targeting agent for nanoparticles.

  19. Resolution of vocal fold leukoplakia during erlotinib treatment for lung cancer.

    Science.gov (United States)

    Francis, David O; Misono, Stephanie; Somerville, Jessica; McWhorter, Andrew; Garrett, C Gaelyn

    2016-02-01

    Treatment of vocal fold leukoplakia is complicated because it is associated with a high rate of recurrence after excision and it has the potential for progression to malignancy. Authors have presented different approaches to management, one of which is directed serial excisional biopsies. Ideally, a topical or systemic agent could be administered to eradicate this troublesome condition. We present the case of a patient with an 8-year history of vocal fold leukoplakia treated with directed serial biopsies who was subsequently diagnosed with non-small-cell lung cancer and treated with erlotinib. He experienced a complete resolution after 2 months of erlotinib therapy for his lung cancer. Immunohistochemistry confirmed that his lesion exhibited a much higher than normal expression of epidermal growth factor receptor (EGFR), which supports the idea that EGFR antagonism may combat EGFR-avid leukoplakia. However, we caution that the clinical observation made herein is an association and should not be misconstrued as a recommendation regarding the safety, efficacy, or economy of using erlotinib for the treatment of vocal fold leukoplakia.

  20. Identification of gene expression profiling associated with erlotinib-related skin toxicity in pancreatic adenocarcinoma patients.

    Science.gov (United States)

    Caba, Octavio; Irigoyen, Antonio; Jimenez-Luna, Cristina; Benavides, Manuel; Ortuño, Francisco M; Gallego, Javier; Rojas, Ignacio; Guillen-Ponce, Carmen; Torres, Carolina; Aranda, Enrique; Prados, Jose

    2016-11-15

    Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients. The study included 34 PDAC patients treated with erlotinib: 21 patients developed any grade of SR, while 13 patients did not (controls). Before administering any chemotherapy regimen and the development of SR, we collected RNA from peripheral blood samples of all patients and studied the differential gene expression pattern using the Illumina microarray platform HumanHT-12 v4 Expression BeadChip. Seven genes (FAM46C, IFITM3, GMPR, DENND6B, SELENBP1, NOL10, and SIAH2), involved in different pathways including regulatory, migratory, and signalling processes, were downregulated in PDAC patients with SR. Our results suggest the existence of a gene expression profiling significantly correlated with erlotinib-induced SR in PDAC that could be used as prognostic indicator in this patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Effects of ketoconazole on the biodistribution and metabolism of [{sup 11}C]loperamide and [{sup 11}C]N-desmethyl-loperamide in wild-type and P-gp knockout mice

    Energy Technology Data Exchange (ETDEWEB)

    Seneca, Nicholas; Zoghbi, Sami S.; Shetty, H. Umesha; Tuan, Edward; Kannan, Pavitra; Taku, Andrew; Innis, Robert B. [Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892 (United States); Pike, Victor W. [Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892 (United States)], E-mail: pikev@mail.nih.gov

    2010-04-15

    Introduction: [{sup 11}C]Loperamide and [{sup 11}C]N-desmethyl-loperamide ([{sup 11}C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [{sup 11}C]loperamide metabolism is N-demethylation to [{sup 11}C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [{sup 11}C]loperamide and [{sup 11}C]dLop in mice, and thereby improve the quality of these radiotracers. Methods: Studies were performed in wild-type and P-gp knockout (mdr-1a/b -/-) mice. During each of seven study sessions, one pair of mice, comprising one wild-type and one knockout mouse, was pretreated with ketoconazole (50 mg/kg, ip), while another such pair was left untreated. Mice were sacrificed at 30 min after injection of [{sup 11}C]loperamide or [{sup 11}C]dLop. Whole brain and plasma samples were measured for radioactivity and analyzed with radio-high-performance liquid chromatography. Results: Ketoconazole increased the plasma concentrations of [{sup 11}C]loperamide and its main radiometabolite, [{sup 11}C]dLop, by about twofold in both wild-type and knockout mice, whereas the most polar radiometabolite was decreased threefold. Furthermore, ketoconazole increased the brain concentrations of [{sup 11}C]loperamide and the radiometabolite [{sup 11}C]dLop by about twofold in knockout mice, and decreased the brain concentrations of the major and most polar radiometabolite in wild-type and knockout mice by 82% and 49%, respectively. In contrast, ketoconazole had no effect on plasma and brain distribution of administered [{sup 11}C]dLop and its radiometabolites in either wild-type or knockout mice, except to increase the low plasma [{sup 11}C]dLop concentration. The least polar radiometabolite of [{sup 11}C]dLop was identified with LC-MS{sup n} as the N-hydroxymethyl analog of [{sup 11}C]dLop and this also behaved as a P-gp substrate. Conclusion: In this study, ketoconazole (50 mg/kg, ip) proved

  2. Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Noemí Reguart

    2010-06-01

    Full Text Available Noemí Reguart1, Andrés Felipe Cardona2, Rafael Rosell31Medical Oncology Service, ICMHO, Hospital Clinic Barcelona, Barcelona, Spain; 2Clinical and Translational Oncology Group, Institute of Oncology, Fundación Santa Fe de Bogotá, Bogotá, D.C., Colombia; 3Medical Oncology Service, Catalan Institute of Oncology, ICO, Hospital Germans Trias i Pujol, Badalona, Barcelona, SpainAbstract: Erlotinib hydrochloride (Tarceva® is a member of a class of small molecule inhibitors that targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR, with anti-tumor activity in preclinical models. Erlotinib represents a new-generation of agents known as “targeted therapies” designed to act upon cancer cells by interfering with aberrant specific activated pathways needed for tumor growth, angiogenesis and cell survival. Since its approval in November 2004 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC after the failure of at least one prior chemotherapy regimen and with a view to improving patients’ outcomes and prevent symptoms, the scientific community has evaluated the potential role of erlotinib in other scenarios such as in maintenance therapy and, in first-line setting for a selected population based on biological markers of response such as mutations of the EGFR. The convenient once-a-day pill administration and the good toxicity profile of erlotinib make it a reasonable candidate for testing in this context. This report provides a review of the role of erlotinib therapy in advanced NSCLC. It summarizes current data and perspectives of erlotinib in upfront treatment and maintenance for advanced NSCLC as well as looking at candidate biomarkers of response to these new targeted-agents.Keywords: erlotinib, tyrosine kinase inhibitors, first line, maintenance, non-small-cell lung cancer

  3. Astronomical forcing of an exceptionally long Sahel wet phase during Marine Isotope Stage 11c

    Science.gov (United States)

    Prange, Matthias; Rachmayani, Rima; Schulz, Michael

    2016-04-01

    Increased rainfall and expanded vegetation over North Africa during the early-to-mid Holocene was related to an intensified West African monsoon and a northward displacement of the monsoon trough triggered by astronomical forcing. Similar wet phases are evidenced for earlier interglacials including Marine Isotope Stage (MIS) 11c (ca. 425-395 ka before present). We performed a series of time slice simulations using the comprehensive coupled climate model CCSM3 including a dynamic vegetation module in order to examine the dynamics of the MIS 11c humid period. Proxy records from a marine sediment core site off Northwest Africa suggest an extremely long Sahel/Sahara wet phase during MIS 11c between ca. 420 and 405 ka ago, revealing that North African rainfall changes did not simply follow local summer insolation. Instead, the climate model simulations suggest an important role of the obliquity-driven intra-hemispheric insolation gradient in forcing Sahelian rainfall changes. The specific phasing between precession and obliquity during the MIS 11c interglacial resulted in the exceptionally long wet phase in the Sahel region. The early part of this wet phase was primarily induced by northern-hemispheric differential warming in response to maximum obliquity around 416 ka before present. As such, this interval may well serve as an analog for potential future Sahel rainfall increase induced by strong northern hemisphere extratropical warming.

  4. Whole body [{sup 11}C]-dihydrotetrabenazine imaging of baboons: biodistribution and human radiation dosimetry estimates

    Energy Technology Data Exchange (ETDEWEB)

    Murthy, Rajan [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); New York State Psychiatric Institute, Department of Neuroscience, Division of Brain Imaging, New York, NY (United States); Harris, Paul; Leibel, Rudolph [Columbia University College of Physicians and Surgeons, Department of Medicine, New York, NY (United States); Simpson, Norman; Parsey, Ramin [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); Van Heertum, Ronald [Columbia University College of Physicians and Surgeons, Department of Radiology, New York, NY (United States); New York State Psychiatric Institute, Department of Neuroscience, Division of Brain Imaging, New York, NY (United States); Mann, J.J. [Columbia University College of Physicians and Surgeons, Department of Psychiatry, New York, NY (United States); Columbia University College of Physicians and Surgeons, Department of Radiology, New York, NY (United States); New York State Psychiatric Institute, Department of Neuroscience, Division of Brain Imaging, New York, NY (United States)

    2008-04-15

    Vesicular monoamine transporter type 2 abundance quantified using the radiotracer [{sup 11}C]-dihydrotetrabenazine (DTBZ) has been used to study diagnosis and pathogenesis of dementia and psychiatric disorders in humans. In addition, it may be a surrogate marker for insulin-producing pancreatic beta cell mass, useful for longitudinal measurements using positron emission tomography to track progression of autoimmune diabetes. To support the feasibility of long-term repeated administrations, we estimate the biodistribution and dosimetry of [{sup 11}C]-DTBZ in humans. Five baboon studies were acquired using a Siemens ECAT camera. After transmission scanning, 165-210 MBq of [{sup 11}C]-DTBZ were injected, and dynamic whole body emission scans were conducted. Time-activity data were used to obtain residence times and estimate absorbed radiation dose according to the MIRD model. Most of the injected tracer localized to the liver and the lungs, followed by the intestines, brain, and kidneys. The highest estimated absorbed radiation dose was in the stomach wall. The largest radiation dose from [{sup 11}C]-DTBZ is to the stomach wall. This dose estimate, as well as the radiation dose to other radiosensitive organs, must be considered in evaluating the risks of multiple administrations. (orig.)

  5. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia

    Science.gov (United States)

    Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a beta2 integrin expressed on human monocytes and a subset of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial c...

  6. 11C-harmine as a potential PET tracer for ductal pancreas cancer: in vitro studies.

    Science.gov (United States)

    Herlin, G; Persson, B; Bergström, M; Långström, B; Aspelin, P

    2003-04-01

    Our objective was to find a tracer in diagnosing human pancreatic cancer using positron emission tomography (PET). For this purpose in vitro test of pancreatic tissues with autoradiography was used. Autoradiography was performed with (11)C-harmine (a MAO-A-inhibitor) with and without competitive inhibition. Tissue preparations were obtained from normal human pancreas and pancreatic cancer. The uptake was compared with rat brain or pig brain, tissues with high expression of MAO-A. Nine autoradiography studies on 16 samples from five different human pancreatic cancers gave a significant level of specific binding of (11)C-harmine in 13, and 3 samples did not give a significant level of specific binding of (11)C-harmine. All 16 samples were analysed with autoradiography. Compared with rat brain, the uptake in the human cancers varied between 9 and 43% except for one tissue preparation which had a too low value for measurement. This study shows expression of MAO-A in human pancreatic cancer. This is readily characterised in vitro. The potential use of (11)C-harmine in the diagnosis of pancreatic cancer using PET might be limited, but further PET studies are necessary.

  7. Visual assessment of [{sup 11}C]PIB PET in patients with cognitive impairment

    Energy Technology Data Exchange (ETDEWEB)

    Suotunen, Timo; Hirvonen, Jussi; Arponen, Eveliina; Teraes, Mika; Seppaenen, Marko [Turku PET Centre, P.O. Box 52, Turku (Finland); Immonen-Raeihae, Pirjo [Turku University Hospital, Turku (Finland); Aalto, Sargo [Turku PET Centre, P.O. Box 52, Turku (Finland); Aabo Academy University, Department of Psychology, Turku (Finland); Lisinen, Irina [University of Turku, Research Centre of Applied and Preventive Cardiovascular Medicine, Turku (Finland); Koski, Kari [Salo Regional Hospital, Neurologic Outpatient Department, Salo (Finland); Sulkava, Raimo [Kuopio University Hospital, Kuopio (Finland); University of Kuopio, Geriatric Unit, School of Public Health and Clinical Nutrition, Kuopio (Finland); Rinne, Juha O. [Turku PET Centre, P.O. Box 52, Turku (Finland); Turku University Hospital, Turku (Finland)

    2010-06-15

    The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4{sup '}-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia. We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects. The evaluation of visual classification as ''normal'' or ''abnormal'' showed good interobserver agreement ({kappa} = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p < 0.001). The most difficult visually assessed brain area was the putamen ({kappa} = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60). Our study shows that visual evaluation of [{sup 11}C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings. (orig.)

  8. Test-retest reproducibility of dopamine D{sub 2/3} receptor binding in human brain measured by PET with [{sup 11}C]MNPA and [{sup 11}C]raclopride

    Energy Technology Data Exchange (ETDEWEB)

    Kodaka, Fumitoshi [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); Jikei University School of Medicine, Department of Psychiatry, Tokyo (Japan); Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Kimura, Yasuyuki; Fujie, Saori; Takano, Harumasa; Fujiwara, Hironobu; Sasaki, Takeshi; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Neuroimaging Program, Molecular Imaging Center, Chiba (Japan); Nakayama, Kazuhiko [Jikei University School of Medicine, Department of Psychiatry, Tokyo (Japan); Halldin, Christer; Farde, Lars [Karolinska Institutet, Department of Clinical Neuroscience, Stockholm (Sweden)

    2013-04-15

    Dopamine D{sub 2/3} receptors (D{sub 2/3}Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D{sub 2/3} {sup HIGH}), which has a high affinity for endogenous dopamine, and low-affinity state (D{sub 2/3} {sup LOW}). The density of D{sub 2/3} {sup HIGH} can be measured with (R)-2-{sup 11}CH{sub 3}O-N-n-propylnorapomorphine ([{sup 11}C]MNPA), while total density of D{sub 2/3} {sup HIGH} and D{sub 2/3} {sup LOW} (D{sub 2/3}Rs) can be measured with [{sup 11}C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [{sup 11}C]MNPA to that of [{sup 11}C]raclopride ([{sup 11}C]MNPA/[{sup 11}C]raclopride) may reflect the proportion of the density of D{sub 2/3} {sup HIGH} to that of D{sub 2/3}Rs. In the caudate and putamen, [{sup 11}C]MNPA/[{sup 11}C]raclopride reflects the proportion of the density of D{sub 2} {sup HIGH} to that of D{sub 2}Rs. To evaluate the reliability of the PET paradigm with [{sup 11}C]MNPA and [{sup 11}C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP{sub ND}) measured with [{sup 11}C]MNPA and of [{sup 11}C]MNPA/[{sup 11}C]raclopride in healthy humans. Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [{sup 11}C]MNPA and [{sup 11}C]raclopride scans. BP{sub ND} values in the caudate and putamen were calculated. Test-retest reproducibility of BP{sub ND} of [{sup 11}C]MNPA and [{sup 11}C]MNPA/[{sup 11}C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). The absolute variability of [{sup 11}C]MNPA BP{sub ND} was 5.30 {+-} 3.96 % and 12.3 {+-} 7.95 % and the ICC values of [{sup 11}C]MNPA BP{sub ND} were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [{sup 11}C]MNPA/[{sup 11}C]raclopride was 6.11 {+-} 3.68 % and 11.60 {+-} 5.70 % and the ICC values of [{sup

  9. Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: a case report and review of the literature.

    Science.gov (United States)

    Togashi, Yosuke; Masago, Katsuhiro; Hamatani, Yasuhiro; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Mishima, Michiaki

    2012-08-01

    The most serious adverse reaction associated with treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is drug-induced interstitial lung disease (ILD). Because EGFR-TKIs are key drugs for patients with non-small cell lung cancer who have somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations), several cases of retreatment with EGFR-TKIs after ILD induced by these drugs have been reported. Here, we present a 68-year-old man with lung adenocarcinoma and leptomeningeal metastases having an EGFR mutation who was retreated with erlotinib after erlotinib-induced ILD. He suffered no ILD recurrence and his leptomeningeal metastases dramatically improved. In addition to the present case, reports of nine patients who were retreated with EGFR-TKIs after ILD were found in the literature. Only one patient had recurrence of ILD (although seven were retreated at a reduced dose of EGFR-TKIs, including the patient with recurrence). In contrast, three patients had no recurrence of ILD even without dose-reduction. These reports suggest that dose-reduction plays a limited role in preventing recurrence. Many patients received corticosteroids during retreatment, but not the one with recurrence of ILD. This may suggest that corticosteroids can prevent recurrence due to their antiinflammatory properties.

  10. Utilidad de 11C-metionina PET/CT en neurooncología

    Directory of Open Access Journals (Sweden)

    Ignacio Casas Parera

    2013-06-01

    Full Text Available La tomografía por emisión de positrones con metionina carbono 11 (11C-metionina PET/TC se utiliza en la evaluación de los tumores primarios del sistema nervioso central. Describimos nuestra experiencia sobre los primeros 4 pacientes con tumores de la serie glial estudiados con 11C-metionina PET/TC. Este es un estudio descriptivo, observacional y prospectivo. Se presentan 4 pacientes entre 38-50 años de edad con diagnóstico de gliomas (clasificación de la OMS. A todos se les realizó RM y 11C-metionina PET/TC para evaluar actividad tumoral y diferenciar progresión tumoral de pseudoprogresión. Caso 1, gliomatosis cerebri grado II posradioterapia. Caso 2, glioblastoma grado IV postratamiento RT + temozolomida. Caso 3, oligodendroglioma grado II posradioterapia en 1993. Caso 4, oligoastrocitoma anaplásico grado III postratamiento RT + temozolomida. El patrón de captación de la 11C-metionina comparativamente con la RM, demostró progresión tumoral en los casos 1, 3 y 4; en el caso 2 mostró captación aunque el diagnóstico final fue pseudoprogresión. A diferencia del PET con 18fluordeoxiglucosa, la captación de 11C-metionina en el tejido cerebral normal y en la pseudoprogresión es baja, y los gliomas se visualizan como áreas metabólicamente activas. En los casos presentados, el 11C-metionina PET/TC proveyó información valiosa sobre el comportamiento y extensión de la lesión, aunque en uno de los casos presentados no diferenció progresión tumoral de pseudoprogresión. El 11C-metionina PET/TC sería una herramienta útil en el estudio y seguimiento de los pacientes con gliomas.

  11. [11C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain

    Science.gov (United States)

    Visser, Anniek KD; Ramakrishnan, Nisha K; Willemsen, Antoon TM; Di Gialleonardo, Valentina; de Vries, Erik FJ; Kema, Ido P; Dierckx, Rudi AJO; van Waarde, Aren

    2014-01-01

    The PET tracer [11C]5-hydroxytryptophan ([11C]5-HTP), which is converted to [11C]5-hydroxytryptamine ([11C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [11C]5-HTP in rat? Male rats were scanned with [11C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [11C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [11C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [11C]5-HTP to [11C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [11C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents. PMID:24084697

  12. [(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain.

    Science.gov (United States)

    Visser, Anniek K D; Ramakrishnan, Nisha K; Willemsen, Antoon T M; Di Gialleonardo, Valentina; de Vries, Erik F J; Kema, Ido P; Dierckx, Rudi A J O; van Waarde, Aren

    2014-01-01

    The PET tracer [(11)C]5-hydroxytryptophan ([(11)C]5-HTP), which is converted to [(11)C]5-hydroxytryptamine ([(11)C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [(11)C]5-HTP in rat? Male rats were scanned with [(11)C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [(11)C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [(11)C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [(11)C]5-HTP to [(11)C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [(11)C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.

  13. PET Imaging of the AT{sub 1} receptor with [{sup 11}C]KR31173

    Energy Technology Data Exchange (ETDEWEB)

    Zober, Tamas G. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Mathews, William B. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Seckin, Esen [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Yoo, Sung-eun [Center for Biological Modulators, Korea Research Institute of Chemical Technology, Daejeon 305-343 (Korea, Republic of); Hilton, John [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Xia Jinsong [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Sandberg, Kathryn [Department of Medicine, Georgetown University, Washington, DC 20057 (United States); Ravert, Hayden T. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Dannals, Robert F. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States); Szabo, Zsolt [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0817 (United States)]. E-mail: zszabo@jhmi.edu

    2006-01-15

    Aim: The goal of this study was to investigate the binding characteristics of [{sup 11}C]KR31173 and its applicability for PET studies of the AT{sub 1} receptor (AT{sub 1}R). Methods: Ex vivo biodistribution and pharmacology were tested in mice. PET imaging was performed in mice, beagle dogs and a baboon. To assess nonspecific binding, PET imaging was performed both before and after pretreatment with a potent AT{sub 1}R antagonist. In the baboon, PET imaging was also performed with the previously developed radioligand [{sup 11}C]L-159,884 for comparison. Results: Ex vivo biodistribution studies in mice showed specific binding rates of 80-90% in the adrenals, kidneys, lungs and heart. Specific binding was confirmed in mice using small animal PET. In dogs, renal cortex tissue concentration at 75-95 min postinjection (pi) was 63 nCi/ml per millicurie at a specific binding rate of 95%. In the baboon renal cortex, tissue activity at 55-75 min pi was 345 nCi/ml per millicurie. In the baboon the specific binding of [{sup 11}C]KR31173 was higher (81%) than the specific binding of [{sup 11}C]L-159,884 (34%). Conclusion: [{sup 11}C]KR31173 shows accumulation and significant specific binding to the AT{sub 1}R in the kidneys of mice, dogs and baboon. These findings suggest that this radioligand is suited for imaging the renal cortical AT{sub 1}R in multiple species.

  14. Biodistribution and radiation dosimetry of [{sup 11}C]raclopride in healthy volunteers

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Maria-Joao; Bourgeois, Sandrine; Lievre, Marie-Angele; Bottlaender, Michel; Gervais, Philippe; Dolle, Frederic; Syrota, Andre [Commissariat a l' Energie Atomique, Departement de Recherche Medicale, Orsay (France); Ricard, Marcel [Institut Gustave Roussy, Service de Physique, Villejuif (France)

    2005-08-01

    This study reports on the whole-body biodistribution and radiation dosimetry of [{sup 11}C]raclopride, a dopamine D{sub 2} receptor antagonist. In three healthy male volunteers, whole-body scans were performed up to 2 h following i.v. injection of 320{+-}65 MBq [{sup 11}C]raclopride. Transmission scans (3 min per step, eight or nine steps according to the height of the subject) in 2D mode were used for subsequent attenuation correction of emission scans. Emission scans (1 min per step, eight or nine steps) were acquired over 2 h. Venous blood samples and urine were collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, lungs, kidneys and liver was fitted to a mono-exponential model, as an uptake phase followed by a mono-exponential washout, for urinary bladder to generate time-activity curves. Using the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. Blood pressure and ECG findings remained unchanged after tracer injection. The analysed blood and urine pharmacological parameters did not change significantly after [{sup 11}C]raclopride injection. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the gall-bladder, kidneys and liver. High activity was observed in the gall-bladder during the whole study. The kidneys, urinary bladder wall, liver and gall-bladder received the highest absorbed doses. The average effective dose of [{sup 11}C]raclopride was estimated to be 6.7{+-}0.4 {mu}Sv/MBq. The amount of [{sup 11}C]raclopride required for adequate dopamine D{sub 2} receptor imaging results in an acceptable effective dose equivalent, permitting two or three repeated clinical PET imaging studies, with the injection of 222 MBq for each study. (orig.)

  15. Quantification of (R)-[{sup 11}C]PK11195 binding in rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Kropholler, M.A.; Boellaard, R.; Kloet, R.W.; Lammertsma, A.A. [VU University Medical Centre, Department of Nuclear Medicine and PET Research, PO Box 7057, Amsterdam (Netherlands); Elzinga, E.H.; Voskuyl, A.E. [VU University Medical Centre, Department of Rheumatology, Amsterdam (Netherlands); Laken, C.J. van der; Dijkmans, B.A.C. [VU University Medical Centre, Department of Rheumatology, Amsterdam (Netherlands); Jan van Breemen Instituut, Amsterdam (Netherlands); Maruyama, K. [Osaka University Graduate School of Medicine, Department of Nuclear Medicine and Tracer Kinetics, Osaka (Japan)

    2009-04-15

    Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[{sup 11}C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[{sup 11}C]PK11195 binding in the knee joints of RA patients. Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[{sup 11}C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[{sup 11}C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V{sub d}) and standardized uptake values (SUV) were evaluated. AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V{sub d} obtained using different input functions (R {sup 2}=0.80-1.00) and between V{sub d} obtained with one- and two-tissue reversible compartment models (R {sup 2}=0.75-0.94). A high correlation was observed between optimal V{sub d} and SUV after injection (R {sup 2}=0.73). (R)-[{sup 11}C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V{sub d}, SUV is a practical alternative for clinical use. (orig.)

  16. [(11)C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET.

    Science.gov (United States)

    Halldin, Christer; Lundberg, Johan; Sóvágó, Judit; Gulyás, Balázs; Guilloteau, Denis; Vercouillie, Johnny; Emond, Patrick; Chalon, Sylvie; Tarkiainen, Jari; Hiltunen, Jukka; Farde, Lars

    2005-12-01

    The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.

  17. The Analysis of Erlotinib on Brain Metastases in Patients with Non-small-cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Baohui HAN

    2009-12-01

    Full Text Available Background and objective Brain metastases are common in non-small-cell lung cancer (NSCLC and the prognosis is poor. Erlotinib is a specific inhibitor of the epidermal growth factor receptor-associated tyrosine kinase (EGFRTKI, which has been gradually used in the treatment for advanced NSCLC. The aim of this study is to evaluate the antitumor efficacy and its relevant factors of erlotinib in NSCLC patients with brain metastases. Methods The clinical data of 30 NSCLC patients with brain metastases were reviewed retrospectively. All of them were treated with erlotinib, given orally 150mg daily. These patients discontinued administration of erlotinib until disease progression, death or intolerable side effects. Results In terms of intracranial lesions, partial response (PR was observed in 2 patients (6.7%, with stable disease (SD in 17 patients (56.7%, for overall disease control rate (DCR of 63.4%. As for systemic disease, PR was observed in 2 patients (6.7%, with SD in 5 patients (16.7%, for overall DCR of 23.4%. There was no statistical difference in DCR among different subtypes of age, gender, smoking history, histology, PS score, the number of brain metastases, the onset of brain metastases, chemotherapy, brain radiotherapy and side effects. The median time to disease progression (MTTP and median survival time (MST was 2.4 months and 7.7 months respectively. The 1 and 2 year survival rate was 38.4% and 15.2%. The univariate analysis showed that the survival time was related to the patients’ PS score, smoking history, brain radiotherapy and chemotherapy. The multivariate analysis indicated that brain radiotherapy was the independent prognostic factor and the relationship between the survival time and smoking history was near to statistical significance. Conclusion The patients receiving brain radiotherapy may have better survival benefit. Non-smokers have a trend to survive longer than smokers. Erlotinib may be effective on brain metastases

  18. Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP).

    Science.gov (United States)

    Cardona, Andrés F; Arrieta, Oscar; Zapata, Martín Ignacio; Rojas, Leonardo; Wills, Beatriz; Reguart, Noemí; Karachaliou, Niki; Carranza, Hernán; Vargas, Carlos; Otero, Jorge; Archila, Pilar; Martín, Claudio; Corrales, Luis; Cuello, Mauricio; Ortiz, Carlos; Pino, Luis E; Rosell, Rafael; Zatarain-Barrón, Zyanya Lucia

    2017-08-01

    Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post-progression tumor specimens were collected for molecular analysis. Post-progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. Mean age was 59.4 ± 13.9 years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8 months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (95% CI: 2.2-36.6). Median overall survival (OS) from treatment initiation was 32.9 months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p = 0.05). Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians.

  19. In vivo imaging of astrocytosis in Alzheimer's disease: an {sup 11}C-L-deuteriodeprenyl and PIB PET study

    Energy Technology Data Exchange (ETDEWEB)

    Santillo, Alexander Frizell [Lund University, Geriatric Psychiatry, Department of Clinical Medicine, Lund (Sweden); Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Gambini, Juan Pablo; Engler, Henry [University of the Republic, Faculty of Medicine and Faculty of Science, Montevideo (Uruguay); Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo (Uruguay); Lannfelt, Lars; Kilander, Lena [Uppsala University, Department of Public Health and Caring Sciences/Geriatrics, Uppsala (Sweden); Laangstroem, Bengt [Uppsala University, Departments of Biochemistry and Organic Chemistry, Uppsala (Sweden); Ulla-Marja, Luohija [Helsinki University Hospital, Helsinki (Finland); Uppsala University, Department of Medical Sciences, Clinical Physiology, Uppsala (Sweden)

    2011-12-15

    Astrocytosis is an important feature of the neuropathology of Alzheimer's disease (AD), yet there is currently no way of detecting this phenomenon in vivo. In this study we examine the retention of the positron emission tomography (PET) tracer {sup 11}C-L-deuteriodeprenyl (DED), thought to bind activated astrocytes, in 9 patients with moderate to severe AD compared with 11 healthy controls. As a measure of amyloid load, {sup 11}C-labelled Pittsburgh Compound B (PIB) retention was determined. Results show a significantly higher {sup 11}C-L-DED retention in the frontal (35.1% increase, p=0.001), parietal (35.2%, p=0.001), temporal (30.9%, p=0.0001) and medial temporal lobes (22.3%, p=0.001) in AD compared to healthy controls after blood flow correction. DED retention in the sensorimotor and occipital cortices, and in white matter and subcortical structures, did not differ between groups. There was a moderate but statistically significant (r=0.492, p=0.01) correlation between DED and PIB retention values. Our conclusion is that DED may serve as an in vivo marker for astrocytosis in AD, providing a window into intermediate processes between amyloidosis and neuronal loss and a means of monitoring immunotherapy. (orig.)

  20. Synthesis of the racemate and individual enantiomers of [[sup 11]C]methylphenidate for studying presynaptic dopaminergic neutron with positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.-S.; Sugano, Y.; Fowler, J.S.; Salata, C. (Brookhaven National Lab., Upton, NY (United States))

    1994-10-01

    Carbon-11 labeled dl-threo-methylphenidate (methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin), a psychostimulant drug widely used to treat attention deficit hyperactivity disorder, was prepared in two steps: O-methylation of the N-protected dl-threo-ritalinic acid derivative with [[sup 11]C]methyl iodide followed by deprotection. The same strategy was applied for the preparation of C-11 labeled individual enantiomers of threo-methylphenidate from N-protected d-threo-l-threo-ritalinic acid. The subsequent C18 sep-pak and reverse-phase HPLC purification resulted in ca. 40% radiochemical yield with a total synthesis time of 40 minutes and an average specific activity of 1.5 Ci/[mu]mole (at EOB). (author).

  1. Hepatic Failure and Hepatorenal Syndrome Secondary to Erlotinib: A Possible Etiology of Complications in a Patient with Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Krishna S Gunturu

    2010-09-01

    Full Text Available We would like to present a case in reference to an article entitled "Hepatic failure and hepatorenal syndrome secondary to erlotinib. Safety reminder” previously published in JOP as Pancreas News in November 2008 [1]. Erlotinib is a epidermal growth factor (EGFR tyrosine kinase inhibitor which is highly expressed and mutated in certain cancers. It binds in a reversible fashion to the adenosine triphosphate (ATP binding site of the receptor [2]. For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change in their intracellular structure exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped. It is approved by the Food and Drug Administration (FDA for pancreatic cancer and non small cell lung cancer [3, 4, 5, 6]. Most of the cytotoxic drugs side effect profile is not completely known [7]. Erlotinib is predominantly metabolized in the liver via cytochrome P450 system, by the enzyme P450 3A4, and excreted in the bile. Based on the in vitro and in vivo data suggesting that erlotinib is cleared primarily by the liver, it is possible that erlotinib exposure may be increased in patients with hepatic dysfunction.

  2. A Retrospective Study of Erlotinib in the Treatment of 70 Patients with Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Mingzhi LI

    2009-12-01

    Full Text Available Background and objective Erlotinib is a small molecular inhibitor of tyrosine kinase. Multiple foreign and demestic studies have confirmed that it can prolong the median progression-free survival time (PFS and the overall survival (OS, which could be more significant in the selected population. In this study we retrospectively oberserved the response, the survival and adverse reaction of erlotinib in non-selected non-small cell lung cancer. Methods The retrospective study included seventy non-small-cell lung cancer patients, who were treated with erlotinib from July 2005 to July 2009. Erlotinib was prescribed at a dose of 150 mg daily. Results Sixty-eight patients were evaluated response. Among these patients, CR 0 case, PR 26 cases, RR (CR+PR 38.2% and SD 24 cases as their best response, disease control rate (DCR=CR+PR+SD 73.5%, PD 18 cases (26.5%. Sixty-three patients were evaluated PFS. The median PFS was 3.0 months. The median PFS of adenocarcinoma and non-adenocarcinoma was 3.0 months vs 2.6 months. The drug-related adverse reactions were skin rash , diarrhea and interstitial lung disease (ILD(4.3%. Conclusion Erlotinib is active in non-small cell lung cancer, and it is much more effective in adenocarcinoma and non-smoking patients. There is no difference in response or suvival concerning the sexuality. It is well tolerated in most patients.

  3. Sunitinib Plus Erlotinib for the Treatment of Advanced/Metastatic Non-Small-Cell Lung Cancer A Lead-In Study

    NARCIS (Netherlands)

    Blumenschein, George R.; Ciuleanu, Tudor; Robert, Francisco; Groen, Harry J. M.; Usari, Tiziana; Ruiz-Garcia, Ana; Tye, Lesley; Chao, Richard C.; Juhasz, Erzsebet

    2012-01-01

    Background: This randomized, double-blind, multicenter study evaluated sunitinib plus erlotinib versus placebo plus erlotinib. Subjects with advanced non-small-cell lung cancer had received prior treatment with a platinum-based regimen. Here, we report safety, pharmacokinetics, and antitumor activit

  4. Silibinin suppresses EMT-driven erlotinib resistance by reversing the high miR-21/low miR-200c signature in vivo

    Science.gov (United States)

    Cufí, Sílvia; Bonavia, Rosa; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; Martin-Castillo, Begoña; Barrajón-Catalán, Enrique; Visa, Joana; Segura-Carretero, Antonio; Joven, Jorge; Bosch-Barrera, Joaquim; Micol, Vicente; Menendez, Javier A.

    2013-01-01

    The flavolignan silibinin was studied for its ability to restore drug sensitivity to EGFR-mutant NSCLC xenografts with epithelial-to-mesenchymal transition (EMT)-driven resistance to erlotinib. As a single agent, silibinin significantly decreased the tumor volumes of erlotinib-refractory NSCLC xenografts by approximately 50%. Furthermore, the complete abrogation of tumor growth was observed with the co-treatment of erlotinib and silibinin. Silibinin fully reversed the EMT-related high miR-21/low miR-200c microRNA signature and repressed the mesenchymal markers SNAIL, ZEB, and N-cadherin observed in erlotinib-refractory tumors. Silibinin was sufficient to fully activate a reciprocal mesenchymal-to-epithelial transition (MET) in erlotinib-refractory cells and prevent the highly migratogenic phenotype of erlotinib-resistant NSCLC cells. Given that the various mechanisms of resistance to erlotinib result from EMT, regardless of the EGFR mutation status, a water-soluble, silibinin-rich milk thistle extract might be a suitable candidate therapy for upcoming clinical trials aimed at preventing or reversing NSCLC progression following erlotinib treatment. PMID:23963283

  5. Resistance mechanisms to erlotinib in the non-small cell lung cancer cell line, HCC827 examined by RNA-seq

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Alcaraz, Nicolas; Ditzel, Henrik

    Background: Erlotinib, an EGFR selective reversible inhibitor, has dramatically changed the treatment of non-small cell lung cancer (NSCLC) as approximately 70% of patients show significant tumor regression upon treatment. However, all patients eventually relapse due to development of acquired...... - in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively), and prepared cDNA libraries of purified RNA from biological duplicates using TruSeq® Stranded Total RNA Ribo-Zero™ Gold.......0.10 and differential expression analysis by CuffDiff from the Cufflinks package v.2.2.1. Results: Significant differences in viability between the resistant clones and parental HCC827 were observed when incubated with erlotinib. Importantly, the resistant clones did not acquire the T790M mutation or other EGFR...

  6. Identification of resistance mechanisms in erlotinib-resistant subclones of the non-small cell lung cancer cell line HCC827 by exome sequencing

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Alcaraz, Nicolas; Lund, Rikke Raaen

    Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression upon treatment (Santarpia et. al., 2013). However, all patients relapse due to development of acquired resistance, which...... mutations in erlotinib-resistant subclones of the NSCLC cell line, HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively). DNA libraries of each subclone and the parental HCC827 cell line were prepared in biological duplicates using...... exhibited a significant difference in viability over a time course of 25 days when treated with erlotinib. Importantly, the resistant clones did not acquire the T790M or other EGFR or KRAS mutations, potentiating the identification of novel resistance mechanisms in these clones. For the sensitive and the 3...

  7. Automatic extraction of forward stroke volume using dynamic 11C-acetate PET/CT

    DEFF Research Database (Denmark)

    Harms, Hans; Tolbod, Lars Poulsen; Hansson, Nils Henrik

    was then calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured in the left ventricular outflow tract by cardiovascular magnetic resonance using phase-contrast velocity mapping within two weeks of PET imaging. Results...... TruePoint 64 PET/CT scanner after bolus injection of 399±27 MBq of 11C-acetate. The LV-aortic time-activity curve (TAC) was extracted automatically from dynamic PET data using cluster analysis. The first-pass peak was derived by automatic extrapolation of the down-slope of the TAC. FSV...... = 0.001). Conclusions: FSV can be obtained automatically and reliably using dynamic 11C-acetate PET/CT and cluster analysis, although a small overestimation is observed when compared to FSV determined from MRI. This method could potentially be generalized to other tracers, although this requires...

  8. Nuclear imaging of neuroinflammation: a comprehensive review of [{sup 11}C]PK11195 challengers

    Energy Technology Data Exchange (ETDEWEB)

    Chauveau, Fabien; Camp, Nadja van; Tavitian, Bertrand [Service Hospitalier Frederic Joliot, Laboratoire d' Imagerie Moleculaire Experimentale, CEA, Institut d' Imagerie BioMedicale, Orsay (France); INSERM, U803, Orsay (France); Boutin, Herve [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Dolle, Frederic [Service Hospitalier Frederic Joliot, Laboratoire d' Imagerie Moleculaire Experimentale, CEA, Institut d' Imagerie BioMedicale, Orsay (France)

    2008-12-15

    Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [{sup 11}C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [{sup 11}C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents. (orig.)

  9. ATP11c is critical for phosphatidylserine internalization and B lymphocyte differentiation

    Science.gov (United States)

    Yabas, Mehmet; Teh, Charis E.; Frankenreiter, Sandra; Lal, Dennis; Roots, Carla M.; Whittle, Belinda; Andrews, Daniel T.; Zhang, Yafei; Teoh, Narci C.; Sprent, Jonathan; Tze, Lina E.; Kucharska, Edyta M.; Kofler, Jennifer; Farell, Geoffrey C.; Bröer, Stefan; Goodnow, Christopher C.; Enders, Anselm

    2011-01-01

    Subcompartments of the plasma membrane are believed to be critical for lymphocyte responses but few genetic tools exist to test their function. Here we describe a new X-linked B cell deficiency syndrome in mice caused by mutations in Atp11c, a member of the P4 ATPase family thought to serve as flippases concentrating aminophospholipids in the cytoplasmic leaflet of cell membranes. Defective ATP11c decreased the rate of phosphatidylserine translocation in pro-B cells, greatly reduced pre-B and B cell numbers independent of Bcl2-inhibited apoptosis or immunoglobulin gene rearrangement and abolished pre-B cell expansion in response to an Il7 transgene. The only other abnormalities noted were anemia, hyperbilirubinemia and hepatocellular carcinoma. These results identify an intimate connection between phospholipid transport and B lymphocyte function. PMID:21423173

  10. Daunorubicin and doxorubicin inhibit the [{sup 11}C]choline accumulation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Mikecz, Pal [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary)], E-mail: pal@pet.dote.hu; Marian, Terez; Miklovicz, Tuende; Galuska, Laszlo [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Krasznai, Zoltan; Toth, Agnes; Goda, Katalin [Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Tron, Lajos [Department of Nuclear Medicine, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary); Hernadi, Zoltan; Krasznai, Zoard T. [Department of Obstetrics and Gynecology, University of Debrecen, Medical and Health Science Centre, 4012 Debrecen, Nagyerdei krt. 98 (Hungary)

    2009-10-15

    We studied how very short (10-40 min) incubation with anthracycline derivatives modifies the accumulation of PET tumor-diagnostic radiotracers in cancer cells. The human ovarian A2780 and A2780AD, human B lymphoid JY, human epidermoid KB-3-1 and KB-V-1, and smooth muscle DDT1 MF-2 cells were pre-incubated with daunorubicin and doxorubicin, and the uptake of [{sup 18}F]FDG and [{sup 11}C]choline was measured. Anthracycline treatment decreased remarkably the [{sup 11}C]choline accumulation in a concentration dependent manner, while it did not modify significantly the [{sup 18}F]FDG uptake of the cells.

  11. 11C-6-羟基-2-(4-甲基氨苯)苯并噻唑的合成研究%Synthesis of N-methyl- [11C] 2- (4-methylaminophenyl) -6-hydroxybenzothiazole

    Institute of Scientific and Technical Information of China (English)

    彭添兴; 颜和平; 范文博

    2007-01-01

    自动化合成脑内老年斑沉积显像剂11C-6-羟基-2-(4-甲基氨苯)苯并噻唑{[N-甲基-11C]6-OH-BTA-1,11C-PIB},研究了不同淋洗液等对合成效率的影响.结果表明,11C-PIB合成时间约为50 min,未校正11C衰变的情况下,放化产率为10%,放化纯95%~97%.

  12. Preparation of (21-/sup 11/C)progesterone. A potential receptor binding radiotracer

    Energy Technology Data Exchange (ETDEWEB)

    Vaalburg, W.; Terpstra, J.W.; Wiegman, T.; Ishiwata, K.; Paans, A.M.J.; Woldring, M.G.

    Clinically, the in vivo determination of progesterone receptor density by PET is of interest to estimate the response to chemotherapy. Since PET, in combination with a suitable radiopharmaceutical provides a useful tool for the in vivo localisation and quantification of receptors in tissues, we decided to investigate the potential of (21-/sup 11/C)progesterone as a radiopharmaceutical. The synthesis of this compound will be discussed.

  13. Kinetic analysis of [11C]vorozole binding in the human brain with positron emission tomography.

    Science.gov (United States)

    Logan, Jean; Kim, Sung Won; Pareto, Deborah; Telang, Frank; Wang, Gene-Jack; Fowler, Joanna S; Biegon, Anat

    2014-01-01

    Using positron emission tomography, we investigated the kinetics of [11C]vorozole ([11C]VOR), a radiotracer for the enzyme aromatase that catalyzes the last step in estrogen biosynthesis. Six subjects were scanned under baseline conditions followed by retest 2 weeks later. The retest was followed by a blocking study with 2.5 mg of the aromatase inhibitor letrozole. The binding potential (BP(A)ND) was estimated from a Lassen plot using the total tissue distribution volume (VT) for baseline and blocked. for the thalamus was found to be 15 times higher than that for the cerebellum. From the letrozole studies, we found that [11C]VOR exhibits a slow binding compartment (small k4) that has a nonspecific and a blockable component. Because of the sensitivity of VT to variations in k4, a common value was used for the four highest binding regions. We also considered the tissue uptake to plasma ratio for 60 to 90 minutes as an outcome measure. Using the ratio method, the difference between the highest and lowest was 2.4 compared to 3.5 for the VT. The ratio method underestimates the high regions but is less variable and may be more suitable for patient studies. Because of its kinetics and distribution, this tracer is not a candidate for a bolus infusion or reference tissue methods.

  14. {sup 11}C-Choline PET/pathology image coregistration in primary localized prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Grosu, Anca-Ligia; Prokic, Vesna [University of Freiburg, Department of Radiation Oncology, Freiburg (Germany); Technical University of Munich, Department of Radiation Oncology, Munich (Germany); Weirich, Gregor [Technical University of Munich, Institute of Pathology, Munich (Germany); Wendl, Christina; Geinitz, Hans; Molls, Michael [Technical University of Munich, Department of Radiation Oncology, Munich (Germany); Kirste, Simon [University of Freiburg, Department of Radiation Oncology, Freiburg (Germany); Souvatzoglou, Michael; Schwaiger, Markus [Technical University of Munich, Department of Nuclear Medicine, Munich (Germany); Gschwend, Juergen E.; Treiber, Uwe [Technical University of Munich, Department of Urology, Munich (Germany); Weber, Wolfgang A. [Memorial Sloan-Kettering Cancer Center, Molecular Imaging and Therapy Service, New York (United States); Krause, Bernd Joachim [Technical University of Munich, Department of Nuclear Medicine, Munich (Germany); University of Rostock, Department of Nuclear Medicine, Rostock (Germany)

    2014-12-15

    The aim of this study was to develop a methodology for the comparison of pathology specimens after prostatectomy (post-S) with PET images obtained before surgery (pre-S). This method was used to evaluate the merit of {sup 11}C-choline PET/CT for delineation of gross tumour volume (GTV) in prostate cancer (PC). In 28 PC patients, {sup 11}C-choline PET/CT was performed before surgery. PET/CT data were coregistered with the pathology specimens. GTV on PET images (GTV-PET) was outlined automatically and corrected manually. Tumour volume in the prostate (TVP) was delineated manually on the pathology specimens. Based on the coregistered PET/pathology images, the following parameters were assessed: SUVmax and SUVmean in the tumoral and nontumoral prostate (NP), GTV-PET (millilitres) and TVP (millilitres). PET/pathology image coregistration was satisfactory. Mean SUVmax in the TVP was lower than in the NP: 5.0 and 5.5, respectively (p = 0.093). Considering the entire prostate, SUVmax was located in the TVP in two patients, in the TVP and NP in 12 patients and exclusively in NP in 14 patients. Partial overlap the TVP and GTV-PET was seen in 71 % of patients, and complete overlap in 4 %. PET/pathology image coregistration can be used for evaluation of different imaging modalities. {sup 11}C-Choline PET failed to distinguish tumour from nontumour tissue. (orig.)

  15. Varenicline-Induced Elevation of Dopamine in Smokers: A Preliminary [(11)C]-(+)-PHNO PET Study.

    Science.gov (United States)

    Di Ciano, Patricia; Guranda, Mihail; Lagzdins, Dina; Tyndale, Rachel F; Gamaleddin, Islam; Selby, Peter; Boileau, Isabelle; Le Foll, Bernard

    2016-05-01

    Varenicline, a nicotinic partial agonist, is the most effective treatment for tobacco use disorder. However, its mechanism of action is still unclear and may involve stimulating dopaminergic transmission. Here we used PET imaging with [(11)C]-(+)-PHNO to explore for the first time the impact of varenicline on dopamine transmission in the D2-rich striatum and D3-rich extra-striatal regions and its relationship with craving, withdrawal and smoking. Eleven treatment-seeking smokers underwent two PET scans with [(11)C]-(+)-PHNO, each following 12-h overnight smoking abstinence both prior to receiving varenicline and following 10-11 days of varenicline treatment (ie, at steady-state drug levels). Subjective measures of craving and urges to smoke were also assessed on the days of the PET scans. Varenicline treatment significantly reduced [(11)C]-(+)-PHNO binding in the dorsal caudate (p=0.008) and reduced some craving measures. These findings provide the first evidence that varenicline is able to increase DA levels in the human brain, a factor that may contribute to its therapeutic efficacy.

  16. Kinetic models for analysing myocardial [{sup 11}C]palmitate data

    Energy Technology Data Exchange (ETDEWEB)

    Jong, Hugo W.A.M. de [University Medical Centre Utrecht, Department of Radiology and Nuclear Medicine, Utrecht (Netherlands); VU University Medical Centre, Department of Nuclear Medicine and PET Research, Amsterdam (Netherlands); Rijzewijk, Luuk J.; Diamant, Michaela [VU University Medical Centre, Diabetes Centre, Amsterdam (Netherlands); Lubberink, Mark; Lammertsma, Adriaan A. [VU University Medical Centre, Department of Nuclear Medicine and PET Research, Amsterdam (Netherlands); Meer, Rutger W. van der; Lamb, Hildo J. [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands); Smit, Jan W.A. [Leiden University Medical Centre, Department of Endocrinology, Leiden (Netherlands)

    2009-06-15

    [{sup 11}C]Palmitate PET can be used to study myocardial fatty acid metabolism in vivo. Several models have been applied to describe and quantify its kinetics, but to date no systematic analysis has been performed to define the most suitable model. In this study a total of 21 plasma input models comprising one to three compartments and up to six free rate constants were compared using statistical analysis of clinical data and simulations. To this end, 14 healthy volunteers were scanned using [{sup 11}C]palmitate, whilst myocardial blood flow was measured using H{sub 2} {sup 15}O. Models including an oxidative pathway, representing production of {sup 11}CO{sub 2}, provided significantly better fits to the data than other models. Model robustness was increased by fixing efflux of {sup 11}CO{sub 2} to the oxidation rate. Simulations showed that a three-tissue compartment model describing oxidation and esterification was feasible when no more than three free rate constants were included. Although further studies in patients are required to substantiate this choice, based on the accuracy of data description, the number of free parameters and generality, the three-tissue model with three free rate constants was the model of choice for describing [{sup 11}C]palmitate kinetics in terms of oxidation and fatty acid accumulation in the cell. (orig.)

  17. Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response

    Science.gov (United States)

    Roberts, Lydia M; Ledvina, Hannah E; Tuladhar, Shraddha; Rana, Deepa; Steele, Shaun P; Sempowski, Gregory D; Frelinger, Jeffrey A

    2015-01-01

    Alveolar macrophages play a critical role in initiating the immune response to inhaled pathogens and have been shown to be the first cell type infected following intranasal inoculation with several pathogens, including Francisella tularensis. In an attempt to further dissect the role of alveolar macrophages in the immune response to Francisella, we selectively depleted alveolar macrophages using CD11c.DOG mice. CD11c.DOG mice express the diphtheria toxin receptor (DTR) under control of the full CD11c promoter. Because mice do not express DTR, tissue restricted expression of the primate DTR followed by treatment with diphtheria toxin (DT) has been widely used as a tool in immunology to examine the effect of acute depletion of a specific immune subset following normal development. We successfully depleted alveolar macrophages via intranasal administration of DT. However, alveolar macrophage depletion was accompanied by many other changes to the cellular composition and cytokine/chemokine milieu in the lung that potentially impact innate and adaptive immune responses. Importantly, we observed a transient influx of neutrophils in the lung and spleen. Our experience serves as a cautionary note to other researchers using DTR mice given the complex changes that occur following DT treatment that must be taken into account when analyzing data. PMID:26029367

  18. Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB

    Science.gov (United States)

    Ances, B.M.; Christensen, J.J.; Teshome, M.; Taylor, J.; Xiong, C.; Aldea, P.; Fagan, A.M.; Holtzman, D.M.; Morris, J.C.; Mintun, M.A.; Clifford, D.B.

    2010-01-01

    Objectives: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-β42 (Αβ42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB), a biomarker for Αβ42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20). Methods: In this case-control study, all participants had an 11C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by χ2 tests. Participants were further divided into either low (0.18 arbitrary units) within cortical regions. Conclusions: Cognitively unimpaired HIV+ participants, even with low CSF Αβ42 (global deficit score; HAND = HIV-associated neurocognitive disorder; LP = lumbar puncture; MCBP = mean cortical binding potential; PiB = Pittsburgh compound B; ROI = region of interest; WUSTL = Washington University in St. Louis. PMID:20534887

  19. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Kayo [Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala SE-75124 (Sweden); Uppsala Imanet, Uppsala SE-75109 (Sweden)]. E-mail: kayo.takahashi@uppsala.imanet.se; Bergstroem, Mats [Uppsala Imanet, Uppsala SE-75109 (Sweden); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-75124 (Sweden); Fraendberg, Pernilla [Uppsala Imanet, Uppsala SE-75109 (Sweden); Vesstroem, Eva-Lotta [Uppsala Imanet, Uppsala SE-75109 (Sweden); Watanabe, Yasuyoshi [Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585 (Japan); Langstroem, Bengt [Uppsala Imanet, Uppsala SE-75109 (Sweden)

    2006-07-15

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [{sup 11}C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K {sub d} of [{sup 11}C]vorozole binding to aromatase in MA was determined to be 0.60{+-}0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [{sup 11}C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  20. Visualizing pancreatic {beta}-cell mass with [{sup 11}C]DTBZ

    Energy Technology Data Exchange (ETDEWEB)

    Simpson, Norman Ray [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Souza, Fabiola [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Witkowski, Piotr [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Maffei, Antonella [Institute of Genetics and Biophysics ' Adriano Buzzati-Traverso' , CNR, Naples 80131 (Italy); Raffo, Anthony [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Herron, Alan [Center for Comparative Medicine and The Department of Pathology, Baylor College of Medicine, Houston, TX 77030 (United States); Kilbourn, Michael [Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0638 (United States); Jurewicz, Agata [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Herold, Kevan [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Liu, Eric [Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20854 (United States); Hardy, Mark Adam [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Van Heertum, Ronald [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Harris, Paul Emerson [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States)]. E-mail: peh1@columbia.edu

    2006-10-15

    {beta}-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, {beta}-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by {beta} cells, with [{sup 11}C]dihydrotetrabenazine ([{sup 11}C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocin-induced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in {beta} cells with the use of [{sup 11}C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

  1. Simple automated preparation of O-[{sup 11}C]methyl-L-tyrosine for routine clinical use

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Yoichi [CYRIC Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578 (Japan); Iwata, Ren [CYRIC Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)]. E-mail: rencyric@cyric.tohoku.ac.jp; Furumoto, Shozo [TUBERO, Tohoku University, Sendai 980-8575 (Japan); Pascali, Claudio [National Cancer Institute, 20133 Milan (Italy); Bogni, Anna [National Cancer Institute, 20133 Milan (Italy); Kubota, Kazuo [International Medical Center, Tokyo 162-8655 (Japan); Ishiwata, Kiichi [Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022 (Japan)

    2005-07-01

    The previously reported preparation of O-[{sup 11}C]methyl-L-tyrosine ([{sup 11}C]MT), a promising tumor imaging agent, has been now considerably simplified and automated. Main changes were the use of [{sup 11}C]methyl iodide ([{sup 11}C]MeI) in the reaction with L-tyrosine disodium and the use of solid phase extraction on commercially available cartridges instead of HPLC for the final purification. An injectable saline solution of [{sup 11}C]MT was obtained within 30 min after EOB with radiochemical yield of ca. 60% (decay-corrected, based on [{sup 11}C]MeI). Radiochemical purity was over 97%. The automated preparation was carried out using a miniature module employing manifold valves.

  2. Preparation of (/sup 11/C)buprenorphine - a potential radioligand for the study of the opiate receptor system in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Luthra, S.K.; Pike, V.W.; Brady, F.; Horlock, P.L.; Prenant, C.; Crouzel, C.

    1987-01-01

    A method is described for the preparation of (/sup 11/C)buprenorphine in high specific activity, based on the reaction of N-(de-cyclopropylmethyl)buprenorphine with ''no carrier added'' (1-/sup 11/C)cyclopropanecarbonyl chloride followed by reduction with lithium aluminium hydride. The (1-/sup 11/C)cyclopropanecarbonyl chloride is itself prepared from cyclotron-produced (/sup 11/C)carbon dioxide. The overall preparation time is 57 min from the end of radionuclide production, and the radiochemical yield is ca 20%, (decay-corrected from (/sup 11/C)-carbon dioxide). (/sup 11/C)Buprenophine has potential as a radio-ligand for the study of the opiate receptor system in vivo by means of position emission tomography.

  3. Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway

    Science.gov (United States)

    Zheng, Yuan-ting; Yang, Hui-ying; Li, Tao; Zhao, Bei; Shao, Teng-fei; Xiang, Xiao-qiang; Cai, Wei-min

    2015-01-01

    Aim: Blockade of EGFR by EGFR tyrosine kinase inhibitors such as erlotinib is insufficient for effective treatment of human pancreatic cancer due to independent activation of the Akt pathway, while amiloride, a potassium-sparing diuretic, has been found as a potential Akt inhibitor. The aim of this study was to investigate the anticancer effects of combined amiloride with erlotinib against human pancreatic cancer cells in vitro. Methods: Cell proliferation, colony formation, cell cycle and apoptosis were analyzed in 4 human pancreatic cancer cell lines Bxpc-3, PANC-1, Aspc-1 and CFPAC-1 treated with erlotinib or amiloride alone, or in their combination. The synergistic analysis for the effects of combinations of amiloride and erlotinib was performed using Chou-Talalay's combination index isobolographic method. Results: Amiloride (10, 30, and 100 μmol/L) concentration-dependently potentiated erlotinib-induced inhibition of cell proliferation and colony formation in the 4 pancreatic cancer cell lines. Isobolographic analysis confirmed that combinations of amiloride and erlotinib produced synergistic cytotoxic effects. Amiloride significantly potentiated erlotinib-induced G0/G1 cell-cycle arrest and apoptosis in Bxpc-3 and PANC-1 cells. Amiloride inhibited EGF-stimulated phorsphorylation of AKT, and significantly enhanced erlotinib-induced downregulation of phorsphorylation of EGFR, AKT, PI3K P85 and GSK 3β in Bxpc-3 and PANC-1 cells. Conclusion: Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway. Treatment of pancreatic cancer patients with combination of erlotinib and amiloride merits further investigation. PMID:25864651

  4. Maintenance erlotinib in advanced nonsmall cell lung cancer: cost-effectiveness in EGFR wild-type across Europe

    Directory of Open Access Journals (Sweden)

    Walleser S

    2012-09-01

    Full Text Available Silke Walleser,1 Joshua Ray,2 Helge Bischoff,3 Alain Vergnenègre,4 Hubertus Rosery,5 Christos Chouaid,6 David Heigener,7 Javier de Castro Carpeño,8 Marcello Tiseo,9 Stefan Walzer21Health Economic Consultancy, Renens, Switzerland; 2F Hoffmann-La Roche Pharmaceuticals AG, Basel, Switzerland; 3Thoracic Hospital of Heidelberg, Heidelberg, Germany; 4Limoges University Hospital, Limoges, France; 5Assessment-in-Medicine GmbH, Loerrach, Germany; 6Hospital Saint Antoine, Paris, France; 7Hospital Grosshansdorf, Grosshansdorf, Germany; 8University Hospital La Paz, Madrid, Spain; 9University Hospital of Parma, Parma, ItalyBackground: First-line maintenance erlotinib in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC has demonstrated significant overall survival and progression-free survival benefits compared with best supportive care plus placebo, irrespective of epidermal growth factor receptor (EGFR status (SATURN trial. The cost-effectiveness of first-line maintenance erlotinib in the overall SATURN population has been assessed and published recently, but analyses according to EGFR mutation status have not been performed yet, which was the rationale for assessing the cost-effectiveness of first-line maintenance erlotinib specifically in EGFR wild-type metastatic NSCLC.Methods: The incremental cost per life-year gained of first-line maintenance erlotinib compared with best supportive care in patients with EGFR wild-type stable metastatic NSCLC was assessed for five European countries (the United Kingdom, Germany, France, Spain, and Italy with an area-under-the-curve model consisting of three health states (progression-free survival, progressive disease, death. Log-logistic survival functions were fitted to Phase III patient-level data (SATURN to model progression-free survival and overall survival. The first-line maintenance erlotinib therapy cost (modeled for time to treatment cessation, medication cost in later lines, and

  5. EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.

    Directory of Open Access Journals (Sweden)

    Claire E Le Pichon

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.

  6. New Synthetic Route of Two Active Isomeric Metabolites of Erlotinib and Their Bioactivity Studies against Several Tumor Cell Lines%New Synthetic Route of Two Active Isomeric Metabolites of Erlotinib and Their Bioactivity Studies against Several Tumor Cell Lines

    Institute of Scientific and Technical Information of China (English)

    李汉青; 李梦瑶; 李载权; 李良; 毕姗姗; 邓晨辉; 陈睿; 周田彦; 卢炜

    2011-01-01

    The synthesis and differential antiproliferative activity of two active isomeric metabolites of erlotinib were in- vestigated. This synthetic process had demonstrated to avoid the unstable 4-chloroquinazoline intermediates and long procedures. New intermediates and final compounds were identified by IH NMR, 13C NMR and ESI-TOF MS, and their purities were determined by high performance liquid chromatography. In vitro proliferative assay indi- cated that these two metabolites possessed antiproliferative activity against some conventional tumor cell lines and EGFR tyrosine kinase over-expression tumor cell lines as compared to erlotinib control, and their antitumor activity in cellular level was first reported here.

  7. Preliminary Ionization Efficiencies of {sup 11}C and {sup 14}O with the LBNL ECR Ion Sources

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Z.Q.; Cerny, J.; Guo, F.Q.; Joosten, R.; Larimer, R.M.; Lyneis, C.M.; McMahan, P.; Norman, E.B.; O' Neil, J.P.; Powell, J.; Rowe, M.W.; VanBrocklin, H.F.; Wutte, D.; Xu, X.J.; Haustein, P.

    1998-10-05

    High charge states, up to fully stripped {sup 11}C and {sup 14}O ion, beams have been produced with the electron cyclotron resonance ion sources (LBNL, ECR and AECR-U) at Lawrence Berkeley National Laboratory. The radioactive atoms of {sup 11}C and {sup 14}O were collected in batch mode with an LN{sub 2} trap and then bled into the ECR ion sources. Ionization efficiency as high as 11% for {sup 11}C{sup 4+} was achieved.

  8. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas

    Directory of Open Access Journals (Sweden)

    Ibrahim eQaddoumi

    2014-04-01

    Full Text Available Background. Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG. Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy in children with newly diagnosed HGG. Methods. Following maximum surgical resection, patients between 3 and 21 years with nonmetastatic HGG received local radiotherapy at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement. Erlotinib started on day 1 of radiotherapy (120 mg/m2 per day and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS was estimated for patients with intracranial anaplastic astrocytoma (AA and glioblastoma.Results. Median age at diagnosis for 41 patients with intracranial tumors (21 with glioblastoma and 20 with AA was 10.9 years (range, 3.3 to 19 years. The 2-year PFS for patients with AA and glioblastoma was 15% ± 7% and 19% ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n=11, dermatologic (n=5, and metabolic (n=4. One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis. Conclusions. Although therapy with erlotinib was mostly well tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and glioblastoma.

  9. Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Herman, Joseph M., E-mail: jherma15@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Fan, Katherine Y.; Wild, Aaron T.; Hacker-Prietz, Amy [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Wood, Laura D. [Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Blackford, Amanda L. [Department of Oncology Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Ellsworth, Susannah [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Zheng, Lei; Le, Dung T.; De Jesus-Acosta, Ana [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Hidalgo, Manuel [Centro Nacional de Investigaciones Oncologicas, Madrid (Spain); Donehower, Ross C. [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Schulick, Richard D.; Edil, Barish H. [Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado (United States); Choti, Michael A. [Department of Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Hruban, Ralph H. [Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); and others

    2013-07-15

    Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. Methods and Materials: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m{sup 2} twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m{sup 2} on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). Results: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. Conclusion: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

  10. Food Labels

    Science.gov (United States)

    ... Surgery? Choosing the Right Sport for You Shyness Food Labels KidsHealth > For Teens > Food Labels Print A ... have at least 95% organic ingredients. continue Making Food Labels Work for You The first step in ...

  11. Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-{sup 11}C-propyl]n-propylnorapomorphine

    Energy Technology Data Exchange (ETDEWEB)

    Palner, Mikael [Neurobiology Research Unit, Rigshospitalet, University of Copenhagen, DK-2300, Copenhagen (Denmark); Center for Integrated Molecular Brain Imaging, Copenhagen (Denmark)], E-mail: mikael.palner@nru.dk; McCormick, Patrick [PET Centre, Centre for Addiction and Mental Health, M5T 1RB, Toronto, ON (Canada); Gillings, Nic [Center for Integrated Molecular Brain Imaging, Copenhagen (Denmark); PET and Cyclotron Unit, Rigshospitalet, DK-2300, Copenhagen (Denmark); Begtrup, Mikael [Center for Integrated Molecular Brain Imaging, Copenhagen (Denmark); Institute for Medicinal Chemistry, Pharmaceutical Faculty, University of Copenhagen, DK-2300, Copenhagen (Denmark); Wilson, Alan A. [PET Centre, Centre for Addiction and Mental Health, M5T 1RB, Toronto, ON (Canada); Knudsen, Gitte M. [Neurobiology Research Unit, Rigshospitalet, University of Copenhagen, DK-2300, Copenhagen (Denmark); Center for Integrated Molecular Brain Imaging, Copenhagen (Denmark)

    2010-01-15

    Introduction: Several dopamine D{sub 2} agonist radioligands have been used with positron emission tomography (PET), including [{sup 11}C-]-(-)-MNPA, [{sup 11}C-]-(-)-NPA and [{sup 11}C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D{sub 2} and D{sub 3} receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D{sub 2}/D{sub 3} selectivity. Methods: 2-Cl-[{sup 11}C]-(-)-NPA and [{sup 11}C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [{sup 11}C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed. Results: 2-Cl-[{sup 11}C]-(-)-NPA and [{sup 11}C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[{sup 11}C]-(-)-NPA accumulated slower in the striatum than [{sup 11}C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[{sup 11}C]-(-)-NPA (standard uptake value 0.72{+-}0.24) was approximately half that of [{sup 11}C]-(-)-NPA (standard uptake value 1.37{+-}0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[{sup 11}C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[{sup 11}C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D{sub 2}/D{sub 3} selectivity, that 2-Cl-[{sup 11}C]-(-)-NPA is inferior to [{sup 11}C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to

  12. Phase 2 trial of erlotinib with or without PF-3512676 (CPG 7909, a Toll-like receptor 9 agonist) in patients with advanced recurrent EGFR-positive non-small cell lung cancer.

    Science.gov (United States)

    Belani, Chandra P; Nemunaitis, John J; Chachoua, Abraham; Eisenberg, Peter D; Raez, Luiz E; Cuevas, J Daniel; Mather, Cecile B; Benner, Rebecca J; Meech, Sandra J

    2013-07-01

    This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF-3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade ≥ 3 adverse events in PF-3512676-plus-erlotinib and erlotinib-alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer.

  13. Fast synthesis of 11C-Raciopride and its initial PET study on animal model%11C-Raclopride的快速制备及生物学评价

    Institute of Scientific and Technical Information of China (English)

    张锦明; 田嘉禾; 姚树林; 丁为民; 尹大一; 刘伯里

    2008-01-01

    Objective 11C-Raclopride is a type-2 dopamine receptor(D2R)binding agent used in the study of Parkinson's disease.This study introduced a fast and convenient method for preparation of 11C-Raclopride and reported on the preclinical trial of this receptor tracer on animal studies.Methods 11C-Raclopride was synthesized via reaction of 11C-CH3-Triflate with Nor-Raclopride.The mixture of primary product was water-diluted and loaded on Sep-Pak C18 column for separation.The final product,11C-Raclo-pride,Was purified by column chromatography and then eluted from the C18 column with ethanol.The bio-distribution was studied in SD rats and the in vivo imaging pattern was studied in hem ipark insonjan mon-keys.Results Within 16 min from beginning of processing with 11CO2,the synthetic yield of 11C-Raclo-pride WaS 60%,radiochemical purity(RCP)>95% and specific activity 8 GBq/mmol.The uptake ratios of striatum to cerebellum and cerebral cortex were 4.67 and 6.20,respectively,at 30 min after 11C-Raclo-pride administration.The striatal uptake in normal rat brain could be blocked by N-methylspiperone(NMSP)and raclopride,but not by Nor-raclopride.PET imaging showed higher striatal D2 R uptake on the D2 receptor up-regulated side of the experimental monkeys relative to the contralateral side.Conclusions Column chromatography for purification of 11C-Raclopride Was fast,convenient and with a RCP similar to that of high performance liquid chromatography purification.Preliminary PET findings using animal model suggested that 11C-Raclopride by column chromatogram purification might be considered for clinical use.%目的 建立快速制备11C-雷氯必利(Raclopride)的方法,并对其进行生物学评价.方法 采用固相萃取法制备11C-Raclopride,即用11C-三氟甲基磺酰基甲烷(CH3-Triflate)与去甲基(Nor)-Raclopride反应得粗产品,用水稀释粗产品,将其转移到Sep-Pak C18反相柱,冲洗反相柱,再用乙醇淋洗得11C-Raclopride.研究正常SD大鼠体内11C

  14. In vivo imaging of ''neuroinflammation''. Principles and applications; In-vivo-Darstellung ''neuroinflammatorischer'' Veraenderungen mit [{sup 11}C] PK11195-PET. Grundlagen und Anwendung

    Energy Technology Data Exchange (ETDEWEB)

    Gerhard, A.; Banati, R.B. [MRC Clinical Sciences Centre and Div. of Neuroscience, Faculty of Medicine, Imperial Coll., London (United Kingdom)

    2002-09-01

    Microglia are the brains' resident immunocompetent cells that can be activated by acute as well as chronic pathological stimuli. When activated they express the peripheral benzodiazepine binding site to which the isoquinolin PK11195 binds with high specificity. Labelled with [{sup 11}C], the R-enatiomer [{sup 11}C] PK1195 has been used for positron emission tomography (PET) studies to demonstrate neuroinflammatory changes in vivo. [{sup 11}C](R) PK11195-PET has been successfully used to show in vivo microglial activation in ischemic (stroke), inflammatory (multiple sclerosis) and degenerative (Alzheimer's and Parkinson's disease). Longitudinal studies are in progress to help to clarify the relationship between localisation and extent of microglial activation and the clinical presentations in these disorders. This will help to determine the role of [{sup 11}C](R) PK11195 PET as a diagnostic tool and a surrogate marker of ''neuroinflammation'' in therapeutic trials. (orig.) [German] Mikroglia sind residente immunkompetente Zellen des Gehirns, die durch akute, aber auch langsam voranschreitende, chronische Schaedigungprozesse aktiviert werden. Im aktivierten Zustand exprimieren sie den peripheren Benzodiazepinrezeptor, an den das Isoquinolin PK11195 spezifisch bindet. Radioaktiv markiert kann das R-Enantiomer [{sup 11}C] PK11195 als Ligand in der Positronenemissionstomographie (PET) genutzt werden und ermoeglicht so die In-vivo-Darstellung aktiver ''neuroinflammatorischer'', d.h. die Mikroglia aktivierender, Veraenderungen. Mit der [{sup 11}C](R) PK11195-PET konnte bisher In-vivo-Mikrogliaaktivierung bei ischaemischen (Schlaganfall), entzuendlichen (multiple Sklerose) und degenerativen (Morbus Alzheimer- und Parkinson-Erkrankung) demonstriert werden. Laufende longitudinale Studien werden dazu beitragen, die Beziehung zwischen Lokalisation und Ausmass der Mikrogliaaktivierung und klinischer Krankheitsauspraegung

  15. Synthesis and radiolabeling of N-[4-[4-(2-[{sup 11}C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene -2-carboxamide - a potential radiotracer for D{sub 3} receptor imaging with PET

    Energy Technology Data Exchange (ETDEWEB)

    Kuhnast, Bertrand [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Valette, Heric [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Besret, Laurent [CNRS URA2210, CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Demphel, Stephane [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Coulon, Christine [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Ottaviani, Michele [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Guillermier, Martine [CNRS URA2210, CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Bottlaender, Michel [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France); Dolle, Frederic [Service Hospitalier Frederic Joliot, SHFJ/CEA/DSV, 4 place du General Leclerc, 91401 Orsay (France)]. E-mail: frederic.dolle@cea.fr

    2006-08-15

    FAUC346 (N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene -2-carboxamide), an in vitro D{sub 3}-selective ligand, and its normethyl derivative have been synthesized from commercially available 1-(2-substituted-phenyl)piperazines. FAUC346 has been labeled using [{sup 11}C]methyl triflate in acetone containing aqueous NaOH (5 Eq) at -10 deg. C for 1 min, purified on semipreparative reverse-phase high-performance liquid chromatography (HPLC) and formulated as an intravenous injectable solution using a Sep-Pak Plus C{sub 18} device. Up to 5.5 GBq of [{sup 11}C]FAUC346 (N-[4-[4-(2-[methyl-{sup 11}C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b] thiophene-2-carboxamide), with a specific radioactivity of 45-75 GBq/{mu}mol, could be obtained in 30-35 min, including HPLC purification and formulation starting from 44.4 GBq of [{sup 11}C]carbon dioxide. Preliminary pharmacological evaluation of [{sup 11}C]FAUC346 in rat brain clearly demonstrated in vivo selectivity for D{sub 3} receptors and the absence of radiolabeled metabolite within the brain. These encouraging results, however, could not be confirmed in nonhuman primates; therefore, this radioligand does not appear to have the required pharmacological profile for a positron emission tomography probe for imaging D{sub 3} receptors.

  16. Strategic development on generic anti-cancer drugs Bevacizumab and Erlotinib Hydrochloride for Harbin Pharmaceutical Group

    Institute of Scientific and Technical Information of China (English)

    Cheung Fat Ping

    2011-01-01

    @@ With improved economy, changing life styles, aging population and health care reform, China had a very potential anti-cancer drug market.The patents of popular anti-cancer drugs Avastin and Tarceva would expire in few years.Generic versions of Avastin and Tarceva were Bevacizumab and Erlotinib Hydrochloride respectively.Harbin Pharmaceutical Group was proposed to develop strategically both generic medicines to enter the high-end anti-cancer drug market for targeted cancer therapies.The vital to success of developing the generic drugs were discussed.

  17. Radiosynthesis of (E)-N-(2-[{sup 11}C]methoxybenzyl)-3-phenyl-acrylamidine, a novel subnanomolar NR2B subtype-selective NMDA receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Thominiaux, Cyrille [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Bruin, Beatrice de [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Bramoulle, Yann [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Hinnen, Francoise [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Demphel, Stephane [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Valette, Heric [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Bottlaender, Michel [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Besret, Laurent [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Departement de Recherche Medicale, URA CEA/CNRS 2210, Service Hospitalier Frederic Joliot, CEA/DSV, 4 Place du General Leclerc, F-91401 Orsay (France); Kassiou, Michael [Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050 (Australia); Department of Pharmacology, University of Sydney, NSW 2006 (Australia); Dolle, Frederic [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France)]. E-mail: frederic.dolle@cea.fr

    2006-03-15

    Recently, a novel series of amidines has been described, exhibiting high NR2B-subtype selective N-methyl-D-aspartate (NMDA) antagonist activity with nanomolar or subnanomolar affinity. Within the styrylamidine subclass (E)-N-(2-methoxybenzyl)-3-phenyl-acrylamidine (1), displayed the highest affinity (Ki=0.7nM versus [{sup 3}H]ifenprodil) and was considered an appropriate candidate for isotopic labelling with carbon-11 (T{sub 1/2}: 20.38min) at its methoxy group for imaging of NMDA receptors with PET. Derivative 1 has been labelled from the corresponding nor-analogue using [{sup 11}C]methyl triflate and the following experimental conditions : (1) trapping at -10{sup o}C of [{sup 11}C]methyl triflate in 300{mu}L of acetone containing 0.6-0.8mg of precursor 5 (2.4-3.2{mu}mol) and 5{mu}L of a 3M solution of NaOH in water (about 5eq.); (2) concentration to dryness of the reaction mixture (at 110{sup o}C, using a helium stream for 1-2min); (3) taking up the residue with 0.5mL of the HPLC mobile phase and (4) purification using semi-preparative HPLC (SymmetryPrep{sup (}R) C-18, Waters, 300x7.8mm). Typically, starting from a 1.5 Ci (55.5GBq) [{sup 11}C]CO{sub 2} production batch, 120-240m Ci (4.44-8.88GBq) of [{sup 11}C]-1 (20-40% decay-corrected radiochemical yield, n=5) was obtained within a total synthesis time of 25-30min. Specific radioactivities ranged from 0.8 to 1.2Ci/{mu}mol (29.6-44.4GBq/{mu}mol) at the end of radiosynthesis. No attempts were made to further optimise these reactions, as sufficient material was obtained to allow for preliminary pharmacological characterisation.

  18. Kinetic modelling of [{sup 11}C]flumazenil using data-driven methods

    Energy Technology Data Exchange (ETDEWEB)

    Miederer, Isabelle; Ziegler, Sibylle I.; Liedtke, Christoph; Miederer, Matthias; Drzezga, Alexander [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Spilker, Mary E. [GE Global Research, Computational Biology and Biostatistics Laboratory, Niscayuna, NY (United States); Sprenger, Till [Technische Universitaet Muenchen, Department of Neurology, Klinikum rechts der Isar, Munich (Germany); Wagner, Klaus J. [Technische Universitaet Muenchen, Department of Anaesthesiology, Klinikum rechts der Isar, Munich (Germany); Boecker, Henning [Universitaet Bonn, Department of Radiology, Bonn (Germany)

    2009-04-15

    [{sup 11}C]Flumazenil (FMZ) is a benzodiazepine receptor antagonist that binds reversibly to central-type gamma-aminobutyric acid (GABA-A) sites. A validated approach for analysis of [{sup 11}C]FMZ is the invasive one-tissue (1T) compartmental model. However, it would be advantageous to analyse FMZ binding with whole-brain pixel-based methods that do not require a-priori hypotheses regarding preselected regions. Therefore, in this study we compared invasive and noninvasive data-driven methods (Logan graphical analysis, LGA; multilinear reference tissue model, MRTM2; spectral analysis, SA; basis pursuit denoising, BPD) with the 1T model. We focused on two aspects: (1) replacing the arterial input function analyses with a reference tissue method using the pons as the reference tissue, and (2) shortening the scan protocol from 90 min to 60 min. Dynamic PET scans were conducted in seven healthy volunteers with arterial blood sampling. Distribution volume ratios (DVRs) were selected as the common outcome measure. The SA, LGA with and without arterial input, and MRTM2 agreed best with the 1T model DVR values. The invasive and noninvasive BPD were slightly less well correlated. The full protocol of a 90-min emission data performed better than the 60-min protocol, but the 60-min protocol still delivered useful data, as assessed by the coefficient of variation, and the correlation and bias analyses. This study showed that the SA, LGA and MRTM2 are valid methods for the quantification of benzodiazepine receptor binding with [{sup 11}C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure. (orig.)

  19. Nuclear reactions with 11C and 14O radioactive ion beams

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Fanqing

    2004-12-09

    Radioactive ion beams (RIBs) have been shown to be a useful tool for studying proton-rich nuclides near and beyond the proton dripline and for evaluating nuclear models. To take full advantage of RIBs, Elastic Resonance Scattering in Inverse Kinematics with Thick Targets (ERSIKTT), has proven to be a reliable experimental tool for investigations of proton unbound nuclei. Following several years of effort, Berkeley Experiments with Accelerated Radioactive Species (BEARS), a RIBs capability, has been developed at the Lawrence Berkeley National Laboratory's 88-Inch Cyclotron. The current BEARS provides two RIBs: a 11C beam of up to 2x108 pps intensity on target and an 14O beam of up to 3x104 pps intensity. While the development of the 11C beam has been relatively easy, a number of challenges had to be overcome to obtain the 14O beam. The excellent 11C beam has been used to investigate several reactions. The first was the 197Au(11C,xn)208-xnAt reaction, which was used to measure excitation functions for the 4n to 8n exit channels. The measured cross sections were generally predicted quite well using the fusion-evaporation code HIVAP. Possible errors in the branching ratios of ?? decays from At isotopes as well as the presence of incomplete fusion reactions probably contribute to specific overpredictions. 15F has been investigated by the p(14O,p)14O reaction with the ERSIKTT technology. Several 14O+p runs have been performed. Excellent energy calibration was obtained using resonances from the p(14N,p)14N reaction in inverse kinematics, and comparing the results to those obtained earlier with normal kinematics. The differences between 14N+p and 14O+p in the stopping power function have been evaluated for better energy calibration. After careful calibration, the energy levels of 15F were fitted with an R-matrix calculation. Spins and parities were assigned to the two observed resonances. This new measurement of the 15F ground state supports the disappearance of the Z

  20. [11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome

    Science.gov (United States)

    Jeon, So Yeon; Seo, Seongho; Lee, Jae Sung; Choi, Soo-Hee; Lee, Do-Hyeong; Jung, Ye-Ha; Song, Man-Kyu; Lee, Kyung-Jun; Kim, Yong Chul; Kwon, Hyun Woo; Im, Hyung-Jun; Lee, Dong Soo; Cheon, Gi Jeong; Kang, Do-Hyung

    2017-01-01

    Abstract Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case–control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [11C]-(R)-PK11195. [11C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30–55 years) and 12 control subjects (30–52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [11C]-(R)-PK11195 in the caudate nucleus (t(21) = −3.209, P = 0.004), putamen (t(21) = −2.492, P = 0.022), nucleus accumbens (t(21) = −2.218, P = 0.040), and thalamus (t(21) = −2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = −2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [11C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R2 = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R2 = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments. PMID:28072713

  1. {sup 11}C-ORM-13070, a novel PET ligand for brain α{sub 2C}-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

    Energy Technology Data Exchange (ETDEWEB)

    Luoto, Pauliina; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Virta, Jere; Virtanen, Kirsi; Roivainen, Anne [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Suilamo, Sami [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Turku University Hospital, Department of Oncology and Radiotherapy, Turku (Finland); Herttuainen, Jukka; Hietamaeki, Johanna; Holopainen, Aila; Rouru, Juha; Sallinen, Jukka [Orion Pharma, Espoo and Turku (Finland); Kailajaervi, Marita [GE Healthcare, Turku Imanet, Turku (Finland); Peltonen, Juha M.; Scheinin, Mika; Volanen, Iina [University of Turku, CRST, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku, CRST, Turku (Finland); TYKSLAB, Unit of Clinical Pharmacology, Turku (Finland); University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland)

    2014-10-15

    {sup 11}C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl] -4-(3-methoxy-methylpyridin-2- yl)-piperazine ({sup 11}C-ORM-13070) is a novel PET tracer for imaging of α{sub 2C}-adrenoceptors in the human brain. Brain α{sub 2C}-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of {sup 11}C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of {sup 11}C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of {sup 11}C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of {sup 11}C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged {sup 11}C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged {sup 11}C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min{sup -1} and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 - 4.2 μSv/MBq. {sup 11}C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of {sup 11}C-ORM-13070 was in the same range

  2. Density of CD163+CD11c+ Dendritic Cells Increases and CD103+ Dendritic Cells Decreases in the Coeliac Lesion

    National Research Council Canada - National Science Library

    Beitnes, A.‐C. R; Ráki, M; Lundin, K. E. A; Jahnsen, J; Sollid, L. M; Jahnsen, F. L

    2011-01-01

    ...: CD163 + CD11c − macrophages (74%), and CD11c + cells expressing either CD163 (7%), CD103 (11%) or CD1c (13%). CD103 + and CD1c + DCs belonged to partly overlapping populations, whereas CD163...

  3. IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations

    Science.gov (United States)

    Vazquez-Martin, Alejandro; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Torres-Garcia, Violeta Zenobia; Corominas-Faja, Bruna; Cuyàs, Elisabet; Bonavia, Rosa; Visa, Joana; Martin-Castillo, Begoña; Barrajón-Catalán, Enrique; Micol, Vicente; Bosch-Barrera, Joaquim; Menendez, Javier A.

    2013-01-01

    Using non-small cell lung carcinoma (NSCLC) cells harboring the erlotinib-sensitizing Epidermal Growth Factor Receptor (EGFR) exon 19 mutation delE746-A750, we developed erlotinib-refractory derivatives in which hyperactive Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling associated with enrichment in epithelial-to-mesenchymal transition (EMT)-related morphological and transcriptional features. We then explored whether an IGF-1R/EMT crosstalk was sufficient to promote erlotinib refractoriness in the absence of second-site EGFR mutations, MET and AXL hyperactivation. Transforming Growth Factor-beta1 (TGFβ1)-induced mesenchymal trans-differentiation was sufficient to impede erlotinib functioning in the presence of drug-sensitive delE746-A750 EGFR mutation. Pharmacological blockade of IGF-1R fully prevented the TGFβ1's ability to activate an EMT protein signature [E-cadherin low/vimentin high]. The sole presence of erlotinib was capable of rapidly activate an IGF-1R-dependent, vimentin-enriched mesenchymal-like phenotype in delE746-A750-mutated epithelial cells. Even if transient, NSCLC cells' intrinsic plasticity to undergo crosstalk between IGF-1R and EMT signaling pathways can sufficiently eliminate the erlotinib-sensitizing effect of highly prevalent EGFR mutations and suggests the urgent need for dual IGF-1R/EMT-targeting strategies to circumvent erlotinib resistance. PMID:23994953

  4. NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigenspecific CD4+ T cell polarization

    Directory of Open Access Journals (Sweden)

    Suratt Benjamin T

    2010-07-01

    Full Text Available Abstract Background Nitrogen dioxide (NO2 is an air pollutant associated with poor respiratory health, asthma exacerbation, and an increased likelihood of inhalational allergies. NO2 is also produced endogenously in the lung during acute inflammatory responses. NO2 can function as an adjuvant, allowing for allergic sensitization to an innocuous inhaled antigen and the generation of an antigen-specific Th2 immune response manifesting in an allergic asthma phenotype. As CD11c+ antigen presenting cells are considered critical for naïve T cell activation, we investigated the role of CD11c+ cells in NO2-promoted allergic sensitization. Methods We systemically depleted CD11c+ cells from transgenic mice expressing a simian diphtheria toxin (DT receptor under of control of the CD11c promoter by administration of DT. Mice were then exposed to 15 ppm NO2 followed by aerosolized ovalbumin to promote allergic sensitization to ovalbumin and were studied after subsequent inhaled ovalbumin challenges for manifestation of allergic airway disease. In addition, pulmonary CD11c+ cells from wildtype mice were studied after exposure to NO2 and ovalbumin for cellular phenotype by flow cytometry and in vitro cytokine production. Results Transient depletion of CD11c+ cells during sensitization attenuated airway eosinophilia during allergen challenge and reduced Th2 and Th17 cytokine production. Lung CD11c+ cells from wildtype mice exhibited a significant increase in MHCII, CD40, and OX40L expression 2 hours following NO2 exposure. By 48 hours, CD11c+MHCII+ DCs within the mediastinal lymph node (MLN expressed maturation markers, including CD80, CD86, and OX40L. CD11c+CD11b- and CD11c+CD11b+ pulmonary cells exposed to NO2 in vivo increased uptake of antigen 2 hours post exposure, with increased ova-Alexa 647+ CD11c+MHCII+ DCs present in MLN from NO2-exposed mice by 48 hours. Co-cultures of ova-specific CD4+ T cells from naïve mice and CD11c+ pulmonary cells from NO2

  5. Preclinical studies on [{sup 11}C]MPDX for mapping adenosine A{sub 1} receptors by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Ishiwata, Kiichi; Kimura, Yuichi; Oda, Keiichi; Kawamura, Kazunori; Ishii, Kenji; Senda, Michio [Tokyo Metropolitan Inst. of Gerontology (Japan). Positron Medical Center; Nariai, Tadashi; Wakabayashi, Shinichi [Tokyo Medical and Dental Univ. (Japan). School of Medicine; Shimada, Junichi [Kyowa Hakko Kogyo Co. Ltd., Tokyo (Japan). Pharmaceutical Research Inst.

    2002-09-01

    In previous in vivo studies with mice, rats and cats, we have demonstrated that [{sup 11}C]MPDX ([1-methyl-{sup 11}C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A{sub 1} receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [{sup 11}C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [{sup 11}C]MPDX. We have concluded that [{sup 11}C]MPDX is suitable for mapping adenosine A{sub 1} receptors in the human brain by PET. (author)

  6. Simplified PET measurement for evaluating histamine H{sub 1} receptors in human brains using [{sup 11}C]doxepin

    Energy Technology Data Exchange (ETDEWEB)

    Mochizuki, Hideki [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Kimura, Yuichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan)]. E-mail: ukimura@ieee.org; Ishii, Kenji [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Oda, Keiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Sasaki, Toru [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan); Tashiro, Manabu [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Yanai, Kazuhiko [Department of Pharmacology, Tohoku University School of Medicine, Sendai, 980-8575 (Japan); Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0022 (Japan)

    2004-11-01

    The aim of this study was to develop simplified positron emission tomography measurement using [{sup 11}C]doxepin ([{sup 11}C]DOX) to evaluate histamine H{sub 1} receptors (H1Rs) in human brains. We evaluated the correlation between the distribution volume (DV) of [{sup 11}C]DOX, estimated quantitatively with a two-compartment model, and the [{sup 11}C]DOX uptake obtained at various time intervals and normalized using the metabolite-corrected plasma radioactivity. We found that the static 70- to 90-min images normalized using the plasma radioactivity at 10 min postinjection reflected the DV of [{sup 11}C]DOX-H1R binding.

  7. Elevated serotonin transporter binding in depressed patients with Parkinson's disease: a preliminary PET study with [11C]DASB.

    Science.gov (United States)

    Boileau, Isabelle; Warsh, Jerry J; Guttman, Mark; Saint-Cyr, Jean A; McCluskey, Tina; Rusjan, Pablo; Houle, Sylvain; Wilson, Alan A; Meyer, Jeffrey H; Kish, Stephen J

    2008-09-15

    This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [(11)C]DASB. Depressed PD patients displayed a wide-spread increase (8-68%) in [(11)C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [(11)C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[(11)C]DASB findings in major depression, the present preliminary data suggest that increased [(11)C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Parkinson's disease-and possibly a characteristic of depressive illness in general.

  8. Preclinical Safety Assessment of the 5-HT(2A) Receptor Agonist PET Radioligand [ (11)C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, Anders; Holm, Søren; Hansen, Martin;

    2013-01-01

    PURPOSE: [(11)C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT(2A)) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT(2A) receptors and may have the potential to quantify changes...... in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [(11)C]Cimbi-36, including radiation dosimetry and in vivo pharmacology. PROCEDURES: [(11)C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning......, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [(11)C]Cimbi-36. The 5-HT(2A) receptor agonist actions of [(11)C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed...

  9. Development and in vitro evaluation of core-shell type lipid-polymer hybrid nanoparticles for the delivery of erlotinib in non-small cell lung cancer.

    Science.gov (United States)

    Mandal, Bivash; Mittal, Nivesh K; Balabathula, Pavan; Thoma, Laura A; Wood, George C

    2016-01-01

    Core-shell type lipid-polymer hybrid nanoparticles (CSLPHNPs) have emerged as a multifunctional drug delivery platform. The delivery system combines mechanical advantages of polymeric core and biomimetic advantages of the phospholipid shell into a single platform. We report the development of CSLPHNPs composed of the lipid monolayer shell and the biodegradable polymeric core for the delivery of erlotinib, an anticancer drug, clinically used to treat non-small cell lung cancer (NSCLC). Erlotinib loaded CSLPHNPs were prepared by previously reported single-step sonication method using polycaprolactone (PCL) as the biodegradable polymeric core and phospholipid-shell composed of hydrogenated soy phosphatidylcholine (HSPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000). Erlotinib loaded CSLPHNPs were characterized for physicochemical properties including mean particle size, polydispersity index (PDI), zeta potential, morphology, thermal and infrared spectral analysis, drug loading, in vitro drug release, in vitro serum stability, and storage stability. The effect of critical formulation and process variables on two critical quality attributes (mean particle size and drug entrapment efficiency) of erlotinib loaded CSLPHNPs was studied and optimized. In addition, in vitro cellular uptake, luminescent cell viability assay and colony formation assay were performed to evaluate efficacy of erlotinib loaded CSLPHNPs in A549 cells, a human lung adenocarcinoma cell line. Optimized erlotinib loaded CSLPHNPs were prepared with mean particle size of about 170nm, PDI<0.2, drug entrapment efficiency of about 66% with good serum and storage stability. The evaluation of in vitro cellular efficacy results indicated enhanced uptake and efficacy of erlotinib loaded CSLPHNPs compared to erlotinib solution in A549 cells. Therefore, CSLPHNPs could be a potential delivery system for erlotinib in the therapy of NSCLC.

  10. Phase I Results from a Study of Crizotinib in Combination with Erlotinib in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Ou, Sai-Hong Ignatius; Govindan, Ramaswamy; Eaton, Keith D; Otterson, Gregory A; Gutierrez, Martin E; Mita, Alain C; Argiris, Athanassios; Brega, Nicoletta M; Usari, Tiziana; Tan, Weiwei; Ho, Steffan N; Robert, Francisco

    2017-01-01

    This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC. Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated. Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level. The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  11. Sympathetic nerve damage and restoration after ischemia-reperfusion injury as assessed by {sup 11}C-hydroxyephedrine

    Energy Technology Data Exchange (ETDEWEB)

    Werner, Rudolf A.; Higuchi, Takahiro [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); University of Wuerzburg, Comprehensive Heart Failure Center, Wuerzburg (Germany); Maya, Yoshifumi [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Nihon Medi-Physics Co., Ltd., Research Centre, Chiba (Japan); Rischpler, Christoph [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Muenchen (Germany); Javadi, Mehrbod S. [Johns Hopkins University, Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Baltimore, MD (United States); Fukushima, Kazuhito [Hyogo College of Medicine, Department of Radiology, Hyogo (Japan); Lapa, Constantin [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Herrmann, Ken [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States)

    2016-02-15

    An altered state of the cardiac sympathetic nerves is an important prognostic factor in patients with coronary artery disease. The aim of this study was to investigate regional sympathetic nerve damage and restoration utilizing a rat model of myocardial transient ischemia and a catecholamine analog PET tracer, {sup 11}C-hydroxyephedrine ({sup 11}C-HED). Transient myocardial ischemia was induced by coronary occlusion for 20 min and reperfusion in male Wistar rats. Dual-tracer autoradiography was performed subacutely (7 days) and chronically (2 months) after ischemia, and in control rats without ischemia using {sup 11}C-HED as a marker of sympathetic innervation and {sup 201}TI for perfusion. Additional serial in vivo cardiac {sup 11}C-HED and {sup 18}F-FDG PET scans were performed in the subacute and chronic phases after ischemia. After transient ischemia, the {sup 11}C-HED uptake defect areas in both the subacute and chronic phases were clearly larger than the perfusion defect areas in the midventricular wall. The subacute {sup 11}C-HED uptake defect showed a transmural pattern, whereas uptake recovered in the subepicardial portion in the chronic phase. Tyrosine hydroxylase antibody nerve staining confirmed regional denervation corresponding to areas of decreased {sup 11}C-HED uptake. Serial in vivo PET imaging visualized reductions in the area of the {sup 11}C-HED uptake defects in the chronic phase consistent with autoradiography and histology. Higher susceptibility of sympathetic neurons compared to myocytes was confirmed by a larger {sup 11}C-HED defect with a corresponding histologically identified region of denervation. Furthermore, partial reinnervation was observed in the chronic phase as shown by recovery of subepicardial {sup 11}C-HED uptake. (orig.)

  12. [Prospective study of biotin treatment in patients with erythema due to gefitinib or erlotinib].

    Science.gov (United States)

    Ogawa, Yoshikazu; Kiba, Takayoshi; Nakano, Kikuo; Fujiwara, Keiichi; Taniguchi, Hitoshi; Hosokawa, Atsuko; Nakashima, Toshihisa; Kimoto, Shizue; Kajiume, Sayoko; Okada, Yuuko; Ichiba, Yasunori

    2014-04-01

    Gefitinib anderlotinib, which are epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs), have been usedfor the treatment of inoperable andrecurrent non-small cell lung cancer(NSCLC)patients. These drugs are known to cause a skin rash, one of the major side effects, at a high frequency. Biotin is a water-soluble vitamin, andit belongs to the vitamin B family. It is well known that biotin deficiency increases the risk of skin dermatitis. We administered biotin to four patients with skin rash, all of whom were treatedwith either gefitinib or erlotinib andwere unable to be treatedby a steroid ointment alone. In all patients, administration of biotin reduced the skin rash. Surprisingly, in 2 patients in whom EGFR-TKI therapy was discontinued because of the skin rash, the administration of biotin allowed for long-term gefitinib or erlotinib treatment. Biotin may be considereduseful for the treatment of skin rash causedby EGFR-TKIs. Further trials may be needed to confirm the value of biotin in this setting.

  13. New developments of 11C post-accelerated beams for hadron therapy and imaging

    CERN Document Server

    Augusto, R S; Wenander, F; Penescu, L; Orecchia, R; Parodi, K; Ferrari, A; Stora, T

    2016-01-01

    Hadron therapy was first proposed in 1946 and is by now widespread throughout the world, as witnessed with the design and construction of the CNAO, HIT, PROSCAN and MedAustron treatment centres, among others. The clinical interest in hadron therapy lies in the fact that it delivers precision treatment of tumours, exploiting the characteristic shape (the Bragg peak) of the energy deposition in the tissues for charged hadrons. In particular, carbon ion therapy is found to be biologically more effective, with respect to protons, on certain types of tumours. Following an approach tested at NIRS in Japan [1], carbon ion therapy treatments based on 12C could be combined or fully replaced with 11C PET radioactive ions post-accelerated to the same energy. This approach allows providing a beam for treatment and, at the same time, to collect information on the 3D distributions of the implanted ions by PET imaging. The production of 11C ion beams can be performed using two methods. A first one is based on the production...

  14. PET study of the distribution of [{sup 11}C]fluoxetine in a monkey brain

    Energy Technology Data Exchange (ETDEWEB)

    Shiue, C.-Y.; Shiue, Grace G.; Cornish, Kurtis G.; O' Rourke, Maria F

    1995-07-01

    No-carrier-added [{sup 11}C]fluoxetine (2) was synthesized by methylation of norfluoxetine (1) with [{sup 11}C]H{sub 3}I in 20% radiochemical yield in a synthesis time of 40 min from EOB with a specific activity of 0.48 Ci/{mu}M (EOB). In vivo study in mouse indicated that the uptake of 2 in mouse tissues was high and the radioactivity remained constant throughout the study. The uptake of 2 in mouse brain was 4%/g. PET study in a Rhesus monkey also showed that the uptakes of 2 in different brain regions were similar and the retention of radioactivity in these regions remained constant throughout the study (80 min). Analysis of arterial plasma by HPLC showed that only 20% of radioactivity in the plasma remained as 2 at 30 min post-injection. These results suggest that the uptake of fluoxetine in monkey brain is probably not receptor mediated. Rather, blood flow, lipophilicity or other transport mechanisms may play a role in its uptake.

  15. Regional increases in [{sup 11}C]flumazenil binding after epilepsy surgery

    Energy Technology Data Exchange (ETDEWEB)

    Savic, I. [Huddinge Hospital, Dept. of Neurology (Sweden); Blomqvist, G. [Karolinska Hospital, Dept. of Clinical Neurophysiology, Stockholm (Sweden); Halldin, C. [Karolinska Hospital, Dept. of Psychiatry, Stockholm (Sweden); Litton, J.E. [Karolinska Hospital, Dept. of Psychology, Stockholm (Sweden); Gulyas, B. [Karolinska Institute, Div. of Human Brain Research (Sweden)

    1998-05-01

    Introduction - Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [{sup 11}C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. Methods - In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [{sup 11}C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. Results - Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic regions and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29{+-}17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. Conclusion - Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans. (au) 41 refs.

  16. Elevated [11C]-D-deprenyl uptake in chronic Whiplash Associated Disorder suggests persistent musculoskeletal inflammation.

    Directory of Open Access Journals (Sweden)

    Clas Linnman

    Full Text Available There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer (11C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that (11C-D-deprenyl is a promising tracer for these purposes.

  17. Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.

    NARCIS (Netherlands)

    Heine, R. ter; Bosch, R.T. van den; Schaefer-Prokop, C.M.; Lankheet, N.A.; Beijnen, J.H.; Staaks, G.H.; Westerlaken, M.M. van der; Malingre, M.M.; Brand, J.J. van den

    2012-01-01

    INTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potent

  18. A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure.

    Science.gov (United States)

    Thepot, Sylvain; Boehrer, Simone; Seegers, Valérie; Prebet, Thomas; Beyne-Rauzy, Odile; Wattel, Eric; Delaunay, Jacques; Raffoux, Emmanuel; Hunault, Mathilde; Jourdan, Eric; Chermat, Fatiha; Sebert, Marie; Kroemer, Guido; Fenaux, Pierre; Adès, Lionel

    2014-12-01

    Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

  19. A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas†

    Science.gov (United States)

    Raizer, Jeffrey J.; Abrey, Lauren E.; Lassman, Andrew B.; Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Aldape, Kenneth D.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh; DeAngelis, Lisa M.; Lieberman, Frank; Cloughesy, Timothy F.; Robins, H. Ian; Dancey, Janet; Prados, Michael D.

    2010-01-01

    The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 × 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where ≤1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs. PMID:20150371

  20. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib

    NARCIS (Netherlands)

    Janjigian, Y Y; Groen, H J; Horn, L; Smit, E F; Fu, Y; Wang, F; Shahidi, M; Denis, L J; Pao, W; Miller, V A

    2011-01-01

    7525^ Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This "acquired resistance" (AR) is a

  1. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib

    NARCIS (Netherlands)

    Janjigian, Y. Y.; Groen, H. J.; Horn, L.; Smit, E. F.; Fu, Y.; Wang, F.; Shahidi, M.; Denis, L. J.; Pao, W.; Miller, V. A.

    2011-01-01

    Background: Despite initial responses to reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, (erlotinib or gefitinib), all non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations experience disease progression. This “acquired resistance” (AR) is associa

  2. Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition.

    Science.gov (United States)

    Lou, Wei; Chen, Yan; Zhu, Ke-Ying; Deng, Huizi; Wu, Tianhao; Wang, Jun

    2017-08-01

    Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.

  3. Comparison of erlotinib and pemetrexed as second-/third-line treatment for lung adenocarcinoma patients with asymptomatic brain metastases

    Directory of Open Access Journals (Sweden)

    He YY

    2016-04-01

    Full Text Available Yayi He,1,* Wenwen Sun,2,* Yan Wang,3,* Shengxiang Ren,1 Xuefei Li,3 Jiayu Li,3 Christopher J Rivard,4 Caicun Zhou,1 Fred R Hirsch4 1Department of Oncology, Shanghai Pulmonary Hospital, 2Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO, USA *These authors contributed equally to this work Objective: Brain metastases occur in one-third of all non-small-cell lung cancer patients. Due to restrictive transport at the blood–brain barrier, many drugs provide poor control of metastases in the brain. The aim of this study was to compare erlotinib with pemetrexed as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases.Methods: From January 2012 to June 2014, all lung adenocarcinoma patients with asymptomatic brain metastases who received treatment with erlotinib or pemetrexed as second-/third-line treatment were retrospectively reviewed. Chi-square and log-rank tests were used to perform statistical analysis.Results: The study enrolled 99 patients, of which 44 were positive for EGFR mutation. Median progression-free survival (PFS in months was not significantly different between the erlotinib- and pemetrexed-treated groups (4.2 vs 3.4 months; 95% confidence interval [CI]: 2.01–6.40 vs 2.80–5.00, respectively; P=0.635. Median PFS was found to be significantly longer in EGFR mutation–positive patients in the erlotinib-treated group (8.0 months; 95% CI 5.85–10.15 compared to the pemetrexed group (3.9 months; 95% CI: 1.25–6.55; P=0.032. The most common treatment-related side effect was mild-to-moderate rash and the most common drug-related side

  4. Automated radiosyntheses of [6-0-methyl-[sup 11]C]diprenorphine and [6-0-methyl-[sup 11]C]buprenorphine from 3-0-trityl protected precursors

    Energy Technology Data Exchange (ETDEWEB)

    Luthra, S.K.; Brady, F.; Turton, D.R.; Brown, D.J.; Dowsett, K.; Waters, S.L.; Jones, A.K.P. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit); Matthews, R.W.; Crowder, J.C. (North London Univ., London (United Kingdom). School of Applied Chemistry)

    1994-08-01

    The antagonist [6-0-methyl-[sup 11]C]diprenorphine and the mixed agonist/antagonist [6-0-methyl-[sup 11]C]buprenorphine, radioligands for studying the opioid receptor system in vivo with positron emission tomography, were preapred by 0-methylation of (3-0-trityl, 6-desmethyl)diprenorphine and [3-0-trityl,6-desmethyl]buprenorphine, respectively, with [[sup 11]C]iodomethane. The use of the base-stable, acid labile trityl protecting group minimizes the formation of byproducts and allows reproducible radiosyntheses. (author).

  5. Strategy for improved [{sup 11}C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [{sup 11}C]DAA1106

    Energy Technology Data Exchange (ETDEWEB)

    Probst, Katrin C. [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]. E-mail: kp296@wbic.cam.ac.uk; Izquierdo, David [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Bird, Joseph L.E. [BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[Department of Medicine, Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Brichard, Laurent; Franck, Dominic; Fryer, Tim D.; Clark, John C. [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Davies, John R. [Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Richards, Hugh K. [Neurology Unit, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Davenport, Anthony P. [Clinical Pharmacology Unit, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Weissberg, Peter L. [Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Warburton, Elizabeth A. [BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)

    2007-05-15

    Introduction: The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [{sup 11}C]DAA1106 ([{sup 11}C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs. Methods: A four-step synthetic route was devised to prepare DAA1123, the precursor for [{sup 11}C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [{sup 11}C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [{sup 11}C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [{sup 11}C]CH{sub 3}I trapped. Evaluation of [{sup 11}C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry. Results: The standard solution method produced 2.6-5.2 GBq (n=19) of [{sup 11}C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [{sup 11}C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/{mu}mol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [{sup 11}C]DAA1106. In vivo microPET [{sup 11}C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 {mu}mol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry. Conclusions: A robust, high yielding captive solvent method of [{sup 11}C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.

  6. Evaluation of [{sup 11}C]GB67, a novel radioligand for imaging myocardial {alpha}{sub 1}-adrenoceptors with positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Law, M.P.; Osman, S.; Pike, V.W.; Davenport, R.J.; Cunningham, V.J.; Rimoldi, O.; Rhodes, C.G.; Camici, P.G. [MRC Cyclotron Unit, Imperial Coll. School of Medicine, London (United Kingdom); Giardina, D. [Dipt. di Scienze Chimiche, Univ. degli Studi di Camerino, Camerino (Italy)

    2000-01-01

    Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assessing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial {alpha}-adrenoceptors. GB67, a structural and pharmacological analogue of the {alpha}{sub 1}-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbon-11 (t{sub 1/2}=20.4 min) by {sup 11}C-methylation of N-desmethylamido-GB67 (GB99). [{sup 11}C]GB67 was injected intravenously into conscious rats. Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [{sup 11}C]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial {alpha}{sub 1}-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the {alpha}{sub 2}-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the {beta}-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [{sup 11}C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (B{sub max}) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of B{sub max} [{proportional_to}13 pmol.(g tissue){sup -1}] were similar to those [50-170 fmol.(mg protein){sup -1}] reported for myocardial {alpha}{sub 1}-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for {alpha

  7. Risk of brain metastasis reduced after erlotinib treatment in advanced pulmonary adenocarcinoma patients with sensitive EGFR mutation

    Directory of Open Access Journals (Sweden)

    Liu J

    2016-02-01

    Full Text Available Jing Liu,* Ligang Xing,* Xue Meng, Jinbo Yue, Xiangjiao Meng, Peng Xie, Xiaolin Li, Li Kong, Jinming YuDepartment of Radiation Oncology, Shandong Province Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workPurpose: Brain metastasis (BM is associated with impaired quality of life and increased mortality. The study aimed to compare BM risk after erlotinib administration and chemotherapy in stage IIIB/IV pulmonary adenocarcinoma patients harboring epidermal growth factor receptor (EGFR mutation.Patients and methods: Eligible patients underwent match pair process with matching factors, including age, sex, performance status score, first-line or second-line treatment, first-line chemotherapy regimen (for the second-line treatment subgroup, stage IIIB or IV, and genotypes of EGFR mutation. BM and mortality risk of both groups were recorded and compared.Results: In total 129 matched pairs were included for analysis. During a median follow-up of 21.5 months, time to BM risk was longer and incidences of BM within 2 years were lower in patients who received erlotinib than chemotherapy in total population, as well as subgroups of first-line treatment, second-line treatment, stage IIIB, stage IV, exon 19 deletion mutation, and exon 21 L858R mutation. Similar overall survival time and 2-year survival rates were seen in two groups totally or in any subgroup. Multivariate analysis showed that BM was retarded in patients who received erlotinib administration (hazard ratio, 1.695; P=0.001 and in patients who were in stage IIIB (hazard ratio, 1.751; P=0.001.Conclusion: Erlotinib administration decreases BM risk in advanced pulmonary adenocarcinoma patients harboring sensitive EGFR mutations.Keywords: pulmonary adenocarcinoma, brain metastasis, epidermal growth factor receptor, erlotinib, match pair analysis

  8. CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to VCAM-1

    Science.gov (United States)

    Gower, R. Michael; Wu, Huaizhu; Foster, Greg A.; Devaraj, Sridevi; Jialal, Ishwarlal; Ballantyne, Christie M.; Knowlton, Anne A.; Simon, Scott I.

    2010-01-01

    Objective Atherosclerosis is associated with monocyte adhesion to the arterial wall that involves integrin activation and emigration across inflamed endothelium. Involvement of β2-integrin CD11c/CD18 in atherogenesis was recently shown in dyslipidemic mice, which motivates our study of its inflammatory function during hypertriglyceridemia in humans. Methods and Results Flow cytometry of blood from healthy subjects fed a standardized high fat meal revealed that at 3.5 hours postprandial, monocyte CD11c surface expression was elevated and the extent of upregulation correlated with blood triglycerides. Monocytes from postprandial blood exhibited an increased light scatter profile, which correlated with elevated CD11c expression and uptake of lipid particles. Purified monocytes internalized triglyceride-rich lipoproteins isolated from postprandial blood through LRP-1, and this also elicited CD11c upregulation. Lab-on-a-chip analysis of whole blood showed that monocyte arrest on a VCAM-1 substrate under shear flow was elevated at 3.5 hours and correlated with blood triglyceride and CD11c expression. At 7 hours postprandial, blood triglycerides decreased and monocyte CD11c expression and arrest on VCAM-1 returned to fasting levels. Conclusions During hypertriglyceridemia, monocytes internalize lipid, upregulate CD11c, and increase adhesion to VCAM-1. These data suggest that analysis of monocyte inflammation may provide additional framework for evaluating individual susceptibility to cardiovascular disease. PMID:21030716

  9. Synthesis of [{sup 11}C]-S21007 a novel 5HT{sub 3} partial agonist as a potential tracer for PET studies

    Energy Technology Data Exchange (ETDEWEB)

    Guillouet, S.; Barre, L.; Gourand, F. [CEA Centre de Cyceron, 14 -Caen (France); Lasne, M.C. [Centre National de la Recherche Scientifique, 14 - Caen (France); Rault, S. [Caen Univ., 14 (France). Faculte de Pharmacie

    1996-04-01

    5HT{sub 3} receptors have been the focus of much research during the last decade. The presence of these receptors has been demonstrated in many neuronal tissues, both in periphery and in the CNS. The identification of selective agonists and antagonists for this receptor subtype has allowed the discovery of several important new therapeutic applications as the inhibition of pain, migraine, cytotoxic and radiation-induced emesis and treatment of psychoses and anxiety. The first 5HT{sub 3} antagonist labelled with a {beta}+ emitter atom was [{sup 11}C]MDL72222. The PET studies which have been performed with it in the brain of baboon (distribution, kinetics and binding) have established that it was not a good radioligand to detect a specific binding, due to its high lipophilicity. Other radioligands have been developed since, but their affinities for 5HT{sub 3} receptors PET studies have not been demonstrated. Among a series of of tricyclic piperazine derivatives synthesized, S21007 has been described as a novel selective and partial agonist which possesses a good affinity for 5HT{sub 3} receptors (IC{sub 50} = 1nM) versus other 5HT subtypes studied where IC{sub 50} > 1{mu}M. We report here the radiosynthesis of [{sup 11}C]S21007. (author).

  10. Radiation dosimetry and biodistribution of the beta-amyloid plaque imaging tracer {sup 11}C-BTA-1 in humans

    Energy Technology Data Exchange (ETDEWEB)

    Thees, S. [Ulm Univ. (Germany). Klinik fuer Nuklearmedizin; Leipzig Univ. (Germany). Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie; Neumaier, B.; Glatting, G.; Deisenhofer, S.; Reske, S.N.; Mottaghy, F.M. [Ulm Univ. (Germany). Klinik fuer Nuklearmedizin; Arnim, C.A.F. von [Ulm Univ. (Germany). Abt. fuer Neurologie

    2007-07-01

    Aim: [N-methyl-{sup 11}C]2-(4'-(methylaminophenyl)-benzothiazole({sup 11}C-BTA-1)) is a thioflavin-T derivative that has been one of the promising PET tracers for imaging of amyloid plaque distribution in the Alzheimer patients brain in vivo. The biodistribution and dosimetry of this tracer in humans is presented and compared to the results of a previous dosimetry and biodistribution study of another thioflavin-T derivative [N-methyl-{sup 11}C]2-hydroxy-(4'-(methylaminophenyl)-benzothiazole ({sup 11}C-OH-BTA-1)) in baboons. Methods: Five subjects underwent 2D dynamic PET imaging. Source organs were segmented using a semiautomatic algorithm based on clustering. Residence times for each source organ were determined by analytical integration of an exponential fit of the time activity curves. Finally organ doses were estimated using the software OLINDA/EXM. Results: The administration of 286 {+-} 93 MBq {sup 11}C-BTA-1 was well tolerated by all subjects. Effective radiation dose was 4.3 {mu}Sv/MBq, range 3.6-5.0 {mu}Sv/MBq. In four ofthe five subjects the liver, in one of the subjects the gallbladder was the critical organ. Conclusion: The radiation burden of a single dose of 300 MBq {sup 11}C-BTA-1 is within the accepted limits for research purpose. In contrast to the previous non-human primate study revealing the gallbladder as the critical organ for {sup 11}C-6-OH-BTA-1, we found the liver as the critical organ in humans using {sup 11}C-BTA-1. Possible explanations may be (1) a reduced bile concentration of {sup 11}C-BTA-1 due to the absent OH-group or (2) a different hepatic metabolism of thioflavin derivatives in human and baboon. (orig.)

  11. Quantitative measurement of histamine H{sub 1} receptors in human brains by PET and [{sup 11}C]doxepin

    Energy Technology Data Exchange (ETDEWEB)

    Mochizuki, Hideki; Kimura, Yuichi E-mail: ukimura@ieee.org; Ishii, Kenji; Oda, Keiichi; Sasaki, Toru; Tashiro, Manabu; Yanai, Kazuhiko; Ishiwata, Kiichi

    2004-02-01

    The aim of this study is to establish a method for quantitative measurement of histamine H{sub 1} receptor (H1R) in human brain by PET and [{sup 11}C]doxepin ([{sup 11}C]DOX). The estimated parameters with a two-compartment model were stable for the initial values for parameter estimation but those with a three-compartment model were not. This finding suggests that the H1R measured by the [{sup 11}C]DOX and PET can be evaluated with a two-compartment model.

  12. Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

    DEFF Research Database (Denmark)

    Palner, Mikael; McCormick, Patrick; Gillings, Nicolas;

    2010-01-01

    Several dopamine D(2) agonist radioligands have been used with positron emission tomography (PET), including [(11)C-]-(-)-MNPA, [(11)C-]-(-)-NPA and [(11)C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET...... brain images with limited contrast or have affinity for both D(2) and D(3) receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(-)-NPA, a novel PET-tracer candidate with high in vitro D(2)/D(3) selectivity....

  13. A singly charged ion source for radioactive {sup 11}C ion acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Katagiri, K.; Noda, A.; Nagatsu, K.; Nakao, M.; Hojo, S.; Muramatsu, M.; Suzuki, K.; Wakui, T.; Noda, K. [National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555 (Japan)

    2016-02-15

    A new singly charged ion source using electron impact ionization has been developed to realize an isotope separation on-line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive {sup 11}C ion beams. Low-energy electron beams are used in the electron impact ion source to produce singly charged ions. Ionization efficiency was calculated in order to decide the geometric parameters of the ion source and to determine the required electron emission current for obtaining high ionization efficiency. Based on these considerations, the singly charged ion source was designed and fabricated. In testing, the fabricated ion source was found to have favorable performance as a singly charged ion source.

  14. Simple and fully automated preparation of [carbonyl-{sup 11}C]WAY-100635

    Energy Technology Data Exchange (ETDEWEB)

    Wadsak, W.; Ettlinger, D.E; Dudczak, R.; Kletter, K. [Medical Univ. of Vienna (Austria). Dept. of Nuclear Medicine; Mien, L.K. [Medical Univ. of Vienna (Austria). Dept. of Nuclear Medicine; Medical Univ. of Vienna (Austria). Dept. of Psychiatry; Vienna Univ. (Austria). Dept. of Pharmaceutical Technology and Biopharmaceutics; Lanzenberger, R.R. [Medical Univ. of Vienna (Austria). Dept. of Psychiatry; Haeusler, D. [Medical Univ. of Vienna (Austria). Dept. of Nuclear Medicine; Vienna Univ. (Austria). Dept. of Pharmaceutical Technology and Biopharmaceutics; Mitterhauser, M. [Medical Univ. of Vienna (Austria). Dept. of Nuclear Medicine; Vienna Univ. (Austria). Dept. of Pharmaceutical Technology and Biopharmaceutics; General Hospital of Vienna (Austria). Hospital Pharmacy

    2007-07-01

    So far, [carbonyl-{sup 11}C]WAY-100635 is the PET-tracer of choice for 5HT{sub 1A}-receptor-imaging. Since the preparation is still a challenge, we aimed at (1) the evaluation of various essential parameters for the successful preparation, (2) the simplification of the radiosynthesis and (3) the establishment of a safe and fully automated system. The preparation is based on a commercial synthesizer and all chemicals are used without further processing. We found a low failure rate (7.7%), high average yield (4.0 {+-} 1.0 GBq) and a specific radioactivity of 292 {+-} 168 GBq/{mu}mol (both at the end of synthesis, EOS). (orig.)

  15. Automatic extraction of forward stroke volume using dynamic 11C-acetate PET/CT

    DEFF Research Database (Denmark)

    Harms, Hans; Tolbod, Lars Poulsen; Hansson, Nils Henrik;

    , potentially introducing bias if measured with a separate modality. The aim of this study was to develop and validate methods for automatically extracting FSV directly from the dynamic PET used for measuring oxidative metabolism. Methods: 16 subjects underwent a dynamic 27 min PET scan on a Siemens Biograph...... TruePoint 64 PET/CT scanner after bolus injection of 399±27 MBq of 11C-acetate. The LV-aortic time-activity curve (TAC) was extracted automatically from dynamic PET data using cluster analysis. The first-pass peak was derived by automatic extrapolation of the down-slope of the TAC. FSV...... was then calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured in the left ventricular outflow tract by cardiovascular magnetic resonance using phase-contrast velocity mapping within two weeks of PET imaging. Results...

  16. A singly charged ion source for radioactive 11C ion acceleration

    Science.gov (United States)

    Katagiri, K.; Noda, A.; Nagatsu, K.; Nakao, M.; Hojo, S.; Muramatsu, M.; Suzuki, K.; Wakui, T.; Noda, K.

    2016-02-01

    A new singly charged ion source using electron impact ionization has been developed to realize an isotope separation on-line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive 11C ion beams. Low-energy electron beams are used in the electron impact ion source to produce singly charged ions. Ionization efficiency was calculated in order to decide the geometric parameters of the ion source and to determine the required electron emission current for obtaining high ionization efficiency. Based on these considerations, the singly charged ion source was designed and fabricated. In testing, the fabricated ion source was found to have favorable performance as a singly charged ion source.

  17. Dopamine receptors in pituitary adenomas: PET visualization with 11C-N-methylspiperone

    Energy Technology Data Exchange (ETDEWEB)

    Muhr, C.; Bergstroem, M.L.; Lundberg, P.O.; Bergstroem, K.H.; Hartvig, P.; Lundqvist, H.; Antoni, G.; Langstroem B2

    1986-03-01

    Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.

  18. Effects of anesthesia on [11C]raclopride binding in the rat brain

    DEFF Research Database (Denmark)

    Alstrup, Aage Kristian Olsen; Simonsen, Mette; Møller, Arne

    Background Very often rats are anesthetized prior to micro positron emission tomography (microPET) brain imaging in order to prevent head movements. Anesthesia can be administered by inhalation agents, such as isoflurane, or injection mixtures, such as fentanyl-fluanisone-midazolam. Unfortunately....... Materials & Methods Nine male Lew/Mol rats were assigned to either inhalation (isoflurane; N=4) or injection (fentanyl-fluanisone-midazolam; N=5) anesthesia. Catheters were surgically placed in femoral arteries and veins for blood sampling and tracer injection. After a short attenuation scan, the rats were...... PET scanned for 90 minutes after injection of [11C]raclopride. Results We found that rats anesthetized with isoflurane had double the binding potential in the striatum compared with fentanyl-fluanisone-midazolam anesthetized rats. Conclusion Our results are in agreement with other studies showing...

  19. Effects of anesthesia on [11C]raclopride binding in the rat brain

    DEFF Research Database (Denmark)

    Alstrup, Aage Kristian Olsen; Simonsen, Mette; Møller, Arne

    Background Very often rats are anesthetized prior to micro positron emission tomography (microPET) brain imaging in order to prevent head movements. Anesthesia can be administered by inhalation agents, such as isoflurane, or injection mixtures, such as fentanyl-fluanisone-midazolam. Unfortunately......, anesthesia affects a variety of physiological variables, including in the brain. Aim The aim of this study was to compare the effects of inhalation and injection anesthesia on the binding potential of the dopaminergic D2/3 tracer [11C]raclopride used for PET brain imaging in human and animal studies....... Materials & Methods Nine male Lew/Mol rats were assigned to either inhalation (isoflurane; N=4) or injection (fentanyl-fluanisone-midazolam; N=5) anesthesia. Catheters were surgically placed in femoral arteries and veins for blood sampling and tracer injection. After a short attenuation scan, the rats were...

  20. Solid-phase reversible trap for [11C]carbon dioxide using carbon molecular sieves.

    Science.gov (United States)

    Mock, B H; Vavrek, M T; Mulholland, G K

    1995-07-01

    A simple, maintenance-free trapping technique which concentrates and purifies no-carrier-added 11CO2 from gas targets is described. The trap requires no liquid nitrogen cooling and has no moving parts besides solenoid valves. It employs carbon molecular sieves to adsorb 11CO2 selectively from gas targets at room temperature. Nitrogen, O2, CO, NO and moisture in the target gas which could interfere with subsequent radiochemical steps are not retained. Trapping efficiency of 1 g of sieve for 11CO2 from a 240 cm3 target gas dump and helium flush cycle is > 99%, and the adsorbed 11CO2 is recovered quantitatively as a small concentrated bolus from the carbon sieve trap by thermal desorption. This durable trap has performed reliably for more than 1 y with a single charge of carbon sieve. It has simplified the production, and improved the yields of several 11C-radiochemicals at this laboratory.

  1. Clinical utility of 11C-flumazenil positron emission tomography in intractable temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Padma M

    2004-10-01

    Full Text Available BACKGROUND: 11C-flumazenil (FMZ positron emission tomography (PET is a new entrant into the armamentarium for pre-surgical evaluation of patients with intractable temporal lobe epilepsy (TLE. AIMS: To analyze the clinical utility of FMZ PET to detect lesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to magnetic resonance imaging (MRI, 2-Deoxy-2 [18F] fluoro-D-glucose, (18F FDG PET, electrophysiological findings and semiology of epilepsy in patients with intractable TLE. MATERIALS AND METHODS: Patients underwent a high resolution MRI, prolonged Video-EEG monitoring before 18F FDG and 11C FMZ PET studies. Regional cortical FMZ PET abnormalities were defined on co-registered PET images using an objective method based on definition of areas of abnormal asymmetry (asymmetry index {AI}>10%. SETTINGS AND DESIGN: Prospective. STATISTICAL ANALYSIS: Student′s "t" test. RESULTS: Twenty patients (Mean age: 35.2 years [20-51]; M:F=12:8 completed the study. Mean age at seizure onset was 10.3 years (birth-38 years; mean duration, 23.9 years (6-50 years. Concordance with the MRI lesion was seen in 10 patients (nine with hippocampal sclerosis and one with tuberous sclerosis. In the other 10, with either normal or ambiguous MRI findings, FMZ and FDG uptake were abnormal in all, concordant with the electrophysiological localization of the epileptic foci. Remote FMZ PET abnormalities (n=18 were associated with early age of seizure onset (P=0.005 and long duration of epilepsy (P=0.01. CONCLUSIONS: FMZ-binding asymmetry is a sensitive method to detect regions of epileptic foci in patients with intractable TLE.

  2. In vivo detection of prion amyloid plaques using [{sup 11}C]BF-227 PET

    Energy Technology Data Exchange (ETDEWEB)

    Okamura, Nobuyuki; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Shiga, Yusei; Itoyama, Yasuhito [Tohoku University School of Medicine, Department of Neurology, Sendai (Japan); Furumoto, Shozo [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tsuboi, Yoshio [Fukuoka University School of Medicine, Department of Neurology, Fukuoka (Japan); Furukawa, Katsutoshi; Arai, Hiroyuki [Institute of Development, Aging, and Cancer, Tohoku University, Department of Geriatrics and Gerontology, Division of Brain Sciences, Sendai (Japan); Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan); Doh-ura, Katsumi [Tohoku University School of Medicine, Department of Prion Research, 2-1 Seiryo-machi, Aoba-ku, Sendai (Japan)

    2010-05-15

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [{sup 11}C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [{sup 11}C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  3. A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer

    NARCIS (Netherlands)

    Lind, Joline S. W.; Dingemans, Anne-Marie C.; Groen, Harry J. M.; Thunnissen, Frederik B.; Bekers, Otto; Heideman, Danielle A. M.; Honeywell, Richard J.; Giovannetti, Elisa; Peters, Godefridus J.; Postmus, Pieter E.; van Suylen, Robert Jan; Smit, Egbert F.

    2010-01-01

    Purpose: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced

  4. Acute Generalized Exanthematous Pustulosis Induced by Erlotinib (Tarceva with Superimposed Staphylococcus aureus Skin Infection in a Pancreatic Cancer Patient: A Case Report

    Directory of Open Access Journals (Sweden)

    Egbert Liquete

    2012-05-01

    Full Text Available Acute generalized exanthematous pustulosis (AGEP is a rare acute reaction that is drug induced in 90% of the cases and characterized by a widespread, sterile pustular rash. Erlotinib, a small-molecule EGFR tyrosine kinase inhibitor, has been approved by the FDA for patients with pancreatic cancer and non-small cell lung cancer. Skin rash is a well-known side effect related with all EGFR blocking agents. It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival. We report a case of rare presentation of AGEP involving an adverse effect of erlotinib. The commonly reported adverse effects of erlotinib are mild skin eruptions. However, our case describes the rare presentation of AGEP induced by erlotinib. The estimated incidence rate of AGEP is approximately 1–5 cases per million/year.

  5. Evaluation of [O-methyl-{sup 11}C]RS-15385-197 as a positron emission tomography radioligand for central {alpha}{sub 2}-adrenoceptors

    Energy Technology Data Exchange (ETDEWEB)

    Hume, S.P.; Hirani, E.; Opacka-Juffry, J.; Osman, S.; Myers, R.; Gunn, R.N.; McCarron, J.A.; Pike, V.W. [MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London (United Kingdom); Clark, R.D. [Roche Bioscience, Pharma Division, Palo Alto, CA (United States); Melichar, J.; Nutt, D.J. [Psychopharmacology Unit, School of Medical Science, University of Bristol, Bristol (United Kingdom)

    2000-05-01

    Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-197, were evaluated in rats as potential radioligands to image central {alpha}{sub 2}-adrenoceptors in vivo. The biodistributions of both compounds were comparable with that obtained in an earlier study using tritiated RS-79948-197 and were consistent with the known localisation of {alpha}{sub 2}-adrenoceptors. The maximal signals (total to non-specific binding) were, however, reduced, in the order [{sup 11}C]RS-79948-197 < [{sup 11}C]RS-15385-197 < [{sup 3}H]RS-79948-197, primarily due to the difference in radiolabel position (O-methyl for carbon-11 compared with S-ethyl for tritium). This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the non-specific component of brain radioactivity. Nonetheless, the signal ratio of {proportional_to}5 for a receptor-dense tissue compared with the receptor-sparse cerebellum, at 90-120 min after radioligand injection, encouraged the development of [O-methyl-{sup 11}C]RS-15385-197 for human positron emission tomography (PET). Unfortunately, in two human PET scans (each of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution more than an order of magnitude lower than that measured in rats. Following intravenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats demonstrated a higher protein binding of the radioligand in human compared with rat plasma and a lower BUI in the presence of human plasma. It is feasible that a higher affinity of RS-15385-197 for human plasma protein compared with receptor limited the transport of the radioligand. Although one of the PET scans showed a slight heterogeneity in biodistribution of radioactivity which was consistent with the known localisation of {alpha}{sub 2}-adrenoceptors in

  6. [{sup 18}F]Flutemetamol amyloid-beta PET imaging compared with [{sup 11}C]PIB across the spectrum of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Hatashita, Shizuo; Yamasaki, Hidetomo [Shonan-Atsugi Hospital, Neurology, PET Center, Atsugi (Japan); Suzuki, Yutaka; Wakebe, Daichi; Hayakawa, Hideki [Shonan-Atsugi Hospital, Radiology, PET Center, Atsugi (Japan); Tanaka, Kumiko [Shonan-Atsugi Hospital, Pharmacology, PET Center, Atsugi (Japan)

    2014-02-15

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the {sup 18}F-labeled Pittsburgh compound B (PIB) derivative [{sup 18}F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [{sup 18}F]FMM and [{sup 11}C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [{sup 18}F]FMM PET 85 min after injection, 60-min dynamic [{sup 11}C]PIB PET, and cognitive testing. [{sup 18}F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [{sup 18}F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [{sup 11}C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p < 0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6 %) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r = 0.94, n = 145, p < 0.001). [{sup 18}F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [{sup 11}C]PIB PET. (orig.)

  7. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial

    OpenAIRE

    Schuler, M.; Yang, J. C.-H.; Park, K.; Kim, J. -H.; Bennouna, J; Chen, Y.-M.; Chouaid, C.; de Marinis, F.; Feng, J. -F.; Grossi, F; Kim, D.-W.; Liu, X.; Lu, S.; Strausz, J.; Vinnyk, Y.

    2015-01-01

    Background Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy. Patients and methods Patients with relapsed/refractory disease following ≥1 ...

  8. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Johnsson, Anders; Hagman, H; Frödin, J-E

    2013-01-01

    The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC).......The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC)....

  9. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease.

    Science.gov (United States)

    Kamphuis, Willem; Kooijman, Lieneke; Schetters, Sjoerd; Orre, Marie; Hol, Elly M

    2016-10-01

    Amyloid plaques in Alzheimer's disease (AD) mice are surrounded by activated microglia. The functional role of microglia activation in AD is not well understood; both detrimental and beneficial effects on AD progression have been reported. Here we show that the population of activated microglia in the cortex of the APPswe/PS1dE9 mouse AD model is divided into a CD11c-positive and a CD11c-negative subpopulation. Cd11c transcript levels and number of CD11c-positive microglia increase sharply when plaques start to occur and both parameters continue to rise in parallel with the age-related increasing plaque load. CD11c cells are localized near plaques at all stages of the disease development and constitute 23% of all activated microglia. No differences between these two populations were found in terms of proliferation, immunostaining intensity of Iba1, MHC class II, CD45, or immunoproteasome subunit LMP7/β5i. Comparison of the transcriptome of isolated CD11c-positive and CD11c-negative microglia from the cortex of aged APPswe/PS1dE9 with WT microglia showed that gene expression changes had a similar general pattern. However, a differential expression was found for genes involved in immune signaling (Il6, S100a8/Mrp8, S100a9/Mrp14, Spp1, Igf1), lysosome activation, and carbohydrate- and cholesterol/lipid-metabolism (Apoe). In addition, the increased expression of Gpnmb/DC-HIL, Tm7sf4/DC-STAMP, and Gp49a/Lilrb4, suggests a suppressive/tolerizing influence of CD11c cells. We show that amyloid plaques in the APP/PS1 model are associated with two distinct populations of activated microglia: CD11c-positive and CD11c-negative cells. Our findings imply that CD11c-positive microglia can potentially counteract amyloid deposition via increased Aβ-uptake and degradation, and by containing the inflammatory response. Copyright © 2016. Published by Elsevier B.V.

  10. Muscarinic Receptor Occupancy and Cognitive Impairment: A PET Study with [11C](+)3-MPB and Scopolamine in Conscious Monkeys

    OpenAIRE

    Yamamoto, Shigeyuki; Nishiyama, Shingo; Kawamata, Masahiro; Ohba, Hiroyuki; Wakuda, Tomoyasu; Takei, Nori; Tsukada, Hideo; Domino, Edward F.

    2011-01-01

    The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB). The scan sequence was pre-, 2,...

  11. Evaluation of [{sup 11}C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Vries, Erik F.J. de [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)], E-mail: e.f.j.de.vries@ngmb.umcg.nl; Doorduin, Janine; Dierckx, Rudi A.; Waarde, Aren van [Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen (Netherlands)

    2008-01-15

    Background: Overexpression of cyclooxygenase type 2 (COX-2) is triggered by inflammatory stimuli, but it also plays a prominent role in the initiation and progression of various diseases. This study aims to investigate [{sup 11}C]rofecoxib as a positron emission tomography (PET) tracer for COX-2 expression. Methods: [{sup 11}C]Rofecoxib was prepared by methylation of its sulphinate precursor. Regional brain distribution and specific binding of [{sup 11}C]rofecoxib in healthy rats was studied by ex vivo biodistribution and autoradiography. Regional brain distribution and PET imaging studies were also performed on rats with severe encephalitis, caused by nasal infection with herpes simplex virus (HSV). Finally, ex vivo biodistribution and blocking studies were carried in rats with a sterile inflammation, induced by intramuscular turpentine injection. Results: [{sup 11}C]rofecoxib brain uptake in control animals corresponded with the known distribution of COX-2. Pretreatment with NS398 significantly reduced tracer uptake in the cingulate/frontopolar cortex, whereas the reduction in hippocampus approached significance. Ex vivo autoradiography also revealed preferential tracer uptake in hippocampus and cortical areas that could be blocked by NS398. In HSV-infected animals, [{sup 11}C]rofecoxib uptake was moderately increased in all brain regions, but it could not be blocked with indomethacin. Yet, some PET images revealed increased tracer uptake in brain areas with microglia activation. In turpentine-injected animals, [{sup 11}C]rofecoxib uptake in inflamed muscle was not higher than in control muscle and could not be blocked with NS398. Indomethacin caused a slight reduction in muscle uptake. Conclusions: Despite the apparent correlation between [{sup 11}C]rofecoxib uptake and COX-2 distribution in healthy rats, [{sup 11}C]rofecoxib could not unambiguously detect COX-2 overexpression in two rat models of inflammation.

  12. In vivo uptake of [{sup 11}C]choline does not correlate with cell proliferation in human prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Breeuwsma, Anthonius J. [Groningen University Hospital, Department of Urology, Groningen (Netherlands); Groningen University Hospital, PET Centre, Groningen (Netherlands); Pruim, Jan; Vaalburg, Wim [Groningen University Hospital, PET Centre, Groningen (Netherlands); Jongen, Maud M.; Nijman, Rien J.; Jong, Igle J. de [Groningen University Hospital, Department of Urology, Groningen (Netherlands); Suurmeijer, Albert J. [Groningen University Hospital, Department of Pathology, Groningen (Netherlands)

    2005-06-01

    Prostate cancer is the second leading cause of death from cancer among US men. Positron emission tomography (PET) with [{sup 11}C]choline has been shown to be useful in the staging and detection of prostate cancer. The background of the increased uptake of choline in human prostate cancer is not completely understood. The aim of this study was to prospectively investigate the relationship between the [{sup 11}C]choline uptake and the cell proliferation in human prostate cancer. Prostate cancer tissue from 18 patients who had undergone a radical prostatectomy for histologically proven disease was studied. An [{sup 11}C]choline PET scan was performed prior to surgery. Post-prostatectomy specimens were prepared and stained with the antibody MIB-1 for Ki-67, which depicts proliferation. Two independent observers counted the amount of stained nuclei per specimen. Prostate cancer showed Ki-67 staining and high uptake of [{sup 11}C]choline. Statistical analysis showed no significant correlation between [{sup 11}C]choline uptake and Ki-67 staining (R=0.23; P=0.34). No significant relationships were found between the uptake of [{sup 11}C]choline (SUV) and either preoperative PSA (R=0.14; P=0.55) or Gleason sum score (R=0.28; P=0.25). In vivo uptake of [{sup 11}C]choline does not correlate with cell proliferation in human prostate cancer as depicted by Ki-67. Our results suggest that a process other than proliferation is responsible for the uptake of [{sup 11}C]choline in prostate cancer. (orig.)

  13. Evaluation of the kappa-opioid receptor-selective tracer [{sup 11}C]GR103545 in awake rhesus macaques

    Energy Technology Data Exchange (ETDEWEB)

    Schoultz, Bent W. [University of Oslo, Department of Chemistry, Oslo (Norway); Hjornevik, Trine; Willoch, Frode [University of Oslo, Centre for Molecular Biology and Neuroscience and Institute of Basic Medical Sciences, Oslo (Norway); Akershus University Hospital, Department of Nuclear Medicine, Loerenskog (Norway); Marton, Janos [ABX Advanced Biochemical Compounds GmbH, Radeberg (Germany); Noda, Akihiro; Murakami, Yoshihiro; Miyoshi, Sosuke; Nishimura, Shintaro [Medical and Pharmacological Research Center Foundation, Basic Research Department, Hakui City, Ishikawa (Japan); Aarstad, Erik [University College of London, Institute of Nuclear Medicine, London (United Kingdom); Drzezga, Alexander [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Matsunari, Ichiro [Medical and Pharmacological Research Center Foundation, Clinical Research Department, Hakui City, Ishikawa (Japan); Henriksen, Gjermund [University of Oslo, Department of Chemistry, Oslo (Norway); Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany)

    2010-06-15

    The recent development in radiosynthesis of the {sup 11}C-carbamate function increases the potential of [{sup 11}C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor ({kappa}-OR) with PET. In the present study, [{sup 11}C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. Regional brain uptake kinetics of [{sup 11}C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [{sup 11}C]GR103545 was determined in cells transfected with cloned human opioid receptors. In vitro binding assays demonstrated a high affinity of GR103545 for {kappa}-OR (K{sub i} = 0.02 {+-}0.01 nM) with excellent selectivity over {mu}-OR (6 x 10{sup 2}-fold) and {delta}-OR (2 x 10{sup 4}-fold). PET imaging revealed a volume of distribution (V{sub T}) pattern consistent with the known distribution of {kappa}-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. [{sup 11}C]GR103545 is selective for {kappa}-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET. (orig.)

  14. Brain serotonin synthesis in MDMA (ecstasy) polydrug users: an alpha-[(11) C]methyl-l-tryptophan study.

    Science.gov (United States)

    Booij, Linda; Soucy, Jean-Paul; Young, Simon N; Regoli, Martine; Gravel, Paul; Diksic, Mirko; Leyton, Marco; Pihl, Robert O; Benkelfat, Chawki

    2014-12-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[(11) C]methyl-l-tryptophan ((11) C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional (11) C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized (11) C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized (11) C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized (11) C-AMT trapping in the brainstem and pre-frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5-HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms.

  15. Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

    DEFF Research Database (Denmark)

    Jørgensen, Nis Pedersen; Alstrup, Aage Kristian Olsen; Mortensen, Frank Viborg

    2016-01-01

    of inflammation has not previously been investigated. Methods We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously...... and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived...... from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil...

  16. Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

    DEFF Research Database (Denmark)

    Jørgensen, Nis Pedersen; Alstrup, Aage Kristian Olsen; Mortensen, Frank Viborg

    2017-01-01

    of inflammation has not previously been investigated. Methods We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously...... and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived...... from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil...

  17. Tracer kinetic modeling of [(11)C]AFM, a new PET imaging agent for the serotonin transporter.

    Science.gov (United States)

    Naganawa, Mika; Nabulsi, Nabeel; Planeta, Beata; Gallezot, Jean-Dominique; Lin, Shu-Fei; Najafzadeh, Soheila; Williams, Wendol; Ropchan, Jim; Labaree, David; Neumeister, Alexander; Huang, Yiyun; Carson, Richard E

    2013-12-01

    [(11)C]AFM, or [(11)C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [(11)C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of [(11)C]AFM binding potential (BPND) matched well with the known regional SERT densities. For routine use of [(11)C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b') for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [(11)C]AFM is a suitable PET radioligand to image and quantify SERT in humans.

  18. Erlotinib treatment for persistent spontaneous pneumothorax in non-small cell lung cancer: a case report

    Institute of Scientific and Technical Information of China (English)

    REN Sheng-xiang; ZHOU Song-wen; ZHANG Ling; ZHOU Cai-cun

    2010-01-01

    @@ Spontaneous pneumothorax (SP) develops secondary to primary lung cancer. It has a very low incidence and accounts for less than 1% of all cases.1 Once SP develops, the prognosis is usually very poor, and majority of patients live no longer than 3 months.1,2Most patients with advanced stage can not undergo resection due to the poor general condition. Thus, chest tube drainage remains among the treatments of choice although it is not always completely effective in preventing recurrence. In refractory SP, patients would bear the chest tube for their whole life.3 Here we report a case of SP following chemotherapy in adenocarcinoma of the lung with multiple organs metastases. In this case, chest tube drainage was not effective in preventing recurrence of SP.However, the treatment was successful with oral erlotinib,an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).

  19. The synthesis of (R)- and (S)-[N-methyl-{sup 11}C]{beta}, {beta}-difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Gillings, N.M.; Gee, A.D. [PET Centre, Aarhus University Hospital, Aarhus C (Denmark); Inoue, O. [School of Allied Health Sciences, Osaka University Medical School, Osaka (Japan)

    1999-04-01

    In an attempt to elucidate the contribution of the extent of nitrogen protonation on the in vivo binding of methamphetamine in the brain, the enantiomers of [N-methyl-{sup 11}C]{beta},{beta}-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of {beta},{beta}-difluoroamphetamine were prepared from trans-{beta}-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-{beta},{beta}-difluoroamphetamine (3) were then each labelled with carbon-11 (t{sub 1/2}=20.4 min) by N-methylation of the corresponding homochiral {beta},{beta}-difluoroamphetamine with [{sup 11}C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [{sup 11}C]carbon dioxide in 15-16% decay-corrected radiochemical yield, with a radiochemical purity of >99% and specific radioactivity of 50-150 GBq {mu}mol{sup -1} at end of synthesis.

  20. 厄洛替尼致肝损害%Liver damage due to erlotinib

    Institute of Scientific and Technical Information of China (English)

    白帆; 刘阳; 冯雷

    2013-01-01

    1例表皮生长因子受体阳性的初诊78岁男性肺癌患者接受厄洛替尼150 mg,1次/d口服化疗.化疗前丙氨酸转氨酶(ALT) 12 U/L,天冬氨酸转氨酶(AST) 16 U/L,总胆红素(TBil)22.0μmol/L,直接胆红素(DBil) 7.6 μmol/L.化疗2周复查:ALT 30 U/L,AST 33 U/L,TBil 20.0μmol/L,DBil 6.3 μmol/L.化疗2个月患者出现尿色加深,全身皮肤及巩膜黄染.化疗约75 d实验室检查:ALT 368 U/L,TBil 182.1 μmol/L,DBil 155.2μmol/L.停用厄洛替尼,予保肝治疗.停药第4天,ALT 171 U/L,AST 177 U/L,TBil 322.0μmol/L,DBil 278.2 μmol/L.停药第6天,加用甲泼尼龙.停药第12天,ALT 132 U/L,AST 141 U/L,TBil 172.6 μmol/L,DBil 135.4 μmol/L.停用厄洛替尼2个月,ALT 12 U/L,AST 30U/L,TBil 19.8 μmol/L,DBil 13.5 μmol/L.随后换用吉西他滨联合尼妥珠单抗继续化疗6个疗程,未再出现肝功能异常.%A 78-year-old man,who was newly diagnosed with epidermal growth factor receptorpositive lung cancer,received treatment with oral erlotinib 150 mg once daily.Laboratory test before the chemotherapy showed the following values:alanine aminotransferase (ALT) 12 U/L,aspartate aminotransferase (AST) 16 U/L,total bilirubin (TBil) 22.0 μmol/L,direct bilirubin (DBil) 7.6 μmol/L.Two weeks after chemotherapy treatment,re-examination revealed the following values:ALT 30 U/L,AST 33 U/L,TBil 20.0 μmol/L,DBil 6.3 μmol/L.Two months after chemotherapy,the patient presented with dark urine and yellowish whole skin and sclera.Seventy-five days after the chemotherapy,laboratory test showed the following values:ALT 368 U/L,TBil 182.1 μmol/L,DBil 155.2 μmol/L.Erlotinib was discontinued and liver-protective treatment was given.On day 4 after erlotinib discontinuation,the levels of ALT,AST,TBil,and DBil were 171 U/L,177 U/L,322.0 μmol/L,and 278.2 μmol/L,respectively.On day 6 after erlotinib discontinuation,methylprednisolone was added to his regimen.On day 12 after erlotinib discontinuation,the levels of ALT,AST,TBil,and DBil were

  1. [{sup 11}C]d-threo-Methylphenidate, a new radiotracer for the dopamine transporter. Characterization in baboon and human brain

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Volkow, N.D.; Fowler, J.S. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    dl-threo Methylphenidate (MP, Ritalin) is a psychostimulant drug which binds to the dopamine transporter (DAT). We evaluated [{sup 11}C]d-threo-methylphenidate ([{sup 11}C]d-MP), the more active enantiomer, as a radiotracer for the DAT in baboons and human brain. Stereoselectivity, saturability and pharmacological specificity and reproducibility were examined. Stereoselectivity was examined in baboons by comparing [{sup 11C}]d-MP,[{sup 11}C]l-MP and [{sup 11}C]dl-MP. Unlabeled MP was used to assess the reversibility and saturability of the binding. GBR 12909,{beta}-(4-iodophenyl)tropane-2-carboxylic acid methyl ester ({beta}-CIT), tomoxetine and citalopram were used to assess the specificity of the binding. The ratios between the radioactivity in the striatum to that in cerebellum (ST/CB) were 3.3,2.2 and 1.1 for [{sup 11}C]d-MP,[{sup 11}C]dl-MP and [{sup 11}C]l-MP respectively. Most of the striatal binding of [{sup 11}C]d-threo-MP was displaced by injection of nonradioactive MP demonstrating reversibility. Pretreatment with MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) or {beta}-CIT (0.3 mg/kg) reduced ST/CB by about 60% and the ratios of distribution volumes at the steady-state for the triatum to cerebellum (DV{sub st/}DV{sub cb}) by about 50%. Pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, had no effect. Studies of [{sup 11}C]d-MP in the human brain showed highest uptake in basal ganglia with a half clearance time of about 60 minutes. Repeated studies in 6 normal human subjects showed differences in DV{sub st/}DV{sub cb} between -7% and 8%. MP pretreatment decreased BG but no cortical or cerebellar binding and reduced Bmax/Kd by 91%.

  2. (/sup 11/C)methionine pancreatic scanning with positron emission computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Syrota, A.; Comar, D.; Cerf, M.; Plummer, D.; Maziere, M.; Kellershohn, C.

    1979-07-01

    By the use of (/sup 11/C)methionine and positron computed tomography (PCT), images of the pancreas were obtained in 32 patients. The injection of between 10 and 20 mCi of this product enables four to six transverse sections to