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Sample records for 11c labeled erlotinib

  1. Preparation of 11C labelled tamoxifen

    1999-01-01

    The syntheses and HPLC analysis of N-desmethyltamoxifen and carbon-11labelled tamoxifen are described. In order to obtain the N-desmethyltamoxifen,tamoxifencitrate was first converted to tamoxifen free base.N-desmethyltamoxifen wasprepared by reacting tamoxifen free base with 1-chloroethyl-chloroformate(ACE.Cl).For 11C labeling, N-desmethyltamoxifen was heated with 11Cmethyl iodide for 10min at 130℃,and the 11Clabelled compound was purifiedby HPLC on a μBonapak TM C18 column.Injectable 11C-tamoxifen was obtained within 50~60min from EOB (end-of-bombardment) with a labeling yield of 60%~70%.

  2. Quantitative Analysis of [11C]-Erlotinib PET Demonstrates Specific Binding for Activating Mutations of the EGFR Kinase Domain

    J. Ryan Petrulli

    2013-12-01

    Full Text Available Activating mutations of the epidermal growth factor receptor (EGFR occur in multiple tumor types, including non-small cell lung cancer (NSCLC and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [11C]-erlotinib positron emission tomography (PET imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA [11C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 ΔEGFR, and SW620. Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9 had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620, possessing wild-type EGFR (U87, and expressing an activating extracellular domain mutation (U87 ΔEGFR were indistinguishable under both high and low SA scan conditions. The results suggest that [11C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations.

  3. Solid support for [11C]cyanide labelling of radiopharmaceuticals

    [11C]HCN plays a major role in synthesis of 11C-labelled organic radiopharmaceuticals because of its on-line availability as a primary precursor of Carbon-11. [11C]HCN is usually trapped in 0.5-1.0 ml of 0.1 M NaOH or KOH solution for the synthesis of organic labelled compounds. Though [11C]HCN in 0.1 M base can be utilized for labelling base resistant organic compounds, substrates with esters, amide like functional groups cannot be labelled using this method due to the instability of these groups in basic medium. The authors report a novel approach for trapping no-carrier-added [11C]HCN on a silica gel support and its incorporation into model compounds

  4. Adaptation of an automated [11C]methylation system for the loop labeling method using [11C]methyl triflate

    An automated system for preparation of 11C-methylated compounds from [11C]methyl iodide, manufactured by Sumitomo Heavy Industries Ltd., was adapted for the loop labeling method using [11C]methyl triflate. Two 2-way valves on an exchangeable tray were replaced with 3-way valves and a furnace for heating an AgOTf column at 200 deg C was added. The automated system successfully produced [11C]raclopride and [11C]N-methyl-3-piperidyl benzilate in 0.96-1.1 GBq and 1.0-1.3 GBq, respectively, at 40 min after the end of bombardment. (author)

  5. Synthesis of some 11C-labelled alkaloids

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

  6. Chemical and enzymatic approaches for 11C-labelled octopamine synthesis using hydrogen [11C]cyanide

    Octopamine, the β-hydroxy derivative of tyramine, has been the objects of growing interest as biogenic trace amine. Studies using [3H]-labelled p- and m-octopamine have shown that they are both taken up in noradrenergic nerve terminals, accumulated in storage vesicles, and released together with noradrenaline on stimulation. p- and m-[11C]Octopamine have been synthesized from H[11C]CN in two-step sequence. Both chemical and enzymatic procedures have been used for the production of [11C]cyanohydrin intermediates as the key step. The enantiomeric composition of the labelled products obtained through the enzymatic process was assayed by analytical HPLC

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

    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.

  8. Syntheses of 18F-labeled reduced haloperidol and 11C-labeled reduced 3-N-methylspiperone

    18F-Labeled reduced haloperidol and 11C-labeled reduced 3-N-methylspiperone were synthesized in a convenient and quantitative one step reduction from 18F-labeled haloperidol and 11C-labeled N-methylspiperone, respectively. Both products were purified by semipreparative HPLC and were obtained at high specific activity and radiochemical purity. (author)

  9. 11C-labeling of indolealkylamine alkaloids and the comparative study of their tissue distributions

    Five indolealkylamines (N,N-dimethyltryptamine, N-methyltryptamine, bufotenine, O-methylbufotenine, N,N,N-trimethyltryptamine iodide) were labeled with 11C by use of 11CH3I. The labeled compounds were synthesized with a radiochemical yield of 2-50% (based on trapped 11CH3I) in 20-35 min with radiochemical purities of more than 92%. The tissue distributions of these labeled compounds were investigated in rats. In all cases, the accumulations in the liver, lung and small intestine were high. [11C]DMT and [11C]OMB also accumulated to a large extent in the brain, where their accumulation was retained. Brain uptake of three other radiopharmaceuticals was low. [11C]DMT is the radiopharmaceutical of choice for the study of the serotonin action mechanism in the brain, because it has the highest radiochemical yield and the highest brain uptake of these 11C-labeled compounds. (author)

  10. Fixation, retention and exhalation of carrier-free 11C-labelled carbon monoxide by man

    Carrier-free 11C-labelled carbon monoxide was produced by proton irradiation of a nitrogen gas flow target via the 14N(p,α)11C process followed by on-line reduction of the predominantly formed 11C-carbon dioxide with a yield of 0.4 mCi/μAmin. After appropriate quality control about 2 mCi of carrier-free 11C-carbon monoxide in 500 ml of nitrogen gas were inhaled by test subjects in one breath. The 11C-activity distribution was then followed in vivo by scanning above thorax, head, liver, thigh and os sacrum; simultaneously the 11C-activity of the blood was also followed by batch measurement. The data indicate that part of the 11C-activity migrates from the blood into the intercellular space, while another part is exhaled. The 11C-activity leaves the individual organs with a biological half-life ranging from about 120 to 200 min, a time which is short as compared to the one observed for 51Cr-labelled erythrocytes. A radio gas chromatographic analysis of the exhaled air showed that the 11C-activity leaves the body exclusively in the form of 11C-labelled carbon monoxide. Consequently, metabolism of the 11CO into 11Co2 or other compounds can be excluded. (orig.)

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

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

  12. 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

    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.

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

    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 [11C]methylisocyanate with eseroline. [11C]Methylisocyanate was obtained by heating [11C]acetylchloride with tetrabutylammonium azide in toluene. The synthesis of [11C]CH3COC1 involves the carbonation of methylmagnesium bromide in THF with cyclotron produced [11C]carbon dioxide and the addition of phthaloyl dichloride. The [11C]methylisocyanate is distilled into a solution of eseroline in ether with a small piece of sodium. After 10 minutes at 25oC, the solution is purified by HPLC and the appropriate fraction collected. Starting with 55.5 GBq (1.5 Ci) of [11C]carbon dioxide, 0.92-1.48 GBq (25-40 mCi) of [11C]Physostigmine are obtained 57 minutes after EOB. (author)

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

    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).

  15. Dosimetry of D- and L-enantiomers of 11C-labeled tryptophan and valine

    The authors have previously reported the radiation dosimetry of 11C-labeled DL-tryptophan and DL-valine, as well as clinical pancreatic imaging studies with these agents. Because of significant uptake in both normal pancreas and in pancreatic tumors (thought to be due to the presence of the D-enantiomer), differential diagnosis of pancreatic carcinoma was not feasible. High-performance liquid chromatographic (HPLC) methods were developed for rapid resolution of 11C-labeled DL-tryptophan and DL-valine. Radiation dose estimates to the various organs in man were calculated for the D- and L-enantiomers of 11C-labeled tryptophan and valine, based on tissue distribution data in rats. The dose estimates were sufficiently low that 20-mCi doses of each of the enantiomeric amino acids were approved by the FDA for intravenous administration to humans. 21 references, 3 tables

  16. Dosimetry of D- and L-enantiomers of 11C-labeled tryptophan and valine

    We have previously reported the radiation dosimetry of 11C-labeled DL-tryptophan and DL-valine, as well as clinical pancreatic imaging studies with these agents. Because of significant uptake in both normal pancreas and in pancreatic tumors (thought to be due to the presence of the D-enantiomer), differential diagnosis of pancreatic carcinoma was not feasible. High-performance liquid chromatographic (HPLC) methods were developed for rapid resolution of 11C-labeled DL-tryptophan and DL-valine. Radiation dose estimates to the various organs in man were calculated for the D- and L-enantiomers of 11C-labeled tryptophan and valine, based on tissue distribution data in rats. The dose estimates were sufficiently low that 20-mCi doses of each of the enantiomeric amino acids were approved by the FDA for intravenous administration to humans. 21 refs., 3 tabs

  17. Direct synthesis and application of 11C and 13N labelled organic compounds by accelerator

    In the nuclear medicine, the compounds labelled by 11C and 13N, short-lived nuclide, have been used as a diagnostic reagent for PET. We found 80% yield of 11C labelled organic compounds were synthesized by direct irradiation of high energy γ ray to carbon cluster( a kind of fullerene) and other organic reagents. The Electron Linac (Tohoku University) and SF Cyclotron (Tokyo University) were used. By the Electron Linac, the samples were irradiated by Bremsstrahlung generated from platinum plate irradiated with 30 MeV beam using 12C(γ,n)11C. On the SF cyclotron, the mixture between sample and boron was irradiated by 12 MeV proton using 11B(p,n)11C. Many reagents were isolated and refined by a preparative HPLC (high-performance liquid chromatography). Oxine was used as a model compound and experimental results are shown. 54% 11C labeled compounds isolated by sublimation were oxine. This method is very simple and easy. Accordingly, we can use the method to the very complex compound. (S.Y.)

  18. Synthesis of the 11C-labelled β-adrenergic receptor ligands atenolol, metoprolol and propanolol

    The 11C-labelled β-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using [2-11C]isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from [11C]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/μmol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained. (author)

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

    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).

  20. Labelling of polysaccharides using [{sup 11}C]cyanogen bromide. In vivo and in vitro evaluation of {sup 11}C-hyaluronan uptake kinetics

    Westerberg, Goeran; Bergstroem, Mats; Gustafson, Stefan; Lindqvist, Ulla; Sundin, Anders; Laangstroem, Bengt

    1995-02-01

    A method for the {sup 11}C-labelling of polysaccharides in high specific radioactivity is described. Dextran and hyaluronan were treated with [{sup 11}C]cyanogen bromide in aqueous solution at pH 11.5 to give 30-47% radiochemical yields with higher than 98% radiochemical purity in synthesis times of 24-26 min counted from the end of bombardment. Specific radioactivities at the end of synthesis ranged from 0.12 to 3.1 Ci/{mu}mol. The biodistribution kinetics of [{sup 11}C]hyaluronan injected intravenously was studied in rats by means of positron emission tomography, showing a rapid and displaceable uptake in liver. Uptake and displacement of [{sup 11}C]hyaluronan was also demonstrated in cultured rat liver endothelial cells.

  1. Labeling of complex molecules with 18F, 13N, and 11C

    The overall objective during the period covered by this report was to develop a broad spectrum of radiopharmaceuticals labeled with short-lived cyclotron positron emitters, 11C, 13N and 18F. The goals of the program during the last year were: (1) to complete the modular automated system for important precursor production - formaldehyde, methyliodide, cyanide; (2) to perform animal studies with the 18F-glucose analogues 2FDG and 3FDG and measure the constants for both agents in different animals; and (3) to initiate the development of new fatty acid analogues for the myocardial imaging and metabolism. As part of a collaboration with other groups seeking new agents for myocardium and brain, 9-/sup 123m/Te-telluriumheptadecanoic acid as a myocardial imaging agent was studied. This compound could be used for designing new fatty acid analogues labeled with 11C and 18F that stay in the myocardium because of metabolic inhibition

  2. Synthesis of 1- and 3-11C-labelled L-lactic acid using multi-enzyme catalysis

    The synthesis of 1- and 3-11C-labelled L-lactic acid from the corresponding racemic 1- or 3-11C-labelled alanine using a multi-enzymatic reaction route, is presented. DL-[1-11C]Alanine was synthesised by reacting sodium 1-hydroxy-ethyl sulfite with hydrogen [11C]cyanide, obtained from [11C]carbon dioxide, and ammonia followed by acid hydrolysis. DL-[3-11C]-Alanine was synthesised by a methylation of a glycine derivative, N-(diphenylmethylene)-glycine tert-butyl ester, with [11C]methyl iodide, obtained from [11C]carbon dioxide, and subsequent hydrolysis. The racemic 1- or 3-11C-labelled alanine was then converted to pyruvic acid, by D-amino acid oxidase/catalase and glutamic-pyruvic transaminase, which was directly reduced to L-lactic acid by L-lactic dehydrogenase in a one-pot procedure. The total synthesis time was 40 minutes, counted from release of [11C]carbon dioxide. The decay corrected radiochemical yields were ca. 80% for L-[1-11C]lactic acid, based on hydrogen cyanide, and ca. 60% for L-[3-11C]lactic acid, based on carbon dioxide. The radiochemical purities were higher than 99% analysed by HPLC. (author)

  3. Synthesis of sup 11 C-labeled citalopram, a selective serotonin uptake inhibitor

    Ram, Siya (Duke Univ., Durham, NC (USA). Dept. of Radiology)

    1990-01-01

    A procedure for labeling the novel serotonin uptake inhibitor, citalopram (1-(3-dimethylamino)propyl-1-(p-fluorophenyl)-5-phthalancarbonitrile, Lu 10-171 ), with the positron emitting radionuclide {sup 11}C (t{sub 1/2} = 20.4 min) has been developed, in order to permit the pharmacokinetics of this compound to be studied in man. The procedure involves the reaction of ({sup 11}C)iodomethane with desmethylcitalopram in acetone in the presence of sodium hydroxide base at 65deg for 8-10 min; this was followed by purification by a column which contained, in series silica gel and basic alumina, and produces no carrier added ({sup 11}C)citalopram in radiochemical yield (18-66% at EOB) and radiochemical purity (>95%). The specific activity of ({sup 11}C)citalopram was 2.52 x 10{sup 3}-16.06 x 10{sup 3} GBq/mmol (68-434 Ci/mmol) at the end of synthesis. (author).

  4. The use of [11C]diazomethane for labelling a calcium channel antagonist: PN 200-110 (Isrodipine)

    PN 200-110 (Isrodipine), a calcium channel antagonist, was labelled with 11C (t1/2 20.4 min) by a reaction between [11C]diazomethane and the carboxyl precursor. The [11C]CH2N2 is prepared in two stages from [11C]CH4: [11C]CH4→[11C]CHCl3→[11C]CH2N2. When a mixture of nitrogen (95%) and hydrogen (5%) is irradiated with 20 MeV protons (30 min, 30 μ A), 60-80 mCi of product are prepared and purified with HPLC. The 11C product is ready for medical use within 35 min of the end of bombardment. (author)

  5. The preparation of 11C-labelled fluoromethane for the study of regional cerebral blood flow using positron emission tomography

    Fluoromethane, previously labelled with 18F and used as a tracer in the measurement of regional cerebral blood flow, was 11C-labelled by the reaction of 11C-methyl iodide with tetraethylammonium fluoride. Sufficient quantities of radiotracer were prepared with a minimum amount of handling from 15 min target irradiations in the 14N(p, α)11C reaction. Total synthesis time was 25 min from end-of-bombardment, allowing serial blood flow measurements 30 min apart. The use of 11C-fluoromethane as a cerebral blood flow tracer in positron emission tomography is discussed. (orig.)

  6. Modulation of organ uptake of 11C-labelled L-DOPA

    The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[β-11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[β-11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[β-11C]DOPA or L-[18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition

  7. Modulation of organ uptake of {sup 11}C-labelled L-DOPA

    Bergstroem, Mats; Lu Li; Marquez, Marcela; Fasth, Karl Johan; Bjurling, Peter; Watanabe, Yasuyoshi; Eriksson, Barbro; Laangstroem, Bengt

    1997-01-01

    The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of {sup 11}C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[{beta}-{sup 11}C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[{beta}-{sup 11}C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[{beta}-{sup 11}C]DOPA or L-[{sup 18}F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.

  8. Synthesis of 11C-labeled Kendine 91, a histone deacetylase inhibitor

    In the present paper, the synthesis of 11C-labeled Kendine 91 (a HDAC inhibitor which has shown in vitro and in vivo activity in HCT 116 and MOLT 4 human cancer cell lines) is described for the first time. The radiosynthesis has been approached by reaction of the non-radioactive precursor 6-((3-(4-hydroxyphenyl)-5-phenyl-1H-pyrrole-2-carboxamide))hexanehydroxamic acid with [11C]CH3I in basic media. Despite the presence of more than one reactive site in the chemical structure of the precursor, acceptable radiochemical yield (8.2±2.1%, decay corrected to the end of bombardment), specific activity (28.2±9.4 GBq/μmol) and radiochemical purity values (>95%) were obtained in reasonably short preparation times (∼40 min). Despite the moderate radiochemical yield, final radioactivity and radioactivity concentration values (1.8±0.3 GBq and 180 MBq/ml, respectively) should be sufficient for putative in vivo studies in animals. - Highlights: ► We labeled Kendine 91 with carbon-11. ► Despite low yields final radioactivity should allow in vivo studies. ► We synthesized the desmethylated precursor using two routes. ► Microwave assisted Paal–Knorr reaction was more efficient than (3+2) cycloaddition.

  9. A generic model for 11C labelled radiopharmaceuticals for imaging receptors in the human brain

    A large number of radiopharmaceuticals labelled with 11C (half-time 0.340 h) are being developed for positron emission tomographic studies of different types of receptor in the human brain. For most of these agents the available biokinetic data are insufficient to construct realistic compound-specific biokinetic models for calculating the internal radiation dose delivered to persons undergoing investigation. A generic model for brain receptor substances that predicts the internal dose with sufficient accuracy for general radiation protection purposes has, therefore, been developed. Biokinetic data for 13 11C radiopharmaceuticals used clinically for imaging different brain receptors indicate that, despite differences in chemical structure, their uptake and retention in the human brain and other tissues is broadly similar. The proposed model assumes instantaneous deposition of 5% of the injected radioactivity in the brain, with the remaining radioactivity being rapidly and uniformly distributed throughout all other tissues. Elimination from all tissues is assumed to occur with a half-time of 2 h. It is further assumed that 75% of the injected 11C is excreted in the urine, and 25% via the gall bladder, with a half-time of 2 h. This model yields an effective dose of 4.5 x 10-3mSv/MBq, with doses of 3.2 x 10-2, 1.7 x 10-2, 8.7 X 10-3, 5.2 x 10-3, and 3.8 x 10-3mGy MBq-1 to the urinary bladder, gall bladder, kidneys, brain and ovaries, respectively. These doses are well within the range of those reported using compound-specific models for the radiopharmaceuticals studied. (author)

  10. Evaluation of myocardial metabolism, with 13N- and 11C-labeled amino acids and positron computed tomography

    To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with 13N, and of 11C-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all 13N AA, and three (early, intermediate, late) for the two 11C compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for 13N-labeled Ala, Glu, Asp, and Leu, but not for 13N Gln and 11C compounds. Transaminase inhibition shortened the half-times of the late phases of 13N-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of 13N Gln and 11C Oxal; and resulted in a loss of 11C CO2 production and of the intermediate phase for 11C Asp. On the PCT images, 13N activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by 13N NH3 imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia

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

    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

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

    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.

  13. Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [{sup 11}C]-labeled fatty acids

    Angsten, Gertrud [Department of Pediatric Surgery, University Children' s Hospital, S-751 85 Uppsala (Sweden)]. E-mail: gertrud.angsten@surgsci.uu.se; Valind, Sven [Uppsala University PET Centre, Uppsala University, S-751 05 Uppsala (Sweden); Department of Clinical Physiology, University Hospital, S-751 85 Uppsala (Sweden); Takalo, Reijo [Uppsala University PET Centre, Uppsala University, S-751 05 Uppsala (Sweden); Department of Clinical Physiology, University Hospital, S-751 85 Uppsala (Sweden); Neu, Henrik [Uppsala University PET Centre, Uppsala University, S-751 05 Uppsala (Sweden); Department of Organic Chemistry, Uppsala University, S-751 24 Uppsala (Sweden); Meurling, Staffan [Department of Pediatric Surgery, University Children' s Hospital, S-751 85 Uppsala (Sweden); Langstroem, Bengt [Uppsala University PET Centre, Uppsala University, S-751 05 Uppsala (Sweden); Department of Organic Chemistry, Uppsala University, S-751 24 Uppsala (Sweden)

    2005-07-01

    Methods: Anesthetized pigs were studied with [{sup 11}C]-labeled fatty acids (FAs) with carbon chain length ranging from 8 to 16 carbon atoms, during control conditions and during inhibition of carnitine-palmitoyl transferase I (CPT I) with oxfenicine. The myocardial uptake of [{sup 11}C]-FAs from blood was measured together with the relative distribution of [{sup 11}C]-acyl-CoA between rapid mitochondrial oxidation and incorporation into slow turnover lipid pools in the heart. Results: During baseline conditions, the fractional oxidative utilization of palmitate was almost as high as that of carnitine-independent short-chain FAs, unless the carnitine shuttle was inhibited by high levels of lactate. Inhibition of CPT I almost completely blocked the oxidative pathway for palmitic acid and reduced the fractional oxidative utilization, while the rate of oxidative metabolism of acyl-CoA was unaffected. Conclusions: [{sup 11}C]-Labeled FAs allow rapid oxidation to be well separated from esterification into slow turnover lipid pools in the heart of anaesthetized pigs. The fractional oxidative utilization of [{sup 11}C]-palmitate serves well to characterize, in vivo, the carnitine-dependent transfer of long-chain FAs.

  14. Inhibition of carnitine-acyl transferase I by oxfenicine studied in vivo with [11C]-labeled fatty acids

    Methods: Anesthetized pigs were studied with [11C]-labeled fatty acids (FAs) with carbon chain length ranging from 8 to 16 carbon atoms, during control conditions and during inhibition of carnitine-palmitoyl transferase I (CPT I) with oxfenicine. The myocardial uptake of [11C]-FAs from blood was measured together with the relative distribution of [11C]-acyl-CoA between rapid mitochondrial oxidation and incorporation into slow turnover lipid pools in the heart. Results: During baseline conditions, the fractional oxidative utilization of palmitate was almost as high as that of carnitine-independent short-chain FAs, unless the carnitine shuttle was inhibited by high levels of lactate. Inhibition of CPT I almost completely blocked the oxidative pathway for palmitic acid and reduced the fractional oxidative utilization, while the rate of oxidative metabolism of acyl-CoA was unaffected. Conclusions: [11C]-Labeled FAs allow rapid oxidation to be well separated from esterification into slow turnover lipid pools in the heart of anaesthetized pigs. The fractional oxidative utilization of [11C]-palmitate serves well to characterize, in vivo, the carnitine-dependent transfer of long-chain FAs

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

    A method for the rapid production and purification of 11C-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 11CH3I 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. (author)

  16. First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use

    Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [11C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic organic anion-transporting polypeptide (OATP) 1B3. We developed a first automatic preparation system of [11C]Telmisartan to applicable clinical research using a new 11C and 18F multipurpose synthesizer. Two milligrams of precursor (1) in 5 μl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [11C]CH3I for 5 min at 120 deg C. The resultant solution was hydrolyzed with 1 M NaOH at 100 deg C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 μm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. The yield of [11C]Telmisartan for clinical research use was 16.8±2.9% end of bombardment (EOB) as decay corrected (n=8, mean ± standard deviation (SD) in 32-36 min. The radiochemical purity of [11C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. We succeeded in the first synthesis of [11C]Telmisartan for clinical research use by appropriate quality tests. (author)

  17. Use of transfer function and compartmental analysis to quantify 11C-labelled photoassimilate export from wheat leaves

    Compartmental analysis of tracer loss from a leaf after pulse-labelling with carbon isotopes has often been used to infer the flow of photosynthate through the leaf. Recently, a more general approach has been suggested based upon estimation of the transfer function using data from pulse-labelling as well as continuous labelling experiments. A comparison of these two approaches shows that with the same data set they give equivalent physiological interpretations. The measured decline of 11C activity from a wheat leaf after 11CO2 pulse-labelling was extrapolated by compartmental as well as transfer function analysis. Both methods estimated a 66.4% loss of the initially fixed 11C due to export and respiration. The advantage of transfer function analysis, however, is its applicability to continuous-labelling experiments. The model allows the use of the net photosynthetic rate as the reference (100%) value. Data from continuous-labelling experiments with wheat plants indicate diurnal variations in the export of freshly labelled assimilate of between 32.7% and 43.6% of net photosynthesis. (author)

  18. In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N,N-[11C]dimethyltryptamine

    The endogenous hallucinogen, N,N-dimethyltryptamine (DMT), was labeled with carbon-11 and its regional distribution in rat brain studied. [11C]DMT showed higher accumulation in the cerebral cortex, caudate putamen, and amygdaloid nuclei. Studies of the subcellular distribution of [11C]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 [11C]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. (orig.)

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

    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.

  20. In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N,N-[11C]dimethyltryptamine.

    Yanai, K; Ido, T; Ishiwata, K; Hatazawa, J; Takahashi, T; Iwata, R; Matsuzawa, T

    1986-01-01

    The endogenous hallucinogen, N,N-dimethyltryptamine (DMT), was labeled with carbon-11 and its regional distribution in rat brain studied. [11C]DMT showed higher accumulation in the cerebral cortex, caudate putamen, and amygdaloid nuclei. Studies of the subcellular distribution of [11C]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 [11C]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. PMID:3489620

  1. Comparative studies of potential cancer biomarkers carbon-11 labeled MMP inhibitors (S)-2-(4'-[11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid and N-hydroxy-(R)-2-[[(4'-[11C]methoxyphenyl)sulfonyl]benzylamino]-3 -methylbutanamide

    (S)-2-(4'-[11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid ([11C]MSMA) and N-hydroxy-(R)-2-[[(4'-[11C]methoxyphenyl)sulfonyl]benzylamino]-3- methylbutanamide ([11C]CGS 25966), carbon-11 labeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers. [11C]MSMA was prepared by appropriate precursory droxybiphenyl-4-sulfonylamino)-3-methylbutyric acid tert-butyl ester, which was synthesized in eight steps from amino acid (L)-valine in 39.4% chemical yield. This precursor was labeled by [11C]methyl triflate through O-[11C]methylation method at the hydroxyl position of biphenol under basic conditions, followed by a quick acid hydrolysis and isolated by solid-phase extraction (SPE) purification to produce pure target compound [11C]MSMA in 35-55% radiochemical yield, based on 11CO2, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time. [11C]CGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of [11C]MSMA and [11C]CGS 25966 were determined at 45 min post iv injection in breast cancer animal models MCF-7's transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [11C]MSMA and [11C]CGS 25966 in these tumors were 0.95 and 0.42%dose/g in MCF-7's transfected with IL-1α implanted mice, 0.98 and 1.53%dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.21 and 1.09 (T/M, MCF-7's), 0.99 and 0.84 (T/B, MCF-7's), 1.38 and 1.27 (T/M, MDA-MB-435), 1.27 and 1.95 (T/B, MDA-MB-435), respectively. The micro-PET images of [11C]MSMA and [11C]CGS 25966 in both breast cancer athymic mice were acquired for 15 min from a MCF-7's transfected with IL-1α and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (11C]MSMA and [11C]CGS 25966

  2. Design and Synthesis of 11C-Labelled Compound Libraries for the Molecular Imaging of EGFr, VEGFr-2, AT1 and AT2 Receptors: Transition-Metal Mediated Carbonylations Using [11C]Carbon Monoxide

    This work deals with radiochemistry and new approaches to develop novel PET tracers labelled with the radionuclide 11C. Two methods for the synthesis of 11C-labelled acrylamides have been explored. First, [1-11C]-acrylic acid was obtained from a palladium(0)-mediated 11C-carboxylation of acetylene with [11C]carbon monoxide; this could be converted to the corresponding acyl chloride and then combined with benzylamine to form N-benzyl[carbonyl-11C]acrylamide. In the second method, the palladium(0)-mediated carbonylation of vinyl halides with [11C]carbon monoxide was explored. This latter method, yielded labelled acrylamides in a single step with retention of configuration at the C=C double bond, and required less amine compared to the acetylene method. The vinyl halide method was used to synthesize a library of 11C-labelled EGFr-inhibitors in 7-61% decay corrected radiochemical yield via a combinatorial approach. The compounds were designed to target either the active or the inactive form of EGFr, following computational docking studies. The rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine was shown to be a very general reaction and was used to synthesize a library of dual VEGFr-2/PDGFrβ inhibitors that were 11C-labelled at the urea position in 38-78% dc rcy. The angiotensin II AT1 receptor antagonist eprosartan was 11C-labelled at one of the carboxyl groups in one step using a palladium(0)-mediated carboxylation. Autoradiography shows specific binding in rat kidney, lung and adrenal cortex, and organ distribution shows a high accumulation in the intestines, kidneys and liver. Specific binding in frozen sections of human adrenal incidentalomas warrants further investigations of this tracer. Three angiotensin II AT2 ligands were 11C-labelled at the amide group in a palladium(0)-mediated aminocarbonylation in 16-36% dc rcy. One of the compounds was evaluated using in vitro using autoradiography, and in vivo using organ distribution and animal

  3. (-)-N-[11C]propyl-norapomorphine: a positron-labeled dopamine agonist for PET imaging of D2 receptors

    Imaging neuroreceptors with radiolabeled agonists might provide valuable information on the in vivo agonist affinity states of receptors of interest. We report here the radiosynthesis, biodistribution in rodents, and imaging studies in baboons of [11C]-labeled (-)-N-propyl-norapomorphine [(-)-NPA]. (-)-[11C]NPA was prepared by reacting norapomorphine with [11C]propionyl chloride and a lithium aluminum hydride reduction. [11C]Propionyl chloride was prepared by reacting [11C]CO2 with ethylmagnesium bromide, followed by reacting with phthaloyl chloride. The radiochemical yield of (-)-[11C]NPA was 2.5% at end of synthesis (EOS), and the synthesis time was 60 min. The specific activity was 1700±1900 mCi/μmol ( N=7; ranged 110-5200 mCi/μmol at EOS). Rodent biodistribution studies showed high uptake of [11C](-)-NPA in D2 receptor-rich areas, and the striatum/cerebellum ratios were 1.7, 3.4, and 4.4 at 5 min, 30 min, and 60 min postinjection, respectively. Pretreating the animals with haloperidol (1 mg/kg) decreased the striatum/cerebellum ratio at 30 min postinjection to 1.3. (-)-[11C]NPA was also evaluated via baboon positron emission tomography (PET) studies. Under control conditions ( N=4), rapid uptake of the tracer was observed and the striatum/cerebellum ratio reached 2.86±0.15 at 45 min postinjection. Following haloperidol pretreatment (0.2 mg/kg IV), the striatum/cerebellum ratio was 1.29 at 45 min postinjection. The result demonstrated the existence of specific binding of this new tracer to the D2 receptor. To our knowledge, the current finding of a striatum/cerebellum ratio of 2.8 in baboon was the highest reported with a radiolabeled D2 agonist. (-)-[11C]NPA is a promising new D2 agonist PET tracer for probing D2 receptors in vivo using PET

  4. 11C-labelling of the analgesic Tramadol and its major metabolites by selective O- and N-methylation

    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-11C]Tramadol and racemic[N-methyl-11C]Tramadol were prepared by methylation with n.c.a. [11C]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-11C]M2 was obtained. Quaternization of Tramadol or M1 was >15 times slower than O-methylation, and was only observed in the presence of added CH3I carrier. (author)

  5. Synthesis of a 11C-labeled NK1 receptor ligand for PET studies

    Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with 11CH3I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was > 95% and specific activity was routinely > 1000 mCi/μmol [EOS]. The biodistribution of 11C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g ± SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 ± 1.26 (5 min) and 13.49 ± 1.71 (30 min). Brain accumulation was: 1.44 ± 0.06 (5 min), 1.32 ± 0.05 (30 min). These results indicate that 11C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET

  6. Preparation and pharmacokinetics of 11C labeled stavudine (d4T)

    Stavudine, a potent antiviral agent for treating human immunodeficiency virus (HIV) infections, was radiolabeled with 11C by methylation of a specifically designed precursor, 5'-O-(2-tetrahydropyranyl)-5-bromo-2',3'-didehydro-3'-deoxythymidine, with 11C H3I. The radiolabeled drug was isolated by reverse phase HPLC. A total time of approximately 45 minutes was required for synthesis, purification and isolation of 11C stavudine with chemical and radiochemical purities of greater than 98%. 11C stavudine was combined with unlabeled drug (2.0 mg/kg) and used to study its pharmacokinetics in rats by measurement of radioactivity in excised tissues. In this species, there was rapid accumulation of drug in all tissue. In all tissues, with the exceptions of testis and brain, highest concentrations of drug were detected at 5 minutes after injection and decreased monotonically thereafter. The peak concentration (μg/g) of stavudine in blood was 1.78 ± 0.16 and similar levels were achieved in most other tissues; heart 1.66 ± 0.11, lung 1.60 ± 0.15, liver 2.13 ± 0.17, spleen 1.61 ± 0.15, adrenal 1.47 ± 0.20, stomach 1.40 ± 0.11, GI tract 1.44 ± 0.14, skeletal muscle 1.38 ± 0.15 and bone 1.30 ± 0.16. Much higher peak concentrations were achieved in kidney; 7.23 ± 0.57 μg/g. Concentrations in testis were lower and remained relatively constant over 1 hour; peak 0.62 ± 0.14 μg/g at 15 min Brain concentrations were low but increased monotonically over time; peak 0.26 ± 0.02 μg/g at 60 min. Future PET studies with this radiopharmaceutical will allow in vivo measurements of the pharmacokinetics of stavudine in both animal models and human subjects

  7. Labeling of complex molecules with 18F, 13N, and 11C. Progress report, March 1, 1981-February 28, 1982

    The overall objective during the period covered by this report was to develop a broad spectrum of radiopharmaceuticals labeled with short-lived cyclotron produced positron emitters, 11C, 13N and 18F. The progress report of this year will summarize work done in the last three years. The goals of the program during the last three years were: to build and complete the transport system to Nuclear Medicine; to complete the modular automated system for important precursor production: formaldehyde, methyliodide, cyanide; to perform animal studies with the 18F-glucose analogs 2FDG and 3FDG and measure the rate constants and glucose metabolic rates derived from the Sokoloff model for both agents in different animal species; to initiate the development of new fatty acid analogs for myocardial imaging and metabolism; and to develop syntheses for 18F and 11C sugar analogs

  8. Application of Microreactor to the Preparation of C-11-Labeled Compounds via O-[11C]Methylation with [11C]CH3I: Rapid Synthesis of [11C]Raclopride.

    Kawashima, Hidekazu; Kimura, Hiroyuki; Nakaya, Yuta; Tomatsu, Kenji; Arimitsu, Kenji; Nakanishi, Hiroaki; Ozeki, Eiichi; Kuge, Yuji; Saji, Hideo

    2015-01-01

    A new radiolabeling method using a microreactor was developed for the rapid synthesis of [(11)C]raclopride. A chip bearing a Y-shaped mixing junction with a 200 µm (width)×20 µm (depth)×250 mm (length) flow channel was designed, and the efficiency of O-[11C]methylation was evaluated. Dimethyl sulfoxide solutions containing the O-desmethyl precursor or [11C]CH3I were introduced into separate injection ports by infusion syringes, and the radiochemical yields were measured under various conditio...

  9. Synthesis of some 11C-labelled MAO-A inhibitors and their in vivo uptake kinetics in rhesus monkey brain

    Five potential MAO-A inhibitors--harmine, N-methyl-harmine, harmaline, brofaromine, and clorgyline--were labelled with 11C and their brain kinetics evaluated in vivo in rhesus monkey using PET. The compounds were synthesized by alkylation with 11C methyl iodide and obtained in 48-89% radiochemical yield within 40 to 45 min synthesis time and with specific radioactivities in the region of 0.49-2.4 Ci μmol-1 (18-87 GBq μmol-1) at the end of synthesis. The kinetic pattern after administration of MAO-A inhibitors was comparable to that seen in the tracer study when using 11C-brofaromine, 11C-harmaline, or 11C-clorgyline, although the magnitude of uptake markedly increased in the case of brofaromine and harmaline. Both 11C-methylharmine and 11C-harmine showed a significant washout in the inhibition studies. The kinetics of brain uptake with and without MAO-A inhibition is compatible with a significant fraction of the tracer bound to MAO-A for 11C-methylharmine and 11C-harmine, whereas 11C-brofaromine, 11C-harmaline, or 11C-clorgyline did not seem to show specific enzyme binding

  10. Labelling of the solvent DMSO as side reaction of methylations with n.c.a. [11C]CH3I

    Competing labelling of solvent dimethyl sulfoxide (DMSO) can occur during the 11C-methylation of amine precursors. A kinetic analysis of the methylation reaction of DMSO with n.c.a. [11C]CH3I was performed at 120 deg. C resulting in rate constants. The rate constant for the formation of the intermediate, methylated DMSO ([11C]DMSO-M), is compared to the reaction of [11C]CH3I with two tertiary amines, namely Dexetimide and Desmethyloxotremorine-M. The specific activity of the labelled product is reduced due to partial 12C-methylation of the precursor amines by [11C]DMSO-M in cases of significant DMSO labelling as side reaction

  11. 11C-labelling of ohmefentanyl: An agonist for μ-opiate receptor

    Ohmefentanyl: cis-N-[1-(beta-hydroxy-beta-phenylethyl)-3-methyl-4-piperydyl]-N-phenylpropionamide, is a synthetic narcotic analgesic agent with an analgesic activity 28 times more potent than that of fentanyl and 6,300 times more than that of morphine. The authors have developed a method for labelling of this compound with carbon-11 for the purpose of visualizing 'in vivo' the μ receptors by PET

  12. Cyclotron production of molecules labelled with short-lived radioisotopes β+ emitters (15O, 13N, 11C) and their clinical uses

    Clinical use of three short-lived radioisotopes: 15O, 13N and 11C is studied on two complementary aspects. A production and purification system is realized; detection instruments in medical use are studied. The production of labelled molecules with the three radiotracers 15O, 13N, 11C from the target bombardment with charged and accelerated particles was studied

  13. Transport mechanism of 11C-labeled L- and D-methionine in human-derived tumor cells

    Introduction: S-methyl-11C-labeled L- and D-methionine (11C-L- and D-MET) are useful as radiotracers for tumor imaging. However, it is not known whether the transport mechanism of 11C-D-MET is the same as that for 11C-L-MET, which is transported by the amino acid transport system L. In this study, we investigated the transport mechanism of 11C-L- and D-MET by analyzing the expression of transport system genes in human-derived tumor cells. Methods: The expression of transport system genes in human-derived tumor cells was quantitatively analyzed. The mechanism of MET transport in these cells was investigated by incubating the cells with [S-methyl-3H]-L-MET (3H-L-MET) or [S-methyl-3H]-D-MET (3H-D-MET) and the effect of 2-amino-2- norbornane-carboxylic acid, a system L transport inhibitor, or α-(methylamino)isobutyric acid, a system A transport inhibitor, on their transport was measured. The transport and metabolic stability of [S-methyl-14C]-L-MET (14C-L-MET) and 3H-D-MET was also analyzed using bearing mice with H441 or PC14 tumor cells. Results: 3H-D-MET was mainly transported by both systems L and alanine–serine–cysteine (ASC), while system L was involved in 3H-L-MET transport. There was a high correlation between both 3H-L-MET and 3H-D-MET uptake and the expression of amino acid transport system genes. In the in vivo study, H441-cell accumulation of 3H-D-MET was higher than that of 14C-L-MET. Hepatic and renal accumulation of 3H-D-MET was lower than that of 14C-L-MET. Conclusion: The transport mechanism of 3H-D-MET was different from that of 3H-L-MET. Since 3H-D-MET has high metabolic stability, its accumulation reflects the transporter function of system L and ASC.

  14. Evaluation of the brain uptake properties of [1-11C] labeled hexanoate in anesthetized cats by means of positron emission tomography

    Positron emission tomography (PET) was performed on the cat brain to characterize [1-11C] hexanoate and other [1-11C] labeled short and medium-chain fatty acids as a tracer of fatty acid oxidative metabolism. After an intravenous injection the brain uptake of [1-11C] hexanoate reached a peak followed by rapid washout until 2 min (first phase). Subsequently the total brain uptake was again increased and reached to a peak 7-10 min after tracer injection (second phase). The blood radioactivity of unmetabolized [1-11C] hexanoate was rapidly decreased and almost eliminated within the first 2 min, whereas the blood radioactivity of [11C]CO2/HCO3- was gradually increased and reached a peak approximately 5 min after tracer injection. As the effect of circulating [11C]CO2/HCO3- was examined by a bolus intravenous injection of [11C]CO2/HCO3-, the brain uptake of [11C]CO2/HCO3- was rapidly increased right after the injection and changed parallel to the blood level of [11C]CO2/HCO3-. These results suggest that, in contrast to the previous mouse data, the time-activity curve in the cat brain following intravenous injection of [1-11C] hexanoate has a biphasic pattern, the second phase being determined by peripherally originating [11C]CO2/HCO3-, and therefore does not reflect the metabolism of 11C-labeled fatty acid in the brain. (author)

  15. No-carrier-added carbon-11-labeled sn-1,2- and sn-1,3-diacylglycerols by [11C]propyl ketene method

    This article describes the preparation of sn-1,2-[11C]diacylglycerols and sn-1,3-[11C]diacylglycerols by a no-carrier-added reaction based on a labeling method using [1-11C]propyl ketene, which is one of the most potent acylating agents. [1-11C]Propyl ketene was produced by pyrolytic decomposition of [1-11C]butyric acid and was trapped in pyridine containing L-alpha-palmitoyl-lysophosphatidylcholine, producing L-alpha-palmitoyl-2-[1-11C]butyryl-sn-glycero-3-phosphorylcholine. The authors adopted an enzymatic reaction to remove the phosphorylcholine, in which L-alpha-palmitoyl-2-[1-11C]butyryl-sn-glycero-3-phosphorylcholine was incubated with phospholipase C, hydrolyzing to produce 1-palmitoyl-sn-2-[1-11C]butyrylglycerol. Total synthesis time was about 50 minutes and the specific activity was estimated at 93 GBq/mumol (2.5 Ci/mumol) at end of synthesis. Radiochemical yield was 3.8% based on the trapped 11CO2. sn-1,3-[11C]Diacylglycerol was also synthesized by [1-11C]propyl ketene reaction with 1-palmitoyl-sn-glycerol in a single procedure. The regional brain tissue radioactivities obtained in sn-1,2-[11C]diacylglycerol were higher than those of sn-1,3-[11C]diacylglycerol, and the regional values varied widely. In autoradiography of brain slices from conscious rats, sn-1,2-[11C]diacylglycerol incorporation sites were discretely localized, especially in the amygdala, cerebral cortex, and hippocampus, suggesting that intensive neuronal processing occurred in these areas on the basis of phosphatidylinositol turnover

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

    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.

  17. Synthesis and preliminary evaluation of [11C]NE-100 labeled in two different positions as a PET σ receptor ligand

    N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with 11C in two different positions by the alkylation of an N-despropyl precursor with [11C]propyl iodide and of an O-desmethyl precursor with [11C]methyl iodide and was evaluated for the potential as a tracer for mapping σ 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl-11C]NE-100 or [O-methyl-11C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl-11C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl-11C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl-11C]NE-100, but not that of [O-methyl-11C]NE-100. The regional brain distribution assessed with [O-methyl-3H]NE-100 was consistent with the distribution pattern of the σ receptors. Four σ drugs reduced the regional brain uptake of [O-methyl-3H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl-11C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl-11C]NE-100 has limited potential as a PET ligand for mapping σ 1 receptors in the peripheral organs and the CNS because of high nonspecific binding

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

    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 [11C]-labelled pyrrole-2-carboxamide derivates, RS 2315 and RS 2360, along with the characterization of their in vivo properties. Methods: The radiolabelling of [11C]-RS 2315 and [11C]-RS 2360 was accomplished by alkylation of their amide precursors with [11C]CH3I. Biodistribution, blocking and metabolite studies of both tracers were performed in NMRI mice. Finally, a PET study in Sprague-Dawley rats was performed for [11C]-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, [11C]-RS 2360 was more stable than [11C]-RS 2315. Blocking studies in mice could not demonstrate specificity of [11C]-RS 2315 towards MAO-A or MAO-B. The blocking and imaging study with [11C]-RS 2360 on the other hand indicated specific binding in MAO-A at the earliest time points. Conclusions: [11C]-RS 2315 displayed a high nonspecific binding and is therefore not suitable for visualization of MAO-A in vivo. [11C]-RS 2360 on the other hand has potential for mapping MAO-A since specific binding is demonstrated.

  19. Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the Rhesus monkey. A study using positron emission tomography

    5-hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015, 10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(β-11 C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 ± 0.0015 min-1 (n=5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(β-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease. (authors)

  20. Radiosynthesis of ML03, a novel positron emission tomography biomarker for targeting epidermal growth factor receptor via the labeling synthon: [11C]acryloyl chloride

    An automated procedure for the radiosynthesis of the labeling synthon [11C]acryloyl chloride was developed and applied for labeling several N-acryl amides with carbon-11. [11C]-6-acrylamido-4-(3,4-dichloro-6-fluoroanilino)quinazoline (ML03), a novel PET biomarker targeting the epidermal growth factor receptor tyrosine kinase (EGFr-TK) in cancer, was successfully prepared using this labeled synthon in a fully automated manner. Two other potential anticancer drugs were also labeled using the developed methodology. The potency of ML03 to inhibit autophosphorylation of EGFr-TK was evaluated by an ELISA assay indicating a low IC50 of 0.037 nM

  1. Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog.

    Jones, H A; Rhodes, C G; Law, M P; Becket, J M; Clark, J C; Boobis, A R; Taylor, G W

    1991-10-01

    Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data. PMID:1686775

  2. Synthesis and preliminary evaluation of [{sup 11}C]NE-100 labeled in two different positions as a PET {sigma} receptor ligand

    Ishiwata, Kiichi; Noguchi, Junko; Ishii, Shin-Ichi; Hatano, Kentaro; Ito, Kengo; Nabeshima, Toshitaka; Senda, Michio

    1998-04-01

    N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine (NE-100) was labeled with {sup 11}C in two different positions by the alkylation of an N-despropyl precursor with [{sup 11}C]propyl iodide and of an O-desmethyl precursor with [{sup 11}C]methyl iodide and was evaluated for the potential as a tracer for mapping {sigma} 1 receptors in the CNS and peripheral organs by PET. Following i.v. injection of [N-propyl-{sup 11}C]NE-100 or [O-methyl-{sup 11}C]NE-100 into mice, the two tracers showed similar tissue distribution patterns except for the liver and brain. With the coinjected carrier NE-100 or haloperidol, the uptake of [N-propyl-{sup 11}C]NE-100 by the liver, pancreas and spleen was significantly decreased at 15 min after injection, whereas the effect was not significant for [O-methyl-{sup 11}C]NE-100. The coinjection of NE-100 enhanced the brain uptake of the two tracers. Haloperidol also enhanced the brain uptake of [N-propyl-{sup 11}C]NE-100, but not that of [O-methyl-{sup 11}C]NE-100. The regional brain distribution assessed with [O-methyl-{sup 3}H]NE-100 was consistent with the distribution pattern of the {sigma} receptors. Four {sigma} drugs reduced the regional brain uptake of [O-methyl-{sup 3}H]NE-100 to 70%-90% of the control. In an ex vivo autoradiographic study of the rat brain, the uptake of [O-methyl-{sup 11}C]NE-100 was blocked by carrier NE-100 or haloperidol (53%-59% of the control in the cortex), which suggests a receptor-specific distribution. These results show that [O-methyl-{sup 11}C]NE-100 has limited potential as a PET ligand for mapping {sigma} 1 receptors in the peripheral organs and the CNS because of high nonspecific binding.

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

    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. PMID:24285318

  4. 11C-imaging

    Thorpe, Michael R; Ferrieri, Abigail P; Herth, Matthias Manfred;

    2007-01-01

    The long-distance transport and actions of the phytohormone methyl jasmonate (MeJA) were investigated by using the short-lived positron-emitting isotope 11C to label both MeJA and photoassimilate, and compare their transport properties in the same tobacco plants (Nicotiana tabacum L.). There was...

  5. PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

    Introduction: Fatty acid amide hydrolase (FAAH) is part of the endocannabinoid system (ECS) and has been linked to the aetiology of several neurological and neuropsychiatric disorders. So far no useful PET or SPECT tracer for in vivo visualisation of FAAH has been reported. We synthesized and evaluated a carbon-11-labeled URB597 analogue, biphenyl-3-yl [11C]-4-methoxyphenylcarbamate or [11C]-1, as potential FAAH imaging agent. Methods: The inhibitory activity of 1 was determined in vitro using recombinant FAAH. Radiosynthesis of [11C]-1 was performed by methylation using [11C]-CH3I, followed by HPLC purification. Biological evaluation was done by biodistribution studies in wild-type and FAAH knock-out mice, and by ex vivo and in vivo metabolite analysis. The influence of URB597 pretreatment on the metabolisation profile was assessed. Results: [11C]-1 was obtained in good yields and high radiochemical purity. Biodistribution studies revealed high brain uptake in wild-type and FAAH knock-out mice, but no retention of radioactivity could be demonstrated. Metabolite analysis and URB597 pretreatment confirmed the non-FAAH-mediated metabolisation of [11C]-1. The inhibition mechanism was determined to be reversible. In addition, the inhibition of URB597 appeared slowly reversible. Conclusions: Although [11C]-1 inhibits FAAH in vitro and displays high brain uptake, the inhibition mechanism seems to deviate from the proposed carbamylation mechanism. Consequently, it does not covalently bind to FAAH and will not be useful for mapping the enzyme in vivo. However, it represents a potential starting point for the development of in vivo FAAH imaging tools.

  6. Synthesis and characterization of a 11C-labelled derivative of S12968: an attempt to image in vivo brain calcium channels

    [11C]S11568 (3-ethyl 5-methyl 2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4 -dihydropyridine-3,5-dicarboxylate) is a powerful ligand for the visualization of the cardiac calcium channel in vivo using PET. The aim of the present study was to synthesize a lipophilic, nonionized derivative of S11568 to facilitate its penetration into the brain. To increase the lipophilicity and to remove simultaneously the ionic nature of our ligand, the N-tert-butoxycarbonyl (N-Boc) derivative of S11568 was synthesized. An IC50 value of 1.7 nM for this derivative confirmed that both the affinity and selectivity for the calcium channel was unaltered by this chemical modification (S11568 with IC50 value of 9.9 nM). The biologically more active enantiomer of S11568, the levogyre isomer S12968, was labelled with 11C using [11C]iodomethane. The lipophilicity of the N-Boc derivative was increased by a factor of three to four when compared to the parent compound (as determined by the measurement of the octanol/buffer partition coefficients). In vivo, this derivative slightly crosses the blood-brain barrier, as demonstrated by a 4-fold increase (with respect to the parent compound S12968) of the radioactivity in the brain using the 11C-labelled N-Boc S12968. This uptake remained too low to be suitable for imaging calcium channels

  7. Design, Synthesis, and Evaluation of a Low-Molecular-Weight (11)C-Labeled Tetrazine for Pretargeted PET Imaging Applying Bioorthogonal in Vivo Click Chemistry.

    Denk, Christoph; Svatunek, Dennis; Mairinger, Severin; Stanek, Johann; Filip, Thomas; Matscheko, Dominik; Kuntner, Claudia; Wanek, Thomas; Mikula, Hannes

    2016-07-20

    A low-molecular-weight tetrazine labeled with the short-lived positron emitter carbon-11 was developed as a bioorthogonal PET probe for pretargeted imaging. A method for efficient and fast synthesis of this imaging agent is presented using radiolabeling of a readily available precursor. High reactivity with trans-cyclooctenes was observed and in vivo investigations including PET/MR scanning showed homogeneous biodistribution, good metabolic stability, and rapid excretion in naive mice. These properties are key to the success of bioorthogonal (11)C-PET imaging, which has been shown in a simple pretargeting experiment using TCO-modified mesoporous silica nanoparticles. Overall, this (11)C-labeled tetrazine represents a highly versatile and advantageous chemical tool for bioorthogonal PET imaging and enables pretargeting approaches using carbon-11 for the first time. PMID:27308894

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

    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).

  9. (-)-N-[{sup 11}C]propyl-norapomorphine: a positron-labeled dopamine agonist for PET imaging of D{sub 2} receptors

    Hwang, Dah-Ren E-mail: hwang@neuron.cpmc.columbia.edu; Kegeles, Lawrence S.; Laruelle, Marc

    2000-06-01

    Imaging neuroreceptors with radiolabeled agonists might provide valuable information on the in vivo agonist affinity states of receptors of interest. We report here the radiosynthesis, biodistribution in rodents, and imaging studies in baboons of [{sup 11}C]-labeled (-)-N-propyl-norapomorphine [(-)-NPA]. (-)-[{sup 11}C]NPA was prepared by reacting norapomorphine with [{sup 11}C]propionyl chloride and a lithium aluminum hydride reduction. [{sup 11}C]Propionyl chloride was prepared by reacting [{sup 11}C]CO{sub 2} with ethylmagnesium bromide, followed by reacting with phthaloyl chloride. The radiochemical yield of (-)-[{sup 11}C]NPA was 2.5% at end of synthesis (EOS), and the synthesis time was 60 min. The specific activity was 1700{+-}1900 mCi/{mu}mol ( N=7; ranged 110-5200 mCi/{mu}mol at EOS). Rodent biodistribution studies showed high uptake of [{sup 11}C](-)-NPA in D{sub 2} receptor-rich areas, and the striatum/cerebellum ratios were 1.7, 3.4, and 4.4 at 5 min, 30 min, and 60 min postinjection, respectively. Pretreating the animals with haloperidol (1 mg/kg) decreased the striatum/cerebellum ratio at 30 min postinjection to 1.3. (-)-[{sup 11}C]NPA was also evaluated via baboon positron emission tomography (PET) studies. Under control conditions ( N=4), rapid uptake of the tracer was observed and the striatum/cerebellum ratio reached 2.86{+-}0.15 at 45 min postinjection. Following haloperidol pretreatment (0.2 mg/kg IV), the striatum/cerebellum ratio was 1.29 at 45 min postinjection. The result demonstrated the existence of specific binding of this new tracer to the D{sub 2} receptor. To our knowledge, the current finding of a striatum/cerebellum ratio of 2.8 in baboon was the highest reported with a radiolabeled D{sub 2} agonist. (-)-[{sup 11}C]NPA is a promising new D{sub 2} agonist PET tracer for probing D{sub 2} receptors in vivo using PET.

  10. Synthesis and pharmacological evaluation of 11C-labeled piperazine derivative as a PET probe for sigma-2 receptor imaging

    Introduction: Both subtypes of sigma (σ) receptors, σ1 and σ2, are over-expressed in many cancers with σ2 proposed as a biomarker of tumor proliferation. We are interested in developing a high affinity selective σ2 radioligand for in vivo monitoring of proliferative status of solid tumors and response to anti-cancer therapies. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl] piperazine (PB28) represents one of the lead candidates in the development of σ receptor ligands for therapeutic and diagnostic applications. However, the utility of PB28 is limited due to its relatively high lipophilicity. Methods: A more hydrophilic analogue (–)-(S)-1 was radiolabeled with 11C via standard O-alkylation. In vitro autoradiography with [11C](–)-(S)-1 was done using rat brain slices. PET imaging was performed in mice bearing EMT6, C6 or PC-3 tumors after i.v. injection of [11C](–)-(S)-1. Results: [11C](–)-(S)-1 was produced in 53% ± 7% isolated decay-corrected yield with radiochemical and chemical purity over 99% and specific activity greater than 100 GBq/μmol. In vitro autoradiography with [11C(–)-(S)-1 resulted in a heterogeneous binding of the tracer in the rat brain with the highest radioactivity signals in the cortex region followed by cerebellum. This binding was successfully blocked by 10 μM of either haloperidol, (+)-(R)-1 or PB28. For C6 xenografts low target-to-nontarget ratio and high non-specific binding did not allow clear tumor visualization. No accumulation was visible in EMT6 tumor or in PC-3 tumor. Rat and mouse brain uptake was low and homogeneous while stronger signal was detected in the spinal cord. High accumulation of radioactivity was observed in liver and intestine suggesting hepatobiliary clearance. Conclusions: Despite excellent in vitro properties, [11C](–)-(S)-1 did not provide high enough specific binding in vivo and is, therefore, not a useful PET tracer for imaging σ2 expression in tumors

  11. The study of methanol transformation over Cu-modified ZSM-5, Beta zeolite and MCM-41 mesoporous silica using 11C-radioisotope labeling

    Complete text of publication follows. The copper-containing zeolites and mesoporous silica, among other metals, are suitable for dehydrogenation of methanol. The Cu transition metal determines the route of methanol conversion on supports of ZSM-5 and Beta zeolite as well as MCM-41 mesoporous silica. The catalysis mechanism and the catalytic property are concluded from the composition of methanol derivates over Cu-modified catalysts. The Cu ion-exchanged ZSM-5 and Beta zeolite and MCM-41 mesoporous silica were synthesized and characterized using X-ray power diffraction, scanning electron microscope, nitrogen and pyridine adsorption, X-ray fluorescency and FTIR spectroscopy. The 11C-radioactive labeling method (11C radioisotope, T1/2 = 20 min, is a gamma emitter by annihilation of its positron) is suitable for following the process of 11C-methanol con- version i.e. adsorption, desorption and catalytic transformation as well as for investigation of small amounts of molecules over catalysts by very sensitive radioactivity detectors.The 11C radioisotope was produced at cyclotron and the 11C-methanol was synthesized by a classical radiochemical method. After catalysis the 11C-radioactive and non radioactive volatile products were identified by radiogas chromatography hereby radiolabeled compound and -derivates were distinguished from other participant natural, nonradioactive carbon compounds. Along radioactive products dimethyl ether and small hydrocarbons products were formed by Bronsted acid sites of catalysts while formaldehyde and small methyl formate were formed by Cu metal over bifunctional Cu-ZSM-5, Cu-Beta zeolite and mesoporous Cu-MCM-41 silica at 240 deg C. The detection of methoxy methanol and dimethoxy methane confirmed the simultaneous presence of acid and basic sites of catalysts. At higher temperature (400 deg C) the CO and CO2 final products were dominated. In our previous works, methanol conversion to hydrocarbons was observed by dehydration over acid H

  12. Comparison of 99mTc-labeled methionine and 11C methionine radiotracer in the detection of breast carcinomas

    The cost effectiveness and non-availability of Cyclotron in underdeveloped and developing countries is a basic problem. Therefore studies were undertaken after labeling Methionine with generator produced Technetium-99m for its possible use in breast cancer imaging

  13. Synthesis of 11C labelled methyl esters: transesterification of enol esters versus BF3 catalysed esterification-a comparative study

    C-11 labelled methyl esters have been synthesized via the transesterification of enol esters in the presence of C-11 methanol and 1,3 dichlorodibutylstannoxane as catalyst. This method leaves functional groups intact and allows access to a wider variety of C-11 labelled methyl esters compared to the BF3 catalysed ester formation, which uses carboxylic acids and C-11 methanol as starting materials

  14. [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.

    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. PMID:26993065

  15. Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling

    Introduction: LBT-999, (E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane, has been developed for PET imaging of the dopamine transporter. [18F]LBT-999 PET studies in baboons showed a lower brain uptake than [11C]LBT-999 and a high bone uptake, suggesting the presence of interfering metabolites. Therefore, in vitro and in vivo metabolism of these radiotracers was investigated. Methods: Rat and human liver microsomal incubations, baboon plasma and rat brain extracts were analyzed by radio-HPLC and LC-MS-MS. Results: In vitro experiments demonstrated the formation by P450s of five polar metabolites. The main routes of LBT-999 metabolism proposed were N-dealkylation, tolyl-hydroxylation and dealkylation plus tolyl-hydroxylation. In vivo in baboons, [18F]LBT-999 was rapidly converted into a [18F]hydroxylated metabolite likely oxidized in plasma into a [18F]carboxylic acid and into unlabeled N-dealkyl-LBT-999. The latter was detected in baboon plasma and in rat brain by LC-MS-MS. The time course of unchanged [18F]LBT-999 decreased rapidly in plasma and was higher than that of [11C]LBT-999 due to the formation of unlabeled N-dealkyl-LBT-999. In rats, striatum-to-cerebellum ratios of [18F]LBT-999, [18F]hydroxylated and [18F]acidic metabolite were 20, 4.2 and 1.65, respectively, suggesting a possible accumulation of the hydroxylated compound in the striatum. Conclusion: P450s catalyzed the formation of dealkylated and hydroxylated metabolites of LBT-999. In baboons, an extensive metabolism of [18F]LBT-999, with formation of unlabeled N-dealkyl-LBT-999, [18F]fluorobutenaldehyde (or its oxidation product) and [18F]hydroxy-LBT-999 able to penetrate the brain, prevented an easy and accurate estimation of the input function of the radiotracer. CYP3A4 being the main P450 involved in the metabolism of LBT-999, a similar pathway may occur in humans and confound PET quantification.

  16. Preliminary evaluation of 11C labelled 4-(n-2,4-dihydroxybenzyl) amino methyl benzoate a reversible tyrosine kinase inhibitor as a radiopharmaceutical

    Full text: Chronic myeloid leukaemia (CML) is a malignant blood disorder affecting primitive stem cells. The incidence is 1 - 1.5/100,000 in Australia, with 400 new cases presenting each year, Recent reports have shown the incidence of CML to be on the increase. Current diagnosis during the early stage of CML is inadequate; anecdotal evidence suggests early disease detection can improve outcome. The expression of tyrosine kinase p210 (BCR/ABL) as the result of gene translocation is the hallmark of CML. This has lead to a class of compounds called tyrosine kinase inhibitors being investigated both as a diagnostic and therapeutic agents. AG957 is a reversible selective inhibitor of p210 (BCR/ABL) tyrosine phosphorylation; however, it is very susceptible to oxidation in solution. An analogue, 4-(N-2,4-dihydroxybenzyl) amino methyl benzoate was synthesised for the following reasons: we hypothesised by relocating the hydroxyl group from the 5 to the 4 position on the benzene ring, it would be less susceptible to oxidation and still retain its selectivity for p210(BCR/ABL). A three step radiolabelling method of AG957 with 11C was reported by Ackermann et al. The same radiolabelling technique was used for the synthesis of this analogue. This paper reports the suitability of 11C labelled 4-(N-2,4-dihydroxybenzyl) amino methyl benzoate as a pharmaceutical injectable. With our preliminary data on the chemical purity, radiochemical purity and its stability in solution, this compound is suitable for further cell binding and animal studies. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  17. Synthesis and biodistribution of a new radiotracer for in vivo labeling of serotonin uptake sites by PET, cis-N,N-[[sup 11]C]dimethyl-3-(2',4'-dichlorophenyl)-indanamine (cis-[[sup 11]C]DDPI)

    Suehiro, Makiko; Scheffel, U.; Dannals, R.F.; Wilson, A.A.; Ravert, H.T.; Wagner, H.N. Jr. (Johns Hopkins Medical Institutions, Baltimore, MD (United States))

    1992-07-01

    A new PET radiotracer for in vivo labeling of serotonin (5-HT) uptake sites, cis-N,N-[[sup 11]C]dimethyl-3-(2',4'-dichlorophenyl)-indanamine, cis-[[sup 11]C]DDPI, was synthesized and its biological behavior was studied. The radiosynthesis of cis-[[sup 11]C]DDPI was performed by N-methylation of cis-N-methyl-3-(2',4'-dichlorophenyl)-indanamine with [[sup 11]C]iodomethane. The average radiochemical yield was approx. 8%, with an average specific activity of 600 mCi/[mu]mol. Following intravenous administration, cis-[[sup 11]C]DDPI accumulated in mouse brain regions rich in 5-HT uptake sites, such as olfactory tubercles, hypothalamus and frontal cortex. Following pre-injection of 1 mg/kg of paroxetine, a high affinity 5-HT uptake blocker, the binding of cis-[[sup 11]C]DDPI in the olfactory tubercles, hypothalamus and frontal cortex was decreased by 23, 25 and 16%; this corresponds to 73, 82 and 59% of the specific binding in these regions. These results suggest that the accumulation of cis-[[sup 11]C]DDPI in the tissues rich in 5-HT sites is a result of specific binding of cis-[[sup 11]C]DDPI to 5-HT uptake sites. Due to the relatively high non-specific uptake and slow clearance of this compound from non-specific binding sites, the ratio between specific and non-specific binding increased slowly with time, reaching 1.5:1 at 60 min after injection. (Author).

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

    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, [11C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [11C]TPT using small-animal PET. Methods: [11C]TPT was synthesized by the reaction of a desmethyl precursor with [11C]CH3I. In vitro study using [11C]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 [11C]TPT was determined using small-animal PET and the dissection method in mice. Results: The transport of [11C]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-/-Bcrp1-/- mice, PET results indicated that the brain uptake of [11C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [11C]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 [11C]TPT, although the radioactivity in the blood decreased with time. Conclusions: We demonstrated the increase of brain penetration of [11C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

  19. Synthesis of {sup 11}C-labeled desipramine and its metabolite 2-hydroxydesipramine: Potential radiotracers for PET studies of the norepinephrine transporter

    Dort, Marcian E. van; Kim, Jae-Hoon; Tluczek, Louis; Wieland, Donald M

    1997-11-01

    The antidepressant desipramine (DMI) and its principal metabolite 2-hydroxydesipramine (HDMI) have been radiolabeled with {sup 11}C for PET studies. The normethyl precursors of DMI and HDMI were synthesized from iminodibenzyl in 35% and 11% overall yield, respectively. Direct methylation of the normethyl precursor with [{sup 11}C]CH{sub 3}I, followed by HPLC purification, provided [{sup 11}C]DMI and [{sup 11}]HDMI in 18-30% and 15-23% decay-corrected radiochemical yields, respectively, in a 45 min synthesis time from end of bombardment. The specific activities of the two radiotracers were >1459 Ci/mmol at the end of synthesis. [{sup 11}C]DMI and [{sup 11}C]HDMI have potential utility as PET radiotracers for the norepinephrine transporter.

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

    Amato, Ernesto; Italiano, Antonio; Margarone, Daniele; Pagano, Benedetta; Baldari, Sergio; Korn, Georg

    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. 18F, 11C, 13N and 15O 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 18F-, 11C- and 13N-labeled radiopharmaceuticals exploiting fast and efficient microfluidic labeling systems.

  1. In vivo evaluation of [11C]- and [18F]-labelled cocaine analogues as potential dopamine transporter ligands for positron emission tomography

    Four analogues of the potent dopamine transporter ligand, WIN 35,428, were radiolabelled with 11C and 18F at the 2-β-carboxy position for evaluation as potential ligands for imaging dopamine uptake sites by positron emission tomography (PET) namely, methyl (1R-2-exo-3-exo)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2- carboxylate (RTI-32), its 4-chlorophenyl analogue (RTI-31), 2'-fluoroethyl (1R-2-exo-3-exo)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2- carboxylate (FETT) and its 4-chlorophenyl analogue (FECT). Upon intravenous injection in rats, all four radiotracers displayed preferential accumulation of radioactivity in regions known to contain high concentrations of dopamine uptake sites. Competition studies with two of the analogues, [11C]RTI-32 and [18F]FETT, demonstrated that, for both radiotracers, binding was saturable and displayed the appropriate pharmacology as potential PET ligands for imaging the dopamine transporter. Striatum to cerebellar ratios for [11C]RTI-32 (at 90 min post-injection) and [18F]FETT (at 120 min post-injection) were 27 and 21, respectively

  2. A simple, versatile, low-cost and remotely operated apparatus for [11C]acetate, [11C]choline, [11C]methionine and [11C]PIB synthesis

    A simple, efficient and remotely operated synthesis apparatus for carrying out routine [11C]carboxylation, on-column and bubbling [11C]methylation was essential for reliable, day-to-day production of [11C]-labelled PET radiopharmaceuticals. We developed an in-house apparatus specifically applied to the synthesis of [11C]acetate, [11C]choline, [11C]methionine and 2-(4'-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), where high radiochemical purity (≥97%) and moderate radiochemical yields (18% for [11C]PIB, 41-55% for the others) could be achieved. These findings provided evidence that this was a fast, versatile and reliable apparatus suitable for a PET/CT centre with limited financial budget and hot cell space for synthesis of [11C]-labelled radiopharmaceuticals

  3. 1-/sup 11/C-D-glucose and related compounds

    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.

  4. Enhanced radiosyntheses of [11C]raclopride and [11C]DASB using ethanolic loop chemistry

    Introduction: To improve the synthesis and quality control of carbon-11 labeled radiopharmaceuticals, we report the fully automated loop syntheses of [11C]raclopride and [11C]DASB using ethanol as the only organic solvent for synthesis module cleaning, carbon-11 methylation, HPLC purification, and reformulation. Methods: Ethanolic loop chemistry is fully automated using a GE TRACERLab FXC-Pro synthesis module, and is readily adaptable to any other carbon-11 synthesis apparatus. Precursors (1 mg) were dissolved in ethanol (100 μL) and loaded into the HPLC loop. [11C]MeOTf was passed through the HPLC loop and then the labeled products were purified by semi-preparative HPLC and reformulated into ethanolic saline. Results: Both [11C]raclopride (3.7% RCY; > 95% RCP; SA = 20831 Ci/mmol; n = 64) and [11C]DASB, both with (3.0% RCY; > 95% RCP; SA = 15152 Ci/mmol; n = 9) and without (3.0% RCY; > 95% RCP; SA = 10931 Ci/mmol; n = 3) sodium ascorbate, have been successfully prepared using the described methodology. Doses are suitable for human use and the described methods are now employed for routine clinical production of both radiopharmaceuticals at University of Michigan. Conclusions: Ethanolic loop chemistry is a powerful technique for preparing [11C]raclopride and [11C]DASB, and we are in the process of adapting it for other carbon-11 radiopharmaceuticals prepared in our laboratories ([11C]PMP, [11C]PBR28 etc.).

  5. Feasibility of labeled α-acetamido-aminoisobutyric acid as new tracer compound for kinetic labeling of neutral amino acid transport: Preparation of α-(N-[1-11C]acetyl)- and α-(N-[1-14C]acetyl)-aminoisobutyric acid

    The nonphysiological, nonracemic, branched-chain α-acetamido-aminoisobutyric acid was labeled with the carbon isotope 11C with the intention to use it in conjunction with positron emission tomography (PET) to measure the kinetics of amino acid transport in vivo. It was produced by the reaction of the novel 11C-precursor N-[1-11C]acetylpyridinium chloride with α-aminoisobutyric acid. Typically, 2 GBq of α-(N-[1-11C]acetyl)-aminoisobutyric acid were isolated with a specific activity of 12 to 20 GBq · μmol-1 at the time of application, and with a radiochemical purity of >98%. The chemical identity of α-(N-[1-11C]acetyl)-aminoisobutyric acid was confirmed by comparison with α-(N-[1-14C]acetyl)-aminoisobutyric acid that was independently prepared by a standard acetylation procedure of α-aminoisobutyric acid using [1-14C]acetic anhydride. In vivo, both labeled substrates were not metabolized. In cell-culture experiments, 84% of the substrate entered the cells by the sodium-dependent amino acid transport system A, whereas 16% was taken up by the sodium-independent system. The uptake of the radiotracer was measured 20 min and 40 min postinjection in tumor-bearing male Copenhagen rats for assessment of its in vivo biodistribution

  6. Analysis of plasma metabolites during human PET studies with three receptor ligands, [11C]YM-09151-2, [11C]doxepin and [11C]pyrilamine

    Carbon-11 labeled metabolites in human plasma were analyzed by high-performance liquid chromatography during positron emission tomography (PET) studies using the dopamine D2 ligand [11C]YM-09151-2 as well as the histamine H1 ligands [11C]doxepin and [11C]pyrilamine. For all the three tracers, blood clearance of the radioactivity was extremely rapid after an i.v. injection. The plasma protein-binding of [11C]YM-09151-2 and [11C]doxepin had protective effects upon the metabolic alteration of the ligands, whereas [11C]pyrilamine was free from the protein-binding and immediately degraded. The degradation of [11C]doxepin was more rapid in epileptic patients on medication than in normal subjects. These results indicate that analysis of metabolites in the plasma is necessary to determine the accurate arterial input function for quantitative PET measurement. (author)

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

    Introduction: To complement recent studies using the high-affinity 11C-labeled phosphodiesterase-4 (PDE4) inhibitor (R)-rolipram and the less active enantiomer (S)-[11C]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)-[11C]rolipram, (S)-[11C]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)-[11C]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)-[11C]rolipram, suggesting that radiolabeled metabolites of (R)-[11C]rolipram display no specific binding to PDE4. Conclusions: Radiolabeled hydrophilic metabolites are unlikely to compete with (R)-[11C]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

  8. Automated photosynthesis of 11C-glucose

    Glucose and fructose, labelled with 11C, were produced by passing 11CO2 into an evacuated chamber containing spinach leaves. Photosynthesis was carried out by day light lamp illumination. 75-95% of the 11CO2 was absorbed by the leaves and the radioactivity in the leaves was extracted in ethanol as sugars. Radiochemical purity was determined by HPLC. The automated system was controlled by timers. (U.K.)

  9. Preparation of [1-11C]dopamine, [1-11C]p-tyramine and [1-11C]m-tyramine. Autoradiography and PET examination of [1-11C]dopamine in primates

    A method for no-carrier-added 1-11C-labelling of 3-hydroxy-, 4-hydroxy- and 3,4-dihydroxy-substituted phenethylamines is described. [11C]Dopamine, [11C]p-tyramine and [11C]m-tyramine were prepared from on-line produced [11C]nitromethane. Condensation of [11C] nitromethane with various protected and unprotected benzaldehydes was investigated. A one-pot two-step reduction of the substituted 11C-labelled nitrostyrene intermediates gave after hydrolysis and purification the corresponding labelled amines in a total radiochemical yield of 8-20% and a specific radioactivity of 400-1000 Ci/mmol. The radiochemical purity was higher than 98%. [11C]Dopamine was used for in vitro autoradiography on human post-mortem brain sections and for positron emissions tomography (PET) on Cynomolgus monkeys. Autoradiographic examinations of [11C]dopamine binding on human brain section post-mortem demonstrated specific binding in the caudate putamen and the substantia nigra, regions with a dense dopaminergic innervation. Some binding was also seen in the globus pallidum, nucleus ventralis of the thalamus and in nucleus dentatus of the cerebellum, regions where the dopaminergic innervation is very low. In PET examinations of [11C]dopamine binding in Cynomolgus monkeys there was a high uptake of radioactivity in the pituitary, the kidneys and the heart. Any passage of [11C]dopamine across the blood-brain barrier could not be demonstrated. In human PET studies [11C]dopamine has potential as a radioligand for examination of the myocardium, pituitary and kidneys. (Author)

  10. 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

    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.

  11. On-line ( sup 11 C)methylation using ( sup 11 C)methyl iodide for the automated preparation of sup 11 C-radiopharmaceuticals

    Iwata, Ren; Pascali, C.; Yuasa, Mitsuaki; Takahashi, Toshihiro; Ido, Tatsuo (Tohoku Univ., Sendai (Japan). CYRIC); Yanai, Kazuhiko (Tohoku Univ., Sendai (Japan). School of Medicine)

    1992-09-01

    A novel method for the efficient preparation of {sup 11}C-radiopharmaceuticals by on-line ({sup 11}C)methylation using ({sup 11}C)methyl iodide has been developed and applied to a rapid, convenient automated system. ({sup 11}C)Methyl iodide is first trapped in a short column, containing an adsorber and coated substrate, which is connected to an HPLC injector. DMF is then introduced. Alternatively the substrate is added with the DMF. A whole reaction mixture can be easily injected onto a HPLC column for purification by switching the injector valve immediately after the reaction. Thus, radiochemical yields in the preparation of {sup 11}C-labelled doxepin, benztropine, cyproheptadine and N-methylspiperone have been improved remarkably and the synthetic procedure simplified. (author).

  12. On-line [11C]methylation using [11C]methyl iodide for the automated preparation of 11C-radiopharmaceuticals

    A novel method for the efficient preparation of 11C-radiopharmaceuticals by on-line [11C]methylation using [11C]methyl iodide has been developed and applied to a rapid, convenient automated system. [11C]Methyl iodide is first trapped in a short column, containing an adsorber and coated substrate, which is connected to an HPLC injector. DMF is then introduced. Alternatively the substrate is added with the DMF. A whole reaction mixture can be easily injected onto a HPLC column for purification by switching the injector valve immediately after the reaction. Thus, radiochemical yields in the preparation of 11C-labelled doxepin, benztropine, cyproheptadine and N-methylspiperone have been improved remarkably and the synthetic procedure simplified. (author)

  13. In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in Rhesus monkeys

    The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain

  14. Erlotinib-related bilateral anterior uveitis

    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 anterio...

  15. 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.

    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

  16. Species differences in [11C]clorgyline binding in brain

    [11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain . To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain

  17. Production of [11C]cyanide for the synthesis of indole-3-[1-11C]acetic acid and PET imaging of auxin transport in living plants

    Ellison, P A; Jedele, A. M.; Barnhart, T. E.; Nickles, R J; Murali, D; DeJesus, O.T.

    2015-01-01

    Introduction Since its development by Al Wolf and colleagues in the 1970s1, [11C]cyanide has been a useful synthon for a wide variety of reactions, most notably those producing [1-11C]-labeled amino acids2. However, despite its position as rote gas-phase product, the catalytic synthesis is difficult to optimize and often only perfunctorily dis-cussed in the radiochemical literature. Recently, [11C]CN– has been used in the synthesis of indole-3-[1-11C]acetic acid ([11C]IAA), the principal p...

  18. [Erlotinib-induced acneiform eruption].

    Wahl, R U; Megahed, M

    2013-05-01

    A 73-year-old man has been suffering from a pulmonary adenocarcinoma for three years. He has been treated with the EGF-inhibitor erlotinib for the past 18 months. While taking this medication he developed a progressive papulopustular rash on his face and trunk which later spread to his thighs. Topical treatment with methylprednisolone and nadifloxacin, as well as short courses of systemic doxycycline and ciprofloxacin, led to marked improvement and control of his skin condition. PMID:23535946

  19. Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors

    Introduction: The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods: N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results: N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49 ± 3% (decay-corrected) yield, affording 4.1 ± 0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of > 99% and with a specific activity of 78 ± 10 GBq/μmol. Conclusion: A new NR2B PET ligand was developed in high yield. [11C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [11C]4 as an NR2B PET ligand

  20. A proposed method for the determination of cerebral regional intermediary glucose metabolism in humans in vivo using specifically labeled 11C-glucose and positron emission transverse tomography (PETT). I. An animal model with 14C-glucose and rat brain autoradiography

    Based upon data obtained with our arterio-venous technique for the determination of cerebral metabolism in humans in vivo we have proposed a method for the determination of cerebral regional intermediary glucose metabolism in humans in vivo using specifically labeled 11C-glucose and positron emission transverse tomography (PETT). In it we would give the subject successive intravenous injections of [3,4-11C] glucose, [2,5-11C] glucose and [1-11C] glucose. There would be a 30 min period of continuous PETT measurements following each injection and a 2 hr interval after the first and second injections. The data would be used with suitable equations and algorithms to estimate for each specific region of the subject's brain the dynamics of the Embden-Meyerhof-Parnas (EMP) and the tricarboxylic acid cycle (TCA) metabolic pathways and the incorporation of glucose carbons into lactate, and the extent of dilution of glucose carbons into lactate, and the extent of dilution of glucose carbons in traversing the TCA with their subsequent incorporation into other carbon pools of the brain (ie, glutamate, glutamine, GABA, alanine). Using 14C as a model for 11C and autoradiographs made with rat brain slices, we have produced an animal model to demonstrate the feasibility of our proposed method. The resulting autoradiographs have provided evidence of the validity of the predictions made from our arterio-venous data. The model was employed to show the selective reductions in the rates of incorporation of specific carbon atoms of glucose into regions of the rat brain and evidence of altered metabolic pathways following a single electroconvulsive shock (ECS) and after a series of nine ECS

  1. Synthesis of [11C]interleukin 8 using a cell-free translation system and L-[11C]methionine

    Positron emission tomography (PET), which requires a compound labeled with a positron emitter radioisotope as an imaging probe, is one of the most useful and valuable imaging modalities in molecular imaging. It has several advantages over other imaging modalities, particularly in sensitive and quantitative investigations of molecular functions and processes in vivo. Recent advances in biopharmaceuticals development have increased interest in practical methods for proteins and peptides labeling with positron emitter radioisotope for PET molecular imaging. Here, we propose a novel approach for preparing positron emitter-labeled proteins and peptides based on biochemical synthesis using a reconstituted cell-free translation system. In this study, [11C]interleukin 8 (IL-8; MW 9.2 kDa) was successfully synthesized by the cell-free system in combination with L-[11C]methionine. The in vitro biochemical reaction proceeded smoothly and gave maximum radioactivity of [11C]IL-8 at 20 min with a radiochemical yield of 63%. Purification of [11C]IL-8 was achieved by conventional cation exchange and ultrafiltration methods, resulting in enough amount of radioactivity with excellent radiochemical purity (>95%) for small-animal imaging. This study clearly demonstrates that cell-free protein production system combined with positron emitter-labeled amino acid holds great promise as a novel approach to prepare radiolabeled proteins and peptides for PET imaging.

  2. Preparation of [11C]-thymidine and [11C]-2'-arabino-2'-fluoro-β-5-methyl-uridine (FMAU) using a hollow fiber membrane bioreactor system

    A series of hollow fiber membranes containing immobilized enzymes were prepared and used in the synthesis of 11C-labelled nucleosides. 11C-Formaldehyde was produced in an alcohol oxidase/catalase bioreactor and circulated through a thymidylate synthase bioreactor with an appropriate substrate to produce the corresponding 11C-nucleotide. These labellled nucleotides were subsequently dephosphorylated in an alkaline phosphatase bioreactor. The bioreactor approach was amenable to hot-cell conditions and yielded 11C-products in higher yield and shorter synthesis times than conventional chemical approaches. (author)

  3. Development of new radioactive labelling methods (3H and 11C) in luteizing hormone (LH) and its releasing hormone (LRF). Study of physico-chemical properties of LRF by circular dichroism and emission spectroscopy

    After a brief review of present knowledge on the hypothalamus-hypophysis this thesis falls into three parts. The first situates the peptide hormones studied in their biological context. Research on the radioactive labelling of hormonal peptides is dealt with in part two which includes, besides the application of already known tritiation methods to particular problems, the description of a new tritium labelling method and the use of carbon 11 for the kinetic distribution study of a hormone. Part three concerns the physico-chemical study of a hypothalamic hormone. As a contribution towards research on the hypophysary gonadotrophic function regulation, the work involved in all the above three sections was directed towards the luteinising hormone (LH) and its hypothalamic release factor (LRF). During the study of this latter the problem of peptides containing tryptophane arose and was consequently investigated

  4. Synthesis of a selective serotonin uptake inhibitor: ( sup 11 C)citalopram

    Dannals, R.F.; Ravert, H.T.; Wilson, A.A.; Wagner, H.N. Jr. (Johns Hopkins Medical Institutions, Baltimore, MD (USA))

    1990-01-01

    Citalopram, a selective serotonin uptake inhibitor, was labeled with {sup 11}C for non-invasive in vivo studies of serotonin uptake sites in the human brain using positron emission tomography. The synthesis was completed in approximately 17 min using ({sup 11}C)methyl iodide as the precursor. The synthesis, purification, characterization, and determination of specific activity are described. (author).

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

    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

  6. A radiometabolite study of the serotonin transporter PET radioligand [11C]MADAM

    Introduction: 11C]MADAM is a radioligand suitable for PET studies of the serotonin transporter (SERT). Metabolite analysis in human and non-human plasma samples using HPLC separation has shown that [11C]MADAM was rapidly metabolized. A possible metabolic pathway is the S-oxidation which could lead to SOMADAM and SO2MADAM. In vitro evaluation of these two potential metabolites has shown that SOMADAM exhibited a good affinity for SERT and a good selectivity for SERT over NET and DAT. Methods: Comparative PET imaging studies in non-human primate brain with [11C]MADAM and [11C]SOMADAM were carried out, and plasma samples were analyzed using reverse phase HPLC. We have explored the metabolism of [11C]MADAM in rat brain with a view to understand its possible interference for brain imaging with PET. Results: PET imaging studies in non-human primate brain using [11C]SOMADAM indicated that this tracer does not bind with high amounts to brain regions known to be rich in SERT. The fraction of [11C]SOMADAM in non-human primate plasma was approximately 5% at 4 min and 1% at 15 min after [11C]MADAM injection. HPLC analysis of brain sample after [11C]MADAM injection to rats demonstrated that [11C]SOMADAM was not detected in the brain. Conclusions: 11C]SOMADAM is not superior over [11C]MADAM as a SERT PET radioligand. Nevertheless, [11C]SOMADAM has been identified as a minor labeled metabolite of [11C]MADAM measured in monkey plasma. [11C]SOMADAM was not detected in rat brain

  7. [11C]PR04.MZ, a promising DAT ligand for low concentration imaging: synthesis, efficient 11C-0-methylation and initial small animal PET studies

    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.

  8. Synthesis of pyruvate-1-11C as a radiopharmaceutical for tumor imaging

    Pyruvate-1-11C was prepared enzymatically by the exchange reaction of 11CO2 with the carboxyl group of pyruvic acid using pyruvate-ferredoxin oxidoreductase from Clostridium butyricum. 11C-Labeled pyruvate was purified by sublimation in specially made glassware. The radiochemical yield of pure pyruvate-1-11C was 80% 35 min after the end of bombardment. The distribution of 11C in tumor-bearing rabbits after an i.v. injection of pyruvate-1-11C was observed using a gamma camera. In contrast to normal organs, the tumor was positively visualized. We also conducted a number of successful clinical studies. A case of brain tumor which exhibited a positive image on positron-emission tomography (PET) using pyruvate-1-11C is presented. (orig.)

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

    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.

  10. Automatic synthesis of [11C]NKY-722 with high specific activity, using anhydrous [11C] methanol as a precursor

    3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-3,5-pyridine dicarboxylate (NKY-722) was labeled with carbon-11 using anhydrous [11C] methanol. Using a computer controlled equipment, a few GBq of [11C] NKY-722 with the specific activity of 120 - 180 GBq/μmol could by synthesized at the radiochemical purity of > 99% in 10 ml of physiological saline containing Polysolvate-80 (1.5 vol%) and ethyl alcohol (0.75 vol%). Preliminary PET experiments using rats and a rhesus monkey have bee done, and very low accumulation of the compound into the brain, however comparatively higher accumulation in the heart were observed. (author)

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

    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.

  12. Effect of tracer metabolism on PET measurement of [11C]pyrilamine binding to histamine H1 receptors

    The present study was carried out to investigate the time course of [11C]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 [11C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [11C]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 [11C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [11C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [11C]pyrilamine. Based on the rat data, the contribution of 11C-labeled metabolites to total [11C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [11C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [11C]pyrilamine by brain tissue itself. Therefore, [11C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [11C]pyrilamine binding to histamine H1 receptors. (author)

  13. Quality control of 11C-carfentanil

    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 endotoxin, 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. (authors)

  14. New halogenated [11C]WAY analogues, [11C]6FPWAY and [11C]6BPWAY--Radiosynthesis and assessment as radioligands for the study of brain 5-HT1A receptors in living monkey

    [Carbonyl-11C]WAY-100635 ([11C]WAY) is an established radioligand for the study of brain serotonin1A (5-HT1A) receptors in living animals and humans with positron emission tomography (PET). There is a recognised need to develop halogenated ligands for 5-HT1A receptors, either for labelling with longer-lived fluorine-18 for more widespread application with PET or with iodine-123 for application with single photon emission tomography (SPET). Here we used autoradiography and PET to assess two new halogenated anlogues of WAY, namely 6BPWAY and 6FPWAY [N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl))-N-(2- (6-bromo-/fluoro-pyridinyl))cyclohexanecarboxamide] as prospective radioligands, initially using carbon-11 as the radiolabel. Labelling of 6BPWAY and 6FPWAY with carbon-11 was accomplished by acylation of the corresponding secondary amine precursors with [carbonyl-11C]cyclohexanecarbonyl chloride. After incubation of human brain crysections with [11C]6BPWAY or [11C]6FPWAY, the highest accumulation of radioactivity was observed in cortical areas and the hippocampal formation. Both radioligands had high nonspecific binding. There was a rapid accumulation of radioactivity in the monkey brain after intravenous injection of [11C]6BPWAY and [11C]6FPWAY. High accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, areas known to contain a high density of 5-HT1A receptors. The ratios of radioactivity in receptor-rich temporal cortex to that in receptor-poor cerebellum at peak equilibrium were 1.9 (at 10 min) and 3.0 at (at 20 min) for [11C]6BPWAY and [11C]6FPWAY, respectively. In pretreatment experiments with high doses of unlabelled WAY, the level of radioactivity in the frontal and temporal cortex and the raphe nuclei was reduced to the same level as in the cerebellum. Radioactive metabolites of [11C]6FPWAY appeared at a rate similar to those for [11C]WAY, with 17% of the radioactivity in plasma represented by unchanged

  15. [11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

    Introduction: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8-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 in a Boc-protected precursor. The isolated [11C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[11C]-O-methylreboxetine ([11C]MeNER). Results: The radiolabeling technique yielded [11C]NS8880 in low (<10%) but still useful yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. Conclusion: Based on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET

  16. EGFR mutation frequency and effectiveness of erlotinib

    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. MATERIAL...

  17. Automated radiochemical synthesis and biodistribution of [11C]l-α-acetylmethadol ([11C]LAAM)

    Long-acting opioid agonists methadone and l-α-acetylmethadol (LAAM) prevent withdrawal in opioid-dependent persons. Attempts to synthesize [11C]-methadone for PET evaluation of brain disposition were unsuccessful. Owing, however, to structural and pharmacologic similarities, we aimed to develop [11C]LAAM as a PET ligand to probe the brain exposure of long-lasting opioids in humans. This manuscript describes [11C]LAAM synthesis and its biodistribution in mice. The radiochemical synthetic strategy afforded high radiochemical yield, purity and specific activity, thereby making the synthesis adaptable to automated modules. - Highlights: • Radiochemical synthesis of opioid [11C]l-α-acetylmethadol (LAAM) described for the first time. • High radiochemical yield, purity and specific activity. • Easily reproducible and adaptable synthesis to any C-11 automated modules. • [11C]LAAM utility as a PET radiopharmaceutical for assessing brain penetration

  18. Synthesis of racemic, R- and S-[1-11C]-β-hydroxybutyric acid

    Racemic, R- and S-β-hydroxybutyric acid were labelled with 11C in the carboxylic position by a two-step stereospecific synthesis starting with carrier-added [11C]cyanide and R/S, R- or S-propylene oxide. Hydrolysis of the intermediate nitrile with hydrochloric acid gave racemic [1-11C]-β-hydroxybutyric acid and R- or S-[1-11C]-β-hydroxybutyric acid with an enantiomeric excess of 87-97%. The total synthesis time (including HPLC purification) was 45-50 min from end of trapping. The isolated decay-corrected radiochemical yield was 20-30% based on [11C]cyanide. The radiochemical purity of the products was > 99%]. (author)

  19. Radiosynthesis of (tetrazoyl-11C)irbesartan, a non-peptidic angiotensin II antagonist

    With the aim of visualizing myocardial angiotensin II receptors (ATI subtypes), [tetrazoyl-11C]2-n-butyl-1-[(2'-(1H-tetrazole-5-yl)-1,1'-biphenyl-4-yl)methyl]-4-spirocyclo-pentane-2-imidazoline-5-one ([tetrazoyl-11C]irbesartam (SR47436/BMS-186295)) 11 was synthesized in one pot in four steps from [11C]hydrogen cyanide. The labelling process which yielded [tetrazoyl-11C]irbesartan is described in detail and could be applied to the labelling of other ligands which possess the (1H-tetrazole-5-yl) moiety. Positron emission tomography (PET) studies were performed in dogs. Heart, lung and blood time-activity curves did not change. Therefore this new radioligand is not suitable for studying myocardial angiotensin II receptors with PET. (authors)

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

    Donepezil is a highly potent and selective reversible acetylcholinesterase inhibitor. [11C]Donepezil is prepared by methylation with [11C]CH3I 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 11C-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. Interstitial lung disease associated to erlotinib treatment: a case report

    del Castillo, Yolanda; Espinosa, Paulina; Bodí, Fernanda; Alcega, Raquel; Muñoz, Emma; Rabassó, Carlos; Castander, David

    2010-01-01

    Introduction Few cases of pulmonary toxicity related to epidermal growth factor receptor-targeted agents have been described. Case presentation We report a case of a 63-year-old white male with stage IV non-small cell lung cancer treated with erlotinib who developed a interstitial lung disease. Conclusion Respiratory symptoms during treatment with erlotinib should alert clinicians to rule out pulmonary toxicity. Early erlotinib withdrawal and corticoid administration were successful.

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

    11C-methylated inulin, supposedly useful for imaging of brain edema and pulmonary edema, was prepared using cyclotron produced 11CO2. The synthesis consists of the production of 11C-methyl iodide and its coupling with inulin alkoxide sodium in dimethylsulfoxide as solvent. 11C labeled inulin was purified by alcohol precipitation. The radiochemical yield of pure 11C-inulin was 34% of 11CO2 30 min after the end of bombardment. The blood clearance and body distribution of 11C was observed in rabbits after i.v. injection of 11C-inulin. The blood clearance curve was composed of a sum of three exponential functions. The gamma camera image showed that the 11C 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. (orig.)

  3. Synthesis of [[sup 11]C] platelet-activating factor (PAF) analogs for in vivo imaging of PAF receptors

    Sasaki, T.; Ishiwata, K. (Tokyo Metropolitan Inst. of Gerontology, Itabishi (Japan)); Karasawa, K. (Teikyo Univ., Kanagawa (Japan). Faculty of Pharmaceutical Sciences) (and others)

    1993-10-01

    [1-O-hexadecyl-2-O-N], N-dimethylcarbamoyl-sn-glycero-3-phosphocholine[choline methyl-[sup 11]C] ([[sup 11]C])dimethylcarbamoyl-platelet-activating factor (PAF) and 1-O-hexadecyl-2-O-acetyl-sn-glycero-3-phosphocholine[choline methyl-[sup 11]C] ([[sup 11]C]C[sub 16]-PAF) were synthesized as follows. Each of non-labeled dimethylcarbamoyl-PAF and C[sub 16]-PAF was treated with sodium benzene thiolate to derive their desmethyl-precursors containing a dimethylphosphoethanolamine at sn-3. [sup 11]C-Labeled dimethylcarbamoyl-PAF and C[sub 16]-PAF were synthesized by methylation of the respective desmethyl-precursors using [[sup 11]C]CH[sub 3]I. The radiochemical yield of methylation in [[sup 11]C]dimethylcarbamoyl-PAF and [[sup 11]C]C[sub 16]-PAF was about 15 and 10% (decay corrected), respectively. To study the stability to enzymatic hydrolysis, [[sup 11]C]dimethylcarbamoyl-PAF or [[sup 11]C]C[sub 16]-PAF was incubated with mouse plasma at 37[sup o]C. [[sup 11]C]Dimethylcarbamoyl-PAF remained intact for 60 min. On the other hand, almost all the radioactivity of [[sup 11]C]C[sub 16]-PAF was converted into [[sup 11]C]C[sub 16]-lyso-PAF in 5 min. These observations indicate that [[sup 11]C]dimethylcarbamoyl-PAF can be a suitable probe for in vivo imaging of PAF receptors. (author).

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

    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 (t1/2 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]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 [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]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)

  5. [[sup 11]C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with PET

    Suehiro, M.; Scheffel, U.; Ravert, H.T.; Dannals, R.F.; Wagner, H.N. Jr. (The Johns Hopkins Medical Institutions, Baltimore, MD (United States))

    1993-01-01

    The in vivo behavior of the stereoisomers of [[sup 11]C]McN5652, a highly potent serotonin (5-HT) uptake blocker, was determined to evaluate their utility as radiotracers for imaging 5-HT uptake sites by positron emission tomography (PET). After intravenous injection into mice, [[sup 11]C](+)MnN5652 showed markedly higher uptake and longer retention in regions with high density of 5-HT uptake sites than the [[sup 11]C]-labeled racemic mixture, while [[sup 11]C]([minus])McN5652 washed out rapidly. With the [[sup 11]C](+)-enantiomer, the ratio between hypothalamus and cerebellum reached 6 at 90 minutes. The binding of [[sup 11]C](+)McN5652 was inhibited by 45-73% by pre-injection of 5 mg/kg of paroxetine, a selective 5-HT uptake blocker, in all regions examined except cerebellum where no significant effect of the drug was observed. [[sup 11]C]([minus])McN5652 showed no specific binding in any of the regions. The [[sup 11]C]-labeled cis isomer, [[sup 11]C]McN5655, revealed surprisingly low brain penetration and showed no significantly higher uptake in regions of interest than cerebellum. These results suggest that [[sup 11]C](+)McN56542 is a promising candidate as a PET radiotracer for studying 5-HT uptake sites in vivo.

  6. Bilateral anterior uveitis secondary to erlotinib

    Lim, Lik Thai; Blum, Robert Alexander; Cheng, Chee Peng; Hanifudin, Abdul

    2010-01-01

    Bilateral anterior uveitis secondary to erlotinib phone: +44-784-3617788 (Lim, Lik Thai) (Lim, Lik Thai) Ophthalmology Department, Gartnavel General Hospital - Great Western Road - G12 0YN - Glasgow - UNITED KINGDOM (Lim, Lik Thai) Ophthalmology Department, Gartnavel General Hospital - Great Western Road - G12 0YN - Glasgow - UNITED KINGDOM (Blum, Robert Alexander) Ophthalmology Department, Gartnavel General Hospital - Great Western Road - G12 0YN - G...

  7. An automated radiosynthesis of 2-[11C]thymidine using anhydrous [11C]urea derived from [11C]phosgene

    2-[11C]Thymidine has been produced from [11C]methane via [11C]phosgene and [11C]urea. Anhydrous [11C]urea was prepared from [11C]phosgene by reaction with liquid ammonia. This novel approach avoids the problems associated with the synthesis of anhydrous [11C]urea from [11C]cyanide. A fully automated system based on a modular approach and under PLC control has been developed. The system provides 2-[11C]thymidine reliably and reproducibly for clinical PET studies. The radiosynthesis takes 45-50 min from [11C]methane and the average yield was 1.5-3.3 GBq (40-90 mCi). The specific radioactivity was typically in the range 29.6-51.8 GBq μmol-1 (0.8-1.4 Ci μmol-1) at EOS corresponding to 6-12 μg of stable thymidine. The radiochemical yield of 2-[11C]thymidine was ca. 14% from [11C]methane

  8. Erlotinib-Associated Acute Pneumonitis: Report of Two Cases

    Bobbak Vahid

    2007-01-01

    Full Text Available Two cases of erlotinib-associated acute pneumonitis are described. The first patient was started on erlotinib treatment for metastatic non-small cell lung cancer. The second patient was treated with erlotinib for metastatic adenocarcinoma of unknown origin. Both patients developed dyspnea and hypoxemia five to six days after initiation of erlotinib treatment. In both cases, computed tomography scan of the chest showed extensive bilateral ground-glass infiltrates consistent with pneumonitis. In both patients, acute pneumonitis resulted in respiratory failure requiring intubation and mechanical ventilation. Diffuse alveolar hemorrhage was excluded by bronchoscopy in both cases. Bronchoalveolar lavage cultures were negative. Erlotinib treatment was stopped and both patients were treated with corticosteroids. The first patient improved gradually and finally was discharged to a rehabilitation centre, but unfortunately the second patient died of Klebsiella sepsis. Naranjo causality scale in both cases suggested a probable association between erlotinib and pneumonitis. Literature on erlotinib-associated pneumonitis is sparse. The clinical presentation and radiographic findings of erlotinib-associated acute pneumonitis are described.

  9. Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma.

    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

    2010-01-01

    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

  10. Palladium mediated 11C-cyanation and characterization in the non-human primate brain of the novel mGluR5 radioligand [11C]AZD9272

    Introduction: The aims of the present positron emission tomography (PET) study were to set up a system for 11C-cyanation labeling of the selective mGluR5-antagonist [11C]AZD9272 and to perform the first in vivo characterization of [11C]AZD9272 binding in cynomolgus monkeys. Methods: [11C]AZD9272 was labeled using palladium mediated 11C-cyanation. Altogether seven PET measurements were performed in three cynomolgus monkeys including baseline and co-injection experiments with unlabelled AZD9272 (0.04 and 0.4 mg/kg). Radiometabolites in plasma were measured using HPLC. Results: [11C]AZD9272 was prepared in over 50% incorporation yield from hydrogen [11C]cyanide in a total synthesis time of 45–50 min. The radiochemical purity of the radioligand in its final formulation was high (> 99%) and the mean specific radioactivity was 47 GBq/ μmol (1278 Ci/mmol, n = 7) calculated at end of bombardment (EOB). In the baseline measurements 10% of the total injected radioactivity was present in monkey brain at five minutes after i.v. injection. The radioactivity concentration was high in the caudate, cingulate gyrus and thalamus whereas it was moderate in the temporal cortex and lower for the cerebellum. After co-injection with cold AZD9272 the binding of [11C]AZD9272 was reduced in a dose-dependent fashion. Analysis of radiometabolites showed relatively slow metabolism and resulted only in hydrophilic radiometabolites. Conclusion: A fast and efficient method was developed to label AZD9272 with 11C. PET-examination in Cynomolgus monkeys showed that [11C]AZD9272 entered the brain to a high extent, that binding was saturable and that the regional radioactivity pattern was in accordance with the known distribution of mGluR5. The results support further examination of [11C]AZD9272 binding in human subjects

  11. Development of additive [11C]CO2 target system in the KOTRON-13 cyclotron and its application for [11C]radiopharmaceutical production

    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 [11C]CO2, 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 [11C]CO2 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 [11C]CO2 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 [11C]CO2 production under a high beam current. In the application of C-11 labeled radiopharmaceuticals such as [11C]PIB, [11C]DASB, [11C]PBR28, [11C]Methionine and [11C]Clozapine, the radiochemical yields were shown to be 25–38% (decay corrected) with over 166 GBq/μmol of

  12. 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

    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

  13. Development of additive [11C]CO2 target system in the KOTRON-13 cyclotron and its application for [11C]radiopharmaceutical production

    Moon, Byung Seok; Lee, Hong Jin; Lee, Won Kyung; Hur, Min Goo; Yang, Seung Dae; Lee, Byung Chul; Kim, Sang Eun

    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 [11C]CO2, 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 [11C]CO2 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 [11C]CO2 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 [11C]CO2 production under a high beam current. In the application of C-11 labeled radiopharmaceuticals such as [11C]PIB, [11C]DASB, [11C]PBR28, [11C]Methionine and [11C]Clozapine, the radiochemical yields were shown to be 25-38% (decay corrected) with over 166 GBq/μmol of

  14. Tracers development for the PET study of nicotinic receptors: [11C]-mecamylamine and [11C]-SIB 1553A. Tritium and carbon-11 radiolabelling of a serine proteinase inhibitor: the t-PAstop

    In order to develop radiotracers for the Positron Emission Tomography (PET), we labelled both the mecamylamine and SIB-1553A with carbon-11 to study the nicotinic cholinergic receptors (nAChRs). The radiosynthesis of [11C]-t-PAstop and the labelling with tritium of one analogue were realized for cerebral ischemia PET studies. The [11C]-mecamylamine, a non-competitive and non-selective nAChRs antagonist was synthesized in 45 min via a N-[11C]-methylation reaction. In the rat brain, the ex vivo studies showed no radio-metabolite 45 min after the injection of [11C]-mecamylamine. The uptake kinetics in the rat brain or in vivo by PET in the anesthetized baboon or in the conscious monkey, reached a plateau around 45-50 min after injection. However, the saturation or displacement experiments did not permit to exhibit nor a significant difference of labelling between the different cerebral regions nor a specific uptake. In consequence, the [11C]-mecamylamine was not an appropriate radioligand for nAChRs PET study. The labelling of [11C]-SIB 1553A, a selective agonist for the nicotinic β4 subunit, required the synthesis in 5 steps (56% overall yield) of precursor for the incorporation of carbon-11. The radiosynthesis was performed in 36 min by a N-[11C]-methylation reaction (yield: 75%). The [11C]-t-PAstop was obtained from [11C]-KCN with yields from 80 to 90%. For the first time with carbon-11, the formation of an amidine group was realized from a nitrile group. The labelling by isotopic exchange of hydrogen by tritium of the t-PAstop did not permit to obtain the [3H]-t-PAstop but a tritiated analogue. This compound will be used to study its vectorization by micro-encapsulation. (author)

  15. The synthesis of [O-methyl-11C]venlafaxine: a non-classical, fast-acting antidepressant

    As part of our program to develop PET tracers for the 5-HT reuptake site, venlafaxine, a non-classical, fast-acting antidepressant, was selected as a candidate for labelling with 11C for in vivo evaluation. [O-methyl-11C]venlafaxine was produced by the alkylation of O-desmethyl venlafaxine with [11C]methyl iodide followed by HPLC purification and formulation. Radiochemically pure [O-methyl-11C]venlafaxine was obtained in a 30 ± 5% decay corrected radiochemical yield and a specific activity > 50 GBq/μmol(1.4 Ci/μmol) at the end of synthesis. For a typical production starting with 46 GBq (1.3 Ci) [11C]CO2, 5.2 GBq (140 mCi) [O-methyl-11C]venlafaxine was obtained as a sterile, formulated solution in a synthesis time of 30 min (counted from EOB). (Author)

  16. Regional cerebral distribution of 11C-methyl-D-glucose in man

    The reported study was undertaken to investigate if MG is useful to study glucose metabolism in humans, as suggested previously. For that purpose MG was labelled with 11C, and positron emission tomograms were obtained in healthy volunteers and patients with brain disorders. (Auth.)

  17. Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]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 [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. 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.)

  18. In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors

    The potential of the 11C-labeled selective sigma1 receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([11C]SA4503) was evaluated in vivo as a positron emission tomography (PET) ligand for mapping sigma1 receptors in rats. SA4503 is known to have a high affinity (IC50 17.4 nM) and a higher selectivity (sigma1/sigma2=103) for the sigma1 receptor. A high and increasing brain uptake of [11C]SA4503 was found. Pre-, co- and postinjection of cold SA4503 significantly decreased uptake of [11C]SA4503 in the brain, spleen, heart, lung, and kidney in which sigma receptors are present as well as in the skeletal muscle. In the blocking study with one of four sigma receptor ligands including haloperidol, (+)-pentazocine, SA4503, and (-)-pentazocine (in the order of their affinity for sigma1 receptor subtype), SA4503 and haloperidol significantly reduced the brain uptake of [11C]SA4503 to approximately 30% of the control, but the other two benzomorphans did not. A high specific uptake of [11C]SA4503 by the brain was also confirmed by ex vivo autoradiography (ARG) and PET. Ex vivo ARG showed a higher uptake in the vestibular nucleus, temporal cortex, cingulate cortex, inferior colliculus, thalamus, and frontal cortex, and a moderate uptake in the parietal cortex and caudate putamen. Peripherally, the blocking effects of the four ligands depended on their affinity for sigma1 receptors. No 11C-labeled metabolite was detected in the brain 30 min postinjection, whereas approximately 20% of the radioactivity was found as 11C-labeled metabolites in plasma. These results have demonstrated that the 11C-labeled sigma1 receptor ligand [11C]SA4503 has a potential for mapping sigma1 receptors in the central nervous system and peripheral organs

  19. 11C-2-deoxy-D-glucose: Synthesis and preliminary comparison with 11C-D-glucose as a tracer for cerebral energy metabolism in PET studies

    11C-2-Deoxy-D-glucose has been prepared by the reaction of 11C-hydrogen cyanide with a stable precursor, 1-deoxy-2,3:4,5-di-O-isopropylidine-1-iodo-D-arabitol, thereby avoiding the synthesis of starting material immediately prior to labeling. Fast, efficient, and reproducible solvent change from dimethyl sulfoxide to ether by flash chromatography enabled the use of diisobutylaluminium hydride in the reduction of the intermediate nitrile. Hydrolysis of the imine-aluminum complex with sulfuric acid, removal of the isopropylidine protecting groups with formic acid, and HPLC purifiction with an Aminex HPX-87P column yielded 11C-2-deoxy-D-glucose in an aqueous solution, sterile, pyrogen-free, and ready for use in human studies. The radiochemical yield was proportional20% after a synthesis time of 50 min. The 11C-2-deoxy-D-glucose thus obtained is presently being compared with photosynthetically prepared 11C-D-glucose in PET studies of cerebral metabolism. A preliminary report of the regional cerebral metabolic rate of glucose obtained with the two tracers in a healthy subject with visual stimulation is presented. (orig.)

  20. Evaluation of clinial usefulness of [sup 11]C-methionine positron emission tomography ([sup 11]C-MET-PET) as a tool for liver functional imaging

    Enomoto, Kazuo; Matsui, Yoshifumi; Okazumi, Shinichi (Chiba Univ. (Japan). School of Medicine) (and others)

    1994-03-01

    We studied [sup 11]C-MET-PET in 17 clinical cases, 10 patients with obstructive jaundice and 7 normal volunteers, and analyzed its efficacy for the evaluation of hepatic functional reserve in major hepatectomy candidates. Differential absorption ratio (DAR) of [sup 11]C was compared to the hepatic protein synthesis rate (HPS), which is measured as the incorporation rate of [sup 3]H-labeled leucine in protein fraction, using needle biopsied liver specimen obtained from each hepatic segment. In the cases of normal liver function, DAR was well correlated with HPS. Also in jaundice cases with two exceptions, low HPS segment was demonstrated as low DAR segment. Consequently, MET-PET images could clearly provide functional liver imaging. After injection of [sup 11]C-MET, the increase in rate of radioactivity of [sup 11]C in plasma protein fraction was higher in jaundice cases than in normal volunteers, which is in accord with the results of our former study that cholestatic liver has accelerated protein synthesis rate. In summary, since [sup 11]C-MET-PET could demonstrate liver functional imaging, it might be a possible tool for liver function assessment in major hepatectomy candidates. (author).

  1. 5-Fluoro-[β-11C]-L-tryptophan is a functional analogue of 5-hydroxy-[β-11C]-L-tryptophan in vitro but not in vivo

    Introduction: 5-Hydroxy-[β-11C]-L-tryptophan ([11C]HTP) is an established positron emission tomography (PET) imaging agent for neuroendocrine tumors (NETs). It has also been used for other clinical research purposes in neurology and diabetes. However, its widespread use is limited by the short physical half-life of the radionuclide and a difficult radiosynthesis. Therefore, a Fluorine-18 labeled analogue, 5-[18F]Fluoro-L-tryptophan ([18F]FTRP), has been proposed as a functional analogue. There is no published method for the synthesis of L-[18F]FTRP. We have therefore developed a synthesis of 5-fluoro-[β-11C]-L-tryptophan ([11C]FTRP), based on the existing chemo-enzymatic method for [11C]HTP and evaluated the potential usefulness of radiolabeled FTRP as a substitute for [11C]HTP. Methods: The in vitro and in vivo behavior of [11C]FTRP, including the dependence of key enzymes in the serotonergic metabolic pathway, was investigated in NET cell lines, NET xenograft carrying immunodeficient mice, normal rats and in non-human primate. [11C]HTP was used for direct comparison. Results: Uptake of [11C]FTRP in NET cell lines in vitro was mediated by enzymes involved in serotonin synthesis and metabolism, similar to [11C]HTP. In vivo biodistribution, either in rodent or non-human primate, was not affected by selectively inhibiting enzymatic steps in the serotonergic metabolic pathway. Conclusion: [11C]FTRP has in vitro biological function similar to that of [11C]HTP. However, this function is not retained in vivo as shown by biodistribution and PET/CT studies. Radiolabeled FTRP is thus not likely to provide an advantage over [11C]HTP in PET imaging in oncology, neurology or diabetes

  2. [11C]NNC 22-0215, a metabolically stable dopamine D1 radioligand for PET

    NNC 22-0215 has been found to be a metabolically stable dopamine D1 antagonist with high affinity and selectivity for D1 receptors in vitro. We prepared [11C]NNC 22-0215 with a specific radioactivity of about 50 GBq/μmol at time of administration. In PET experiments with [11C]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 11C-labelled benzazepines, previously used as dopamine D1 receptor ligands for PET. Results indicate a significantly slower rate of metabolism for [11C]NNC 22-0215 than for any of the previously labelled benzazepines. Thus [11C]NNC 22-0215 has potential for imaging of selective binding to the dopamine D1 receptors in the human brain with high count rates at time of equilibrium

  3. (/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

    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.

  4. Successful rechallenge with reduced dose of erlotinib in a patient with lung adenocarcinoma who developed erlotinib-associated leukocytoclastic vasculitis: A case report

    SU, BO-AN; SHEN, WAN-LIN; CHANG, SHENG-TSUNG; FENG, LI-YIA; Wu, Chia-Jung; Feng, Yin-Hsun

    2012-01-01

    The oral tyrosine kinase inhibitors of epidermal growth factor, erlotinib and gefitinib, are active in the treatment of non-small cell lung cancer (NSCLC). However, a number of skin manifestations have been found in patients receiving erlotinib therapy. Leukocytoclastic vasculitis is a rare side-effect of erlotinib therapy. However, whether or not erlotinib treatment should be continued when disseminated ulceration of leukocytoclastic vasculitis is encountered remains to be determined. In thi...

  5. 11C-methylations using 11C-methyl iodide and tetrabutylammonium fluoride

    Carbon-11 methylation reactions on functional groups such as phenols and amides require a base when using 11C-methyl iodide. This study demonstrates that tetrabutylammonium fluoride (TBAF) can be used as a base to prepare 11C-radiopharmaceuticals efficiently and in high yield. We have applied this method to raclopride, methylphenidate, PK11195, dihydrotetrabenazine and MDL100907 and have compared the results with the Alumina/KF and hydroxide methods. Our results indicate that TBAF gives equivalent or higher radiochemical yields compared to the other bases even when using as little as 200 μg of precursor. In the case of PK11195 the TBAF method was the only one that provided a reasonable yield of product. (orig.)

  6. {sup 11}C-methylations using {sup 11}C-methyl iodide and tetrabutylammonium fluoride

    Adam, M.J.; Jivan, S.; Huser, J.M.; Lu, J. [TRIUMF Univ. of British Columbia, Vancouver (Canada)

    2000-07-01

    Carbon-11 methylation reactions on functional groups such as phenols and amides require a base when using {sup 11}C-methyl iodide. This study demonstrates that tetrabutylammonium fluoride (TBAF) can be used as a base to prepare {sup 11}C-radiopharmaceuticals efficiently and in high yield. We have applied this method to raclopride, methylphenidate, PK11195, dihydrotetrabenazine and MDL100907 and have compared the results with the Alumina/KF and hydroxide methods. Our results indicate that TBAF gives equivalent or higher radiochemical yields compared to the other bases even when using as little as 200 {mu}g of precursor. In the case of PK11195 the TBAF method was the only one that provided a reasonable yield of product. (orig.)

  7. Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment

    Orzáez, M; Guevara, T; Sancho, M; Pérez-Payá, E

    2012-01-01

    Inhibitors of the tyrosine kinase activity of epidermal growth factor receptor, as erlotinib, have an established role in treating several cancer types. However, resistance to erlotinib, particularly in breast cancer cell lines, and erlotinib treatment-associated disorders have also been described. Also, methods and combination therapies that could reverse resistance and ameliorate non-desirable effects represent a clinical challenge. Here, we show that the ATP non-competitive CDK2/cyclin A inhibitor NBI1 sensitizes erlotinib-resistant tumor cells to the combination treatment (co-treatment) for apoptosis-mediated cell death. Furthermore, in erlotinib-sensitive cells, the effective dose of erlotinib was lower in the presence of NBI1. The analysis in the breast cancer MDA-MB-468 erlotinib-resistant and in lung cancer A549 cell lines of the molecular mechanism underlying the apoptosis induced by co-treatment highlighted that the accumulation of DNA defects and depletion of cIAP and XIAP activates the ripoptosome that ultimately activates caspases-8 and -10 and apoptosis. This finding could have significant implications for future treatment strategies in clinical settings. PMID:23096116

  8. In vivo binding of [11C]nemonapride to sigma receptors in the cortex and cerebellum

    Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D2-like receptor ligand in pharmacological and neurological studies, and 11C-labeled analog ([11C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [11C]NEM binds in vivo to sigma receptors. [11C]NEM and one of six dopamine D2-like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [11C]NEM was measured by a tissue dissection method. The striatal uptake of [11C]NEM was reduced by D2-like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D4 receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D2-like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [11C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [11C]NEM binds in vivo not only to dopamine D2-like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum

  9. 11C-PET imaging reveals transport dynamics and sectorial plasticity of oak phloem after girdling

    De Schepper, Veerle; Bühler, Jonas; Thorpe, Michael; Roeb, Gerhard; Huber, Gregor; van Dusschoten, Dagmar; Jahnke, Siegfried; Steppe, Kathy

    2013-01-01

    Carbon transport processes in plants can be followed non-invasively by repeated application of the short-lived positron-emitting radioisotope 11C, a technique which has rarely been used with trees. Recently, positron emission tomography (PET) allowing 3D visualisation has been adapted for use with plants. To investigate the effects of stem girdling on the flow of assimilates, leaves on first order branches of two-year-old oak (Quercus robur L.) trees were labelled with 11C by supplying 11CO2-...

  10. Radiosynthesis of [11C]glyburide for in vivo imaging of BCRP function with PET

    Complete text of publication follows: Objectives: The human breast cancer resistance protein (BCRP/ABCG2) belongs to the ABC-transporter super-family in which P-gp (MDR1/ABCB1) is probably the most emblematic and best known member. BCRP, which was initially discovered in multidrug resistant breast cancer cell lines, is also highly expressed in numerous tissues e.g. the blood-brain barrier (BBB). BCRP confers upon these tissues resistance to chemotherapeutic agents but also transports drugs and xenobiotics thus participating to the ADME processes although the biochemical mechanisms remain largely unknown to date. The hypoglycaemic sulfonylurea glyburide (glibenclamide) has been described as a specific substrate of BCRP in vitro and in vivo. Its isotopic labelling with the positron emitter carbon-11 (20.4 min) would provide a valuable tool to study in vivo with PET the BCRP transport activity. Herein are reported the synthesis of desmethyl-glyburide (2), as precursor, as well as the preparation of [11C]glyburide ([11C]-1) using [11C]methyl triflate as radio-methylation agent. Methods: Chemistry: Desmethyl-glyburide (2), as precursor for [11C]labelling, was obtained in one chemical step by treating glyburide (1) with a 1 M solution of BBr3 (4 eq.) in dichloromethane at low temperature (-90 C to - 20 C). Radiochemistry: Carbon-11 labeling of glyburide (1) was performed using a TRACERLab FX-C Pro synthesizer (GEMS) and comprised (1) trapping at -10 C of [11C]MeOTf in acetone (0.3 mL) containing the precursor 2 (0.5-0.8 mg) and aq. 3N NaOH (5 μL); (2) heating at 110 C for 2 min; (3) dilution in 1.0 mL of the HPLC mobile phase and purification using semi-preparative reversed-phase HPLC (Waters SymmetryR C-18 - eluent: CH3CN / H2O / TFA: 45 / 55 / 0.1 (v:v:v) - flow rate: 5 mL/min - detection at 254 nm) and (4) SepPakR Plus C-18-based formulation for i.v. injection. The measurement of log P and log D7.4 was performed using the shaked flask method. Results: The desmethyl

  11. High molar activity of [11C]TCH346 via [11C]methyl triflate using the 'wet' [11C]CO2 reduction method

    [11C]TCH346, a compound acting on the glycolytic enzyme, glycerol-aldehyde-3-phosphate dehydrogenase, was produced under optimised conditions by methylation of the desmethyl compound with no-carrier added (n.c.a.) [11C]methyl triflate. An i.v. injectable solution of n.c.a. [11C]TCH346 containing 4040±1550 MBq (n=6) containing a molar activity between 40 and 5700 GBq/μmol and a radiochemical purity of >99% was obtained within 30 min (after EOB) by irradiation of nitrogen gas containing 0.5% oxygen with 16.5 MeV protons at 45 μA for 30 min. The alkylation reagent [11C]methyl triflate was prepared via on-line conversion of [11C]methyl iodide. For the formation of [11C]methyl iodide, [11C]carbon dioxide from the target chamber was reduced by a lithium aluminium hydride solution, and the methanol obtained on-line was converted using triphenylphosphine diiodide. The molar activity of [11C]TCH346 could be improved from 40 up to nearly 5700 GBq/μmol during the optimisation of the synthesis using the same stock solution of lithium aluminium hydride solution in tetrahydrofuran

  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

    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

    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...

  14. Erlotinib-related keratopathy in a patient underwent laser in situ keratomileusis.

    Kau, Hui-Chuan; Tsai, Chieh-Chih

    2016-09-01

    Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor. Since there is a wide expression of the epidermal growth factor receptors in the epithelial tissues of ocular surface and adnexa, ocular adverse reactions may happen during systemic administration of erlotinib. Previously reported ocular adverse reactions of erlotinib include trichomegaly, periorbital rash, ectropion, blepharitis, persistent corneal epithelial defect, corneal ulcer and perforation. We report the first case of erlotinib-related keratopathy in a patient who had received laser in situ keratomileusis. The patient presented a special picture of flap striae related to erlotinib. Improvement of keratopathy after cessation of erlotinib was demonstrated. PMID:26340340

  15. Radiopharmaceutical for differential diagnosis of tuberculoma: synthesis of 2-( sup 11 C)cyano-isonicotinic acid hydrazide

    Somawardhana, C.W.; Sajjad, M.; Lambrecht, R.M. (King Faisal Specialist Hospital and Research Centre, Riyadh (Saudi Arabia))

    1991-01-01

    The radiochemical synthesis of 2-({sup 11}C)cyano-isonicotinic acid hydrazide was accomplished. Carbon-11 labelled cyano-group was introduced at the 2-position of the pyridine ring of 1-methoxy-4-methoxycarbonyl pyridinium methyl sulfate via a Riessert-Kaufmann type reaction. The reaction was performed on a solid support (silica gel) to yield no-carrier-added methyl 2-({sup 11}C)cyano-isonicotinate in (32.4 +- 12%) (EOB) yield. This method is unique for the incorporation of ({sup 11}C)HCN to base sensitive substrates. The carbon-11 labelled methyl ester was treated with hydrazine hydrate to obtain 2-({sup 11}C)cyano-isonicotinic acid hydrazide. The final radiochemical yield was 10% (EOB) and the synthesis time was approximately 35 min. (author).

  16. Radiopharmaceutical for differential diagnosis of tuberculoma: synthesis of 2-[11C]cyano-isonicotinic acid hydrazide

    The radiochemical synthesis of 2-[11C]cyano-isonicotinic acid hydrazide was accomplished. Carbon-11 labelled cyano-group was introduced at the 2-position of the pyridine ring of 1-methoxy-4-methoxycarbonyl pyridinium methyl sulfate via a Riessert-Kaufmann type reaction. The reaction was performed on a solid support (silica gel) to yield no-carrier-added methyl 2-[11C]cyano-isonicotinate in (32.4 ± 12%) (EOB) yield. This method is unique for the incorporation of [11C]HCN to base sensitive substrates. The carbon-11 labelled methyl ester was treated with hydrazine hydrate to obtain 2-[11C]cyano-isonicotinic acid hydrazide. The final radiochemical yield was 10% (EOB) and the synthesis time was approximately 35 min. (author)

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

    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.

  18. Noninvasive measurement of liver regeneration with positron emission tomography and [2-11C]thymidine

    The feasibility of liver regeneration determination with [2-11C]thymidine and positron emission tomography was investigated in partially hepatectomized rats. Serial tomographic scans were performed over a 120-minute period after injection of [2-11C]thymidine together with tritium-labeled thymidine. Within 10 minutes after injection, positron emission tomography scans showed a twofold higher hepatic uptake in regenerating than in nonregenerating livers. Time-activity curves over the liver area indicated that the maximal uptake was followed by a faster decrease of 11C radioactivity in controls than in regenerating animals, so that total 11C activity remaining in the liver at 120 minutes accounted for 68% of maximum in regenerating and only 38% in controls. Tissue distribution studies performed at 120 minutes showed that total 11C radioactivity, expressed in percent injected dose per gram, was six times higher in regenerating livers than in controls (0.62% ± 0.07% in regenerating livers and 0.10% ± 0.03% in nonregenerating livers; P less than 0.001) and correlated with 3H radioactivity measured in the nuclear fraction (r = 0.92; P less than 0.001). When the hepatic uptake was expressed in percent of dose per organ, the difference between both groups increased (2.31% ± 0.23% in regenerating livers and 0.29% ± 0.02% in nonregenerating livers; P less than 0.001) because of higher weight of regenerating livers than of nonregenerating livers (3.83 ± 0.11 g in regenerating livers and 2.96 ± 0.16 g in nonregenerating livers; P less than 0.001). In other organs examined, no difference in 11C radioactivity was found between the two groups of rats. These results indicated the potential usefulness of [2-11C]thymidine and positron emission tomography for noninvasive measurement of liver regeneration

  19. Radiosynthesis of [11C]SB-705498, a selective transient receptor potential Vanilloid 1 (TRPV1) receptor antagonist

    Complete text of publication follows: Objectives: The transient receptor potential vanilloid 1 (TRPV1) receptor, previously known as the vanilloid receptor 1 (VR1), is a non-selective cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptor is involved in pain and sensitisation associated with tissue injury and inflammation and therefore represents a pharmacological target of choice for the development of novel therapeutic agents for the treatment of chronic pain, migraine and gastrointestinal disorders. Among a novel series of pyrrolidinyl ureas recently discovered by GSK, SB-705498 (1, namely 1-(2-bromophenyl)-3-[(R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-yl]urea) has been identified as a potent, selective and orally bioavailable TRPV1 antagonist and considered for positron emission tomography studies. SB-705498 (1) has therefore been isotopically labelled with the short-lived positron-emitter carbon-11 (t1/2: 20.38 min) at its urea site using [11C]phosgene in a one-pot two-step process, via the intermediate preparation of 2-bromophenyl [11C]isocyanate. Methods: Carbon-11-labeling of SB-705498 comprises: (A) Trapping of [11C]phosgene (radio-synthesized from cyclotron-produced [11C]methane via [11C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1 to 2 minutes in 250 μL of acetonitrile containing 0.6 μmole of 2-bromoaniline (2) giving 2-bromophenyl [11C]isocyanate ([11C]-3), followed by (B) addition of an excess of chiral (R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-ylamine (4, 40 μmoles in 500 μL of acetonitrile) as the second amine and reaction at room temperature for an additional one minute giving the desired urea derivative ([11C]SB-705498 ([11C]-1)), (C) dilution of the crude reaction mixture with water (500 μL) containing 4% (v:v) of DEA, injection and purification on a semi-preparative Waters SymmetryR C18 HPLC column (eluent: H2O / CH

  20. Synthesis of [11C]N-methyl tetrahydroaminoacridine, a potent acetylcholine esterase inhibitor

    Tetrahydroaminoacridine (THA) is a potent central acting acetylcholine esterase (AChE) inhibitor which might be used as therapeutic agent in the treatment of Alzheimer's disease (AZD). In order to study the AChE activity in the brain by PET, the authors selected N-methyl THA, a potent AChE inhibitor, as a potential radioligand. In this paper, they report the synthesis and labelling of N-methyl THA with [11C]methyl iodide

  1. Correlative cluster analysis of [11C]CFT and [11C]raclopride images in positron emission tomography

    Aim: [11C]CFT and [11C]raclopride were used to evaluate pre-synaptic dopamine transporter availability and post-synaptic dopamine D2 receptor binding, respectively, by positron emission tomography (PET). A combined study with these tracers are useful for the differential diagnosis of Parkinson's disease. The aim of this work is development of a new method that can automatically analyze and display regional status of pre- and post-synaptic dopaminergic functions. Materials and Methods: Brain images with [11C]CFT and [11C]raclopride were obtained using a 3-dimensional (3D) PET camera (HEADTOME-V, Shimadzu Co., Ltd.) and were co-registered to the individual structural brain image by magnetic resonance imaging (MRI) using the method of automatic multimodality image registration. Correlation between the [11C]CFT uptake and the [11C]raclopride uptake was calculated pixel-by-pixel over the striatum. The pixels in the striatum were clustered into 3 or 4 segments by a hierarchical method, and the a clustered 3D image was reconstructed. Thus, the clustered image can be displaced in arbitrary angles. This method was applied to several patients with Parkinson's disease, that were early to moderate in stages, and showed symmetric or asymmetric PET images. Results: A clustered transaxial brain image of Parkinson's disease superimposed on MRI, contained a segment which showed high uptake of both [11C]CFT and [11C]raclopride and a segment which showed high uptake of [11C]raclopride but low uptake of [11C]CFT). The former and latter corresponded to caudate nucleus and putamen, respectively. The clustered 3D transaxial image effectively demonstrated the regional differences of pre- and post-synaptic dopaminergic functions. Conclusion: The present cluster analysis is clinically useful for objective evaluation of dopaminergic functions of patients with the parkinsonism by PET with [11C]CFT and [11C]raclopride

  2. Simple one-pot synthesis of cyclopropane (/sup 11/C) carbonyl chloride. Synthesis and biodistribution of (/sup 11/C) cyclorphan

    McPherson, D.W.; Hwang, D.-R.; Fowler, J.S.; Wolf, A.P.; MacGregor, R.M.; Arnett, C.D.

    1986-05-01

    A rapid, one-pot, synthesis of cyclopropane (/sup 11/C) carbonyl chloride was developed. This synthesis proceeded in 80% radio-chemical yield (EOB) in a synthesis time of 10 minutes. This acid chloride was then used to synthesize a model compound, (/sup 11/C)cyclorphan, by alkylation of norlevorphanol followed by reduction of the intermediate (/sup 11/C)amide in an overall synthesis time of 55 minutes and a radiochemical yield of 15% (EOB). The biodistribution of (/sup 11/C)cyclorphan in control and naloxone pretreated mice showed non-specific binding and rapid clearance from brain.

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

    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).

  4. Erlotinib, erlotinib-sulindac vs. placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer

    Gross, Neil D.; Bauman, Julie E.; Gooding, William E.; Denq, William; Thomas, Sufi M.; Wang, Lin; Chiosea, Simion; Hood, Brian L.; Flint, Melanie S.; Sun, Mai; Conrads, Thomas P.; Ferris, Robert L.; Johnson, Jonas T.; Kim, Seungwon; Argiris, Athanassios; Wirth, Lori; Nikiforova, Marina N.; Siegfried, Jill M.; Grandis, Jennifer R.

    2014-01-01

    Purpose The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic anti-tumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a non-selective COX inhibitor, vs. placebo. Experimental Design Patients with untreated, operable Stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after 7-14 days of treatment. The primary endpoint was change in Ki-67 proliferation index. We hypothesized an ordering effect in Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX-2 signaling intermediates. Results From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki-67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, p=0.04). Wilcoxon pairwise contrasts confirmed greater Ki-67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo p=0.043; erlobinib vs. placebo, p=0.027). There was a significant trend in ordering of Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, p =0.0185). Low baseline pSrc correlated with greater Ki-67 reduction (R2 = .312, p = 0.024). Conclusions Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. PMID:24727329

  5. A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [{sup 11}C]2-[2-dimethylaminomethylphenylthio]-5-fluorophenylamine ([{sup 11}C]AFA)

    Huang Yiyun E-mail: hh285@columbia.edu; Narendran, Raj; Bae, Sung-A; Erritzoe, David; Guo Ningning; Zhu Zhihong; Hwang, D.-R.; Laruelle, Marc

    2004-08-01

    A new serotonin transporter (SERT) ligand, [{sup 11}C]2-[2-(dimethylaminomethylphenylthio)]-5-fluorophenylamine (10, [{sup 11}C]AFA), was synthesized and evaluated as a candidate PET radioligand in pharmacological and pharmacokinetic studies. As a PET radioligand, AFA (8) can be labeled with either C-11 or F-18. In vitro, AFA displayed high affinity for SERT (K{sub i} 1.46{+-}0.15 nM) and lower affinity for norepinephrine transporter (NET, K{sub i} 141.7{+-}47.4 nM) or dopamine transporter (DAT, K{sub i} >10,000 nM). [{sup 11}C]AFA (10) was prepared from its monomethylamino precursor 9 by reaction with high specific activity [{sup 11}C]methyl iodide. Radiochemical yield was 43{+-}20% based on [{sup 11}C]methyl iodide at end of bombardment (EOB, n = 10) and specific activity was 2,129 {+-} 1,369 Ci/mmol at end of synthesis (EOS, n = 10). Biodistribution studies in rats indicated that [{sup 11}C]AFA accumulated in brain regions known to contain high concentrations of SERT. Binding in SERT-rich brain regions was reduced significantly by pretreatment with either the cold compound 8 or with the selective serotonin reuptake inhibitor (SSRI) citalopram, but not by the selective norepinephrine reuptake inhibitor nisoxetine, thus underlining its in vivo binding selectivity and specificity for SERT. Imaging experiments in baboons demonstrated that the uptake pattern of [{sup 11}C]AFA in the baboon brain is consistent with the known distribution of SERT, with highest activity levels in the midbrain and thalamus, followed by striatum, hippocampus, and cortical regions. Activity levels in the baboon brain peaked at 15-40 min after radioligand injection, indicating a fast uptake kinetics for [{sup 11}C]AFA. Pretreatment of the baboon with citalopram (4 mg/kg) significantly reduced the specific binding of [{sup 11}C]AFA in all SERT-containing brain regions. Kinetic analysis revealed that the regional equilibrium specific to non-specific partition coefficients (V{sub 3}&apos

  6. A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA)

    A new serotonin transporter (SERT) ligand, [11C]2-[2-(dimethylaminomethylphenylthio)]-5-fluorophenylamine (10, [11C]AFA), was synthesized and evaluated as a candidate PET radioligand in pharmacological and pharmacokinetic studies. As a PET radioligand, AFA (8) can be labeled with either C-11 or F-18. In vitro, AFA displayed high affinity for SERT (Ki 1.46±0.15 nM) and lower affinity for norepinephrine transporter (NET, Ki 141.7±47.4 nM) or dopamine transporter (DAT, Ki >10,000 nM). [11C]AFA (10) was prepared from its monomethylamino precursor 9 by reaction with high specific activity [11C]methyl iodide. Radiochemical yield was 43±20% based on [11C]methyl iodide at end of bombardment (EOB, n = 10) and specific activity was 2,129 ± 1,369 Ci/mmol at end of synthesis (EOS, n = 10). Biodistribution studies in rats indicated that [11C]AFA accumulated in brain regions known to contain high concentrations of SERT. Binding in SERT-rich brain regions was reduced significantly by pretreatment with either the cold compound 8 or with the selective serotonin reuptake inhibitor (SSRI) citalopram, but not by the selective norepinephrine reuptake inhibitor nisoxetine, thus underlining its in vivo binding selectivity and specificity for SERT. Imaging experiments in baboons demonstrated that the uptake pattern of [11C]AFA in the baboon brain is consistent with the known distribution of SERT, with highest activity levels in the midbrain and thalamus, followed by striatum, hippocampus, and cortical regions. Activity levels in the baboon brain peaked at 15-40 min after radioligand injection, indicating a fast uptake kinetics for [11C]AFA. Pretreatment of the baboon with citalopram (4 mg/kg) significantly reduced the specific binding of [11C]AFA in all SERT-containing brain regions. Kinetic analysis revealed that the regional equilibrium specific to non-specific partition coefficients (V3'') of [11C]AFA are similar to those of [11C]McN5652, but lower than those of [11C]AFM or [11C

  7. Ex Vivo and In Vivo Evaluation of the Norepinephrine Transporter Ligand [11C]MRB for Brown Adipose Tissue Imaging

    Introduction: It has been suggested that brown adipose tissue (BAT) in humans may play a role in energy balance and obesity. We conducted ex vivo and in vivo evaluation using [11C]MRB, a highly selective NET (norepinephrine transporter) ligand for BAT imaging at room temperature, which is not achievable with [18F]FDG. Methods: PET images of male Sprague–Dawley rats with [18F]FDG and [11C]MRB were compared. Relative [18F]FDG or [11C]MRB retention at 20, 40 and 60 min post-injection was quantified on awake rats after exposing to cold (4 °C for 4 h) or remaining at room temperature. Rats pretreated with unlabeled MRB or nisoxetine 30 min before [11C]MRB injection were also assessed. The [11C]MRB metabolite profile in BAT was evaluated. Results: PET imaging demonstrated intense [11C]MRB uptake (SUV of 2.9 to 3.3) in the interscapular BAT of both room temperature and cold-exposed rats and this uptake was significantly diminished by pretreatment with unlabeled MRB; in contrast, [18F]FDG in BAT was only detected in rats treated with cold. Ex vivo results were concordant with the imaging findings; i.e. the uptake of [11C]MRB in BAT was 3 times higher than that of [18F]FDG at room temperature (P = 0.009), and the significant cold-stimulated uptake in BAT with [18F]FDG (10-fold, P = 0.001) was not observed with [11C]MRB (P = 0.082). HPLC analysis revealed 94%–99% of total radioactivity in BAT represented unchanged [11C]MRB. Conclusions: Our study demonstrates that BAT could be specifically labeled with [11C]MRB at room temperature and under cold conditions, supporting a NET-PET strategy for imaging BAT in humans under basal conditions.

  8. Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FXC-Pro

    As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [11C]acetate and [11C]palmitate, can be automated on the GE Tracerlab FXC-Pro by utilizing Grignard reactions. Radiochemical purities of the [11C]acetate and the [11C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n=3) and 10% (n=5), respectively. These data comprise the validation trials for site qualification of clinical production of both radiopharmaceuticals. -- Graphical abstract: Automated syntheses of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FXC-Pro are reported. Radiochemical purities of the [11C]acetate and the [11C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n=3) and 10% (n=5), respectively.

  9. The Buecherer-Strecker synthesis of D- and L-(1-11C)tyrosine and the in vivo study of 0100L-(1-11C)tyrosine in human brain using positron emission tomography

    The synthesis of D- and L-(1-11C)tyrosine, starting with 11C-cyanide, is reported. DL-(1-11C)tyrosine was prepared by the Buecherer-Strecker reaction, from carrier added 11C-cyanide with an incorporation of 80% in 20 min. The isolation of the pure D- and L-amino acid isomers from the enantiomeric mixture was accomplished within 15 min by preparative HPLC using a chiral stationary phase and a phosphate buffer as the mobile phase. Typically, the total synthesis time was 50 min (including purification) from end of trapping of 11C-cyanide, with a radiochemical yield of D- and L-amino acid of 40%-60%. The D- and L-(1-11C)tyrosine were both obtained optically pure, with a carrier added specific activity of 0.3-0.5 Ci/mmol and a radiochemical purity better than 99%. The 11C labelled L-tyrosine was used in an in vivo study in the human brain using positron emission tomography (PET). (orig.)

  10. Automated radiosynthesis of [11C]morphine for clinical investigation

    To meet a multiple-dose clinical evaluation of the P-gp modulation of [11C]morphine delivery into the human brain, radiosynthesis of [11C]morphine was accomplished on an automated system by N-methylation of normorphine with [11C]CH3I. 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/μmol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28).

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

    The cocaine analogue RTI-121 (3β-(4-iodophenyl)tropane-2β-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 [11C]RTI-55 (2↔-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester) but showed a much greater selectivity for the dopamine compared with the 5-HT uptake site. The results indicate that [11C]RTI-121 could be used in preference to [11C]RTI-55 in man. Experimentally, [11C]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

  12. Radiotracer synthesis from [11C]-iodomethane: a remarkably simple captive solvent method

    A new method of [11C]-methylation is described, which attains the goals of simplicity, high radiochemical yields, speed, versatility, and automation. A standard high performance liquid chromatography (HPLC) injection loop on a standard HPLC injection valve is loaded with a solution (80 μL) of precursor (0.3-1.0 mg) in dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (+ base if required). At ambient temperature [11C]-iodomethane is passed through the loop for 3-4 min with >90% trapping of activity. After a further 1-5 min, the contents of the loop are quantitatively injected onto the HPLC column for purification. Radiochemical yields are equal to or superior to conventional solution methods in all cases, even though no heat is applied. [11C]-labeled radiotracers that have been prepared by this method for human or animal studies include Raclopride, N-methylspiperone, Ro 15-1788, FLB 457, RTI-32, Rolipram, SCH 23390, and SKF 82957. Since no vials, transfer lines, cooling, heating, or sealing valves are required, no transfer losses occur, yields are high, and cleanup is minimal, this 'loop method' is ideal for most radiopharmaceuticals prepared from [11C]-iodomethane

  13. Synthesis and preclinical evaluation of the radiolabeled P-glycoprotein inhibitor [11C]MC113

    Objectives: With the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with 11C and evaluated using small-animal PET. Methods: [11C]MC113 was synthesized by reaction of O-desmethyl MC113 with [11C]methyl triflate. Small-animal PET was performed with [11C]MC113 in FVB wild-type and Mdr1a/b(-/-) mice (n = 3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n = 5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15 mg/kg). Results: Brain uptake of [11C]MC113, expressed as area under the time-activity curve from time 0 to 60 min (AUC0-60), was moderately but not significantly increased in Mdr1a/b(-/-) compared with wild-type mice (mean ± SD AUC0-60, Mdr1a/b(-/-): 88 ± 7 min, wild-type: 62 ± 6 min, P = 0.100, Mann Whitney test). In the tumor model, AUC0-60 values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC50) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375 ± 60 nM for MC113 versus 8.5 ± 2.5 nM for tariquidar. Conclusion: [11C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [11C]MC113 was only to a low extent effluxed by Pgp. However, [11C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors.

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

    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

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

    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.

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

    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.

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

    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 [11C]cyanide followed by acid hydrolysis to afford [11C]GVG with high radiochemical yields (> 35%, not optimized) and high specific activity (2-5 Ci/micromol). The [11C]cyanide trapping was achieved at minus5 C with a mixture of Kryptofix and K2CO3 without using conventional aqueous trapping procedure [7]. At this temperature, the excess NH3 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

  18. A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors

    Padda, Sukhmani K.; Krupitskaya, Yelena; Chhatwani, Laveena; Fisher, George A; Colevas, Alexander D.; San Pedro-Salcedo, Melanie; Decker, Rodney; Latz, Jane E.; Wakelee, Heather A.

    2011-01-01

    Purpose Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated. Methods This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with...

  19. The gene expression profile of CD11c

    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

  20. 11C-PET imaging reveals transport dynamics and sectorial plasticity of oak phloem after girdling

    Veerle eDe Schepper

    2013-06-01

    Full Text Available Carbon transport processes in plants can be followed non-invasively by repeated application of the short-lived positron-emitting radioisotope 11C, a technique which has rarely been used with trees. Recently, positron emission tomography (PET allowing 3D visualisation has been adapted for use with plants. To investigate the effects of stem girdling on the flow of assimilates, leaves on first order branches of two-year-old oak (Quercus robur L. trees were labelled with 11C by supplying 11CO2-gas to a leaf cuvette. Magnetic resonance imaging gave an indication of the plant structure, while PET registered the tracer flow in a stem region downstream from the labelled branches. After repeated pulse labelling, phloem translocation was shown to be sectorial in the stem: leaf orthostichy determined the position of the phloem sieve tubes containing labelled 11C. The observed pathway remained unchanged for days. Tracer time-series derived from each pulse and analysed with a mechanistic model showed for two adjacent heights in the stem a similar velocity but different loss of recent assimilates. With either complete or partial girdling of bark within the monitored region, transport immediately stopped and then resumed in a new location in the stem cross-section, demonstrating the plasticity of sectoriality. One day after partial girdling, the loss of tracer along the interrupted transport pathway increased, while the velocity was enhanced in a non-girdled sector for several days. These findings suggest that lateral sugar transport was enhanced after wounding by a change in the lateral sugar transport path and the axial transport resumed with the development of new conductive tissue

  1. Erlotinib-induced Rosacea-like Dermatitis.

    Rezaković, Saida; Paštar, Zrinjka; Bukvić Mokos, Zrinka; Pavliša, Gordana; Kovačević, Suzana

    2016-04-01

    Skin and skin adnexa toxicities are the most common side effects associated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and occur in most patients receiving this therapy. The majority of these cutaneous side effects are transient, reversible, and dose dependent. Although these symptoms are in general not severe, they significantly affect quality of life and can have a serious effect on treatment compliance as well as the treatment regimen. The most common early symptoms present as papulopustules on an erythematous base, usually localized in seborrheic areas. This clinical presentation is commonly described as "acneiform", although these adverse reactions have clinical presentations, such as rosacea-like and seborrheic-like dermatitis. In this context, we report a case of a 77-year-old man with a medical history of planocellular lung cancer with ipsilateral pulmonary metastasis and mediastinum infiltration who received erlotinib as a third-line therapy, presenting with centrofacial rosaceiform rash as a side effect associated with the use of EGFR-TKIs. The patient had a negative previous history of rosacea. Therefore, symptoms probably occurred as an adverse reaction due to the oncological therapy. Current terminology of early cutaneous adverse reactions caused by EGFR-TKIs refers to "acneiform" or "papulopustular" lesions, excluding less common side effects such as rosacea-like dermatitis so these symptoms might be overlooked and misdiagnosed. Thus, we would like to emphasize the importance of developing a more accurate classification of terms in order to provide early detection of all possible cutaneous side effects, including less common ones, providing specific and timely treatment, and allowing continuation of drug therapy. PMID:27149133

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

    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 presenc...

  3. Human whole-body biodistribution and dosimetry of a new PET tracer, [11C]ketoprofen methyl ester, for imagings of neuroinflammation

    Introduction: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, 11C-labeled ketoprofen methyl ester ([11C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [11C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [11C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. Methods: [11C]KTP-Me was synthesized by rapid C-[11C]methylation of [11C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of > 99% and specific activity of > 25 GBq/μmol at injection. Six young healthy male humans were injected with [11C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. Results: No adverse effects were observed during PET scanning after [11C]KTP-Me injection. [11C]KTP-Me was rapidly metabolized to 11C-labeled ketoprofen ([11C]KTP) within 2–3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7 μSv/MBq, which was comparable to other 11C-labeled radiopharmaceuticals

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

    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

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

    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)

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

    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)

  7. On the chemistry of 11C recoil atoms in alkyl halogenides and hydrogen halides

    The gas phase reactions of 11C recoil atoms which were produced by the nuclear reaction 14N(p,α)11C, were investigated in this present work in mixtures of N2 with CH3Cl, CH3Br and CH3I as well as with HCl, HBr and HI. The radiochemical yields of the gaseous reaction products were determined by radiogaschromatography. By using different columns, the carrier-free compounds produced could be clearly identified. Higher boiling products which occured in the present systems as wall activities were detected in some cases by means of high-pressure liquid chromotography. The formation of the products is discussed in the light of known recoil chemical reactions (abstraction, insertion) where attention is paid to the influence of O2 inhibitors and radiation dose effects. The quite considerable radiochemical yield of 11C-labelled methyl iodide in the N2/HI system enables the development of an on-line system for the recoil synthesis of larger amounts of activity of this important methylating agent for fast 11C labelling. A system was thus developed consisting of a gas dosing unit, target, gas purification system, and collector apparatus which enables the optimization of the product conditions by varying different parameters (proton energy, beam intensity, gas composition) and which enables the production of 11CH3-I activity quantities upto 90 mCi within a radiation and collecting time of 40 minutes at beam intensities of 20 μa and a proton input energy of 16 to 20 MeV. Specific activities of approx. 300 mCi/μmol are achieved. (orig.)

  8. Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

    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...

  9. An automated SPE-based high-yield synthesis of [11C]acetate and [11C]palmitate: no liquid–liquid extraction, solvent evaporation or distillation required

    Introduction: An automated method is described for the rapid and high-yield synthesis of two of the most commonly used radioactive fatty acids: [11C]acetate and [11C]palmitate. Methods: Reaction of [11C]CO2 with the respective Grignard reagents in diethyl ether solution proceeded for 2 min at 40°C. Quenching of the reaction and liberation of nonreacted [11C]CO2 occurred upon addition of a fourfold molar excess of aqueous 0.1 M HCl (acetate) or nonaqueous HCl/Et2O (palmitate). Labeled products were then purified by adsorption to an Alumina-N Sep-Pak Plus cartridge and eluted with either aqueous NaH2PO4 solution (acetate) or 100% ethanol (palmitate). Results: High-performance liquid chromatography analysis confirmed that the radiochemical purity of each product was >98%, and decay-corrected radiochemical yields averaged 33% for [11C]palmitate and 40% for [11C]acetate. Conclusion: The method requires no liquid–liquid extraction, solvent evaporation or distillation capabilities and can be readily adapted to existing radiosynthesis modules.

  10. Reliable set-up for in-loop 11C-carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNO

    Aim of this work was the implementation of a generalized in-loop synthesis for 11C-carboxylations and subsequent 11C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-11C]WAY-100635 and, for the first time, [11C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNO were prepared with high reliability and satisfying outcome. - Highlights: • Generalized method for in-loop 11C-carboxylations implemented. • Grignard reactions successfully tested. • First in-loop procedure for [11C]-(+)PHNO established. • Satisfactory synthesis outcome for both [carbonyl-11C]WAY-100635 and [11C]-(+)PHNO. • No distillation for purification of intermediate required

  11. Synthesis of [1-11C]D-glucosamine and evaluation of its in vivo distribution in rat with PET

    D-Glucosamine is a structural unit of many biologically interesting macromolecules. To investigate the feasibility of using labelled D-glucosamine as a tracer for anabolic processes, a two-step synthetic procedure for specifically labelling D-glucosamine in position 1 with carbon-11 was developed. [11C]Cyanide was reacted with an imine precursor, N-benzyl-D-arabinosylamine, to generate the [1-11C]α-amino nitrile. Reduction to [1-11C]D-glucosamine was accomplished by catalytic hydrogenation using PdC12 and the N-benzyl group was simultaneously removed. The total synthesis time from end-of-trapping of [11C]cyanide was 40-45 min and the decay-corrected radiochemical yield was 5-10% after HPLC isolation. The biodistribution of [1-11C]D-glucosamine in rat following i.v. bolus injection was investigated using positron emission tomography and showed that the availability of this substance for CNS anabolism is low with the primary limitation being the intact blood-brain barrier. (Author)

  12. Alternative methods of making [11C]amides: Application to the preparation of 5-HT1A receptor radioligands

    Many ligands for brain 5-HT1A receptors contain an amide group that is subject to hydrolysis in vivo. In the development of radioligands for use with positron emission tomography (PET), labelling in the carbonyl function of an amide group may be advantageous for avoiding radioactive metabolites that would readily enter the brain to confound PET receptor measurements. Several methods of labelling secondary and tertiary amides in their carbonyl functions with 11C (T1/2 = 20.4 min) have been developed over the past two decades or so. These methods include reaction of a [carbonyl-11C]acid chloride, [carboxyl-11C]magnesium halide carboxylate or [carboxyl-11C]acid with an amine or reaction of [11C]carbon monoxide with an amine plus an aryl halide, alkyl halide or aryl triflate. Some of these processes are successfully promoted with microwaves, palladium complexes, light or thermally initiated radicals. These methods are surveyed here and especially exemplified from research on the development of 5-HT1A receptor radioligands for brain imaging applications with PET. (author)

  13. Preparation and biodistribution in mice of [11C]carfentanil

    A potent μ-opioid agonist, [11C]carfentanil, was prepared by the methylation of carfentanil carboxylic acid with [11C]methyl iodide in order to study brain μ-opioid receptors by positron emission tomography. Synthesis (including purification) was completed within 25 min and the radiochemical yield was approximately 40%. The radiochemical purity of the product was more than 99% and its specific activity was 3.7-7.4 GBq/μmol. Biodistribution studies performed in mice after intravenous injection showed a high brain uptake and rapid blood clearance, so a high brain/blood ratio of 1.5-1.8 was found from 5 to 30 min. Regional cerebral distribution studies in the mouse showed a significantly higher uptake of [11C]carfentanil by the thalamus and striatum than by the cerebellum, with the radioactivity in the striatum disappearing more rapidly than that in the thalamus. Treatment with naloxone significantly reduced the uptake of [11C]carfentanil by the thalamus and striatum. These results indicate that [11C]carfentanil binds specifically to brain μ-opioid receptors. (author)

  14. Improved synthesis of 1-[11C]D-glucose

    An improved synthesis of 1-[11C]D-glucose is described. The major improvement is achieved when a 0.033 M borate buffer at pH 8.1 is used to effect the condensation of D-arabinose with NH411CN. Subsequent reduction of the 1-[11C]D-aldonitriles gives the epimeric sugars 1-[11C]D-glucose and 1-[11C]D-mannose in a ratio of 1.8 ± 0.57 as the major products. The decay corrected radiochemical yield is about 30% for the mixture of sugars. The overall synthesis, starting with the production of NH411CN, is conducted in a dedicated remote system. The remote gantry was easy to build with commercially available valves and glassware, and has been practically trouble-free after more than 2 years of use. Improved purification and quality control of the final product uses ion chromatography and a more efficient resin, and is also described. A preliminary PET study on a macaque has been conducted using 1-[11C]D-glucose obtained with this new improved synthesis. (author)

  15. 18F fluoroethylations: different strategies for the rapid translation of 11C-methylated radiotracers

    Introduction: The translation of 11C-labeled compounds into their respective 18F-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 18F-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 11C-methylated tracers into their 18F-fluoroethylated analogs sharing the same precursor molecules. Methods: Ten methods for the preparation and purification of different 18F-fluoroethylating agents were compared. Subsequently, five 18F-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-[18F]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 18F-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

  16. The synthesis of [O-methyl-{sup 11}C]venlafaxine: a non-classical, fast-acting antidepressant

    Gee, A.D.; Gjedde, A. [Aarhus Univ. Hospital, PET Center, Aarhus (Denmark); Smith, D.F. [Aarhus Univ. Psychiatric Hospital, Inst. for Biological Psychiatry, Risskov (Denmark)

    1997-01-01

    As part of our program to develop PET tracers for the 5-HT reuptake site, venlafaxine, a non-classical, fast-acting antidepressant, was selected as a candidate for labelling with {sup 11}C for in vivo evaluation. [O-methyl-{sup 11}C]venlafaxine was produced by the alkylation of O-desmethyl venlafaxine with [{sup 11}C]methyl iodide followed by HPLC purification and formulation. Radiochemically pure [O-methyl-{sup 11}C]venlafaxine was obtained in a 30 {+-} 5% decay corrected radiochemical yield and a specific activity > 50 GBq/{mu}mol(1.4 Ci/{mu}mol) at the end of synthesis. For a typical production starting with 46 GBq (1.3 Ci) [{sup 11}C]CO{sub 2}, 5.2 GBq (140 mCi) [O-methyl-{sup 11}C]venlafaxine was obtained as a sterile, formulated solution in a synthesis time of 30 min (counted from EOB). (Author).

  17. Optimization and Biodistribution of [(11)C]-TKF, An Analog of Tau Protein Imaging Agent [(18)F]-THK523.

    Kong, Yanyan; Guan, Yihui; Hua, Fengchun; Zhang, Zhengwei; Lu, Xiuhong; Zhu, Tengfang; Zhao, Bizeng; Zhu, Jianhua; Li, Cong; Chen, Jian

    2016-01-01

    The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [(18)F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [(11)C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [(11)C]-TKF can be made by reaction precursor with [(11)C]MeOTf or (11)CH₃I, but [(11)C]MeOTf will give us higher labeling yields and specific activity. [(11)C]-TKF presented better brain uptake in normal mouse than [(18)F]-THK523 (3.23% ± 1.25% ID·g(-1) vs. 2.62% ± 0.39% ID·g(-1) at 2 min post-injection). The acute toxicity studies of [(11)C]-TKF were unremarkable. PMID:27527142

  18. Synthesis and in vivo distribution in the rat of a dopamine agonist: N-([11C]methyl)norapomorphine

    A method for the rapid production and purification of 10,11-dihydroxy-N-([11Cmethyl)norapomorphine ([11C]APO), a dopamine agonist (DA), is described. The potency of this ligand for studying the D2-receptors was examined. The label was introduced by N-methylation of norapomorphine hydrobromide with no-carrier-added (n.c.a.) [11C]CH3I, produced from cyclotron-produced [11C]carbon dioxide. In 60 min (EOB) a radiochemical yield of 15% (corrected for decay) was achieved, based on [11C]CH3I. The specific activity ranged from 5 to 11 GBq/μmol. The distribution, after intravenous injection, was studied in rats. The radioactivity level in the striatum was higher than in the cerebellum and frontal cortex and was decreased after D2-blockade. The highest uptake ratio (1.47) was found at 30 min after injection. Dopamine depletion with reserpine did increase the striatum/cerebellum ratio at a low dosage of [11C]APO (10 nmol/kg). High uptakes of [11C]apomorphine were found in the lungs, liver and kidneys. (author)

  19. Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man.

    van der Doef, Thalia F; Golla, Sandeep Sv; Klein, Pieter J; Oropeza-Seguias, Gisela M; Schuit, Robert C; Metaxas, Athanasios; Jobse, Ellen; Schwarte, Lothar A; Windhorst, Albert D; Lammertsma, Adriaan A; van Berckel, Bart Nm; Boellaard, Ronald

    2016-06-01

    [(11)C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N'-(3-[(11)C]methoxy-phenyl)-N'-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [(11)C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [(11)C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [(11)C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [(11)C]GMOM could be used for quantification of N-methyl-d-aspartate receptors. PMID:26661185

  20. [11C]-MeJDTic: a novel radioligand for κ-opioid receptor positron emission tomography imaging

    Introduction: Radiopharmaceuticals that can bind selectively the κ-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 κ-opioid receptor in vitro, was labeled with carbon-11 and evaluated for in vivo imaging the κ-opioid receptor in mice. Methods: [11C]-MeJDTic was prepared by methylation of JDTic with [11C]-methyl triflate. The binding of [11C]-MeJDTic to κ-opioid receptor was investigated ex vivo by biodistribution and competition studies using nonfasted male CD1 mice. Results: [11C]-MeJDTic exhibited a high and rapid distribution in peripheral organs. The uptake was maximal in lung where the κ receptor is largely expressed. [11C]-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 κ referring agonist), morphine (a μ agonist) and naltrindole (a δ antagonist) demonstrated that this uptake was the result of specific binding to the κ-opioid receptor. Conclusion: These findings suggested that [11C]-MeJDTic appeared to be a promising selective 'lead' radioligand for κ-opioid receptor PET imaging

  1. Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer’s disease patients

    Forsberg, Anton; Juréus, Anders; Cselényi, Zsolt; Eriksdotter, Maria; Freund-Levi, Yvonne; Jeppsson, Fredrik; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Schou, Magnus; Andersson, Jan; Johnström, Peter; Varnäs, Katarina; Halldin, Christer; Farde, Lars

    2013-01-01

    Purpose The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD). Methods In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. Results AZD2995, AZD2184 and PI...

  2. Preclinical PET Neuroimaging of [11C]Bexarotene.

    Rotstein, Benjamin H; Placzek, Michael S; Krishnan, Hema S; Pekošak, Aleksandra; Collier, Thomas Lee; Wang, Changning; Liang, Steven H; Burstein, Ethan S; Hooker, Jacob M; Vasdev, Neil

    2016-01-01

    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 [(11)C]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 [(11)C]bexarotene were studied in rats and nonhuman primates by PET imaging under baseline and greater target occupancy conditions. [(11)C]Bexarotene displays a high proportion of nonsaturable uptake in the brain and is unsuitable for RXR occupancy measurements in the central nervous system. PMID:27553293

  3. In vivo binding of [{sup 11}C]nemonapride to sigma receptors in the cortex and cerebellum

    Ishiwata, Kiichi E-mail: ishiwata@pet.tmig.or.jp; Senda, Michio

    1999-08-01

    Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative dopamine D{sub 2}-like receptor ligand in pharmacological and neurological studies, and {sup 11}C-labeled analog ([{sup 11}C]NEM) has been developed for positron emission tomography (PET) studies. The aim of this study was to evaluate whether [{sup 11}C]NEM binds in vivo to sigma receptors. [{sup 11}C]NEM and one of six dopamine D{sub 2}-like receptor ligands or seven sigma receptor ligands were co-injected into mice, and the regional brain uptake of [{sup 11}C]NEM was measured by a tissue dissection method. The striatal uptake of [{sup 11}C]NEM was reduced by D{sub 2}-like receptor ligands, NEM, haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D{sub 4} receptor ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D{sub 2}-like receptor ligands with affinity for sigma receptors, but not by raclopride. Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)-pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3-PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the striatal uptake, five of them with relatively higher affinity significantly reduced the [{sup 11}C]NEM uptake by the cortex, and four of them reduced that by the cerebellum. We concluded that [{sup 11}C]NEM binds in vivo not only to dopamine D{sub 2}-like receptors in the striatum but also to sigma receptors in other regions such as cortex and cerebellum.

  4. Captive solvent [11C]acetate synthesis in GMP conditions

    Reliable procedure for the production of 1-[11C]acetate in GMP conditions was developed based on a combination of the captive-solvent Grignard reaction conducted in the sterile catheter followed by the convenient solid-phase extraction purification on a series of ion-exchange cartridges. The described procedure proved to be reliable in more than 30 patient productions. The process provides stable radiochemical yields (65% EOB) of sodium acetate (1-[11C]) of the Ph.Eur. quality (radiochemical purity better than 95%) in a short time (5 min)

  5. Synthesis of [O-methyl-{sup 11}C]fluvoxamine - a potential serotonin uptake site radioligand

    Matarrese, M.; Soloviev, D.; Fazio, F. [Consiglio Nazionale delle Ricerche, Milan (Italy); Todde, S.; Magni, F.; Colombo, D.; Galli Kienle, M. [Department of Medical Chemistry and Biochemistry, Milan (Italy)

    1997-06-01

    5-Methoxy-1-[4-(trifluoromethyl)-phenyl]-1-pentanone-0-(2-amin oethyl)oxime (fluvoxamine), a potent clinically used antidepressant, was labelled with carbon-11 (t{sub 1/2} = 20.4 min) as a potential radioligand for the non-invasive assessment of serotonin uptake sites in the human brain with positron emission tomography (PET). The two-step radiochemical synthesis consisted of 0-methylation of an amino-protected desmethyl precursor with [{sup 11}C]methyl iodide under mild conditions in the presence of tetrabutylammonium hydroxide in acetonitrile, followed by deprotection with trifluoroacetic acid. 5-[{sup 11}C]Methoxy-1-[4-(trifluoromethyl)-phenyl]-1-pentanone-0-(2-a minoethyl)oxime was obtained in > 98% radiochemical purity in 40 min with a radiochemical yield of 4 {+-} 2% (non-decay corrected) and a specific radioactivity of 1 {+-} 0.5 Ci/{mu}mol. 5-Hydroxy-1-[4-(trifluoromethyl)-phenyl]-1-pentanone-0-[2-(tert-bu toxycarbonylamino)ethyl]oxime, the precursor for the radiosynthesis of [{sup 11}C]fluvoxamine, was prepared by a convenient three-set synthesis from the pharmaceutical form of fluvoxamine maleate by converting it into the free base, demethylation by trimethyliodosilane and introduction of the BOC-protective group with di-tert-butyl dicarbonate. (author).

  6. Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand

    The potential of a 11C-labeled selective sigma1 receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([11C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma1 receptors in the central nervous system and peripheral organs. [11C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [11C]CH3I, with the decay-corrected radiochemical yield of 39±5% based on [11C]CH3I and with the specific activity of 53±17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [11C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [11C]SA6298 by these organs except for the small intestine, but significant displacement of [11C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (-)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma1 receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [11C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [11C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma1 receptors. The saturable brain uptake of [11C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a

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

    Introduction: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into 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) that has Food and Drug Administration 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) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [11C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [11C-cyano]letrozole fraction in 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. Brain kinetics was not affected by coinjection 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

  8. Development of a fully automated and GMP compliant [11C]-radiosynthesis module

    Full text: The automation of routinely produced and GMP compliant [11C]radiotracers is an important process for any PET centre. Automation allows for highly reproducible synthesis with large amount of radioactivity while minimising exposure to the radiochemist. GMP compliance is required to meet the upcoming regulations for PET radio-pharmaceutical production. Based on these requirements, we have designed at the ARMC PET Centre, a reliable and versatile chemistry module for the production of [11C]-radiotracers. This aim has been achieved by using disposable manifolds and tubing in conjunction with newly prepared reaction vessels. Cross-contamination by subsequent productions of different radiophammaceuticals is then fully prevented. Automation of the synthesis sequences is performed by a PLC Siemens (CPU216), and the programs allows for the production of different radiotracers according to their specific reaction parameters such as temperature and reaction time. Relevant digital and analog parameters are measured throughout the synthesis and fed back to the PLC to allow clear monitoring of the process by the user. Our new radiosynthesis module is based on the conventional production of [11C]-methyliodide, followed by its reaction with the relevant precursor at room temperature using the loop technique. The crude labelled product is then automatically injected into the HPLC column. After collection of the pure product, the mobile phase is discarded, and the final product eluted with ethanol and formulated with a physiological solution using the 'SepPak technique'. The synthesis time is about 30 minutes including purification and formulation of the product. The [11C]-radiosynthesis prototype module is currently under evaluation. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  9. 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

    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.)

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

    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.

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

    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/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-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)

  12. [11C]Sorafenib: Radiosynthesis and preclinical evaluation in tumor-bearing mice of a new TKI-PET tracer

    Introduction: Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo. Methods: Synthetic methods were developed in which sorafenib was labeled at two different positions, followed by a metabolite analysis in rats and a PET imaging study in tumor-bearing mice. Results: [methyl-11C]-1 and [urea-11C]-1 were synthesized in yields of 59% and 53%, respectively, with a purity of > 99%. The identity of the products was confirmed by coinjection on HPLC with reference sorafenib. In an in vivo metabolite analysis [11C]sorafenib proved to be stable. The percentage of intact product in blood–plasma after 45 min was 90% for [methyl-11C]-1 and 96% for [urea-11C]-1, respectively. Due to the more reliable synthesis, further research regarding PET imaging was performed with [methyl-11C]-1 in nude mice bearing FaDu (head and neck cancer), MDA-MB-231 (breast cancer) or RXF393 (renal cancer) xenografts. Highest tracer accumulation at a level of 2.52 ± 0.33 %ID/g was observed in RXF393, a xenograft line extensively expressing the sorafenib target antigen Raf-1 as assessed by immunohistochemistry. Conclusion: In conclusion, we have synthesized [11C]sorafenib as PET tracer, which is stable in vivo and has the capability to be used as PET tracer for imaging in tumor-bearing mice

  13. Automatic synthesis of [11C]raclopride and initial clinical application on Parkinson's disease

    Full text: Background/Aim: Parkinson's disease is a common neurological degenerative disease. The change of dopamine D2 receptors is of great importance in its mechanism. [11C]Raclopride is a PET radiotracer for dopamine D2 receptor. Establish a methods for automatic synthesis of [11]Raclopride on GE Tracerlab FXc. Investigate the changes of dopamine D2 receptor in Parkinson's disease patients after the introduction of piribedil with [11C]Raclopride PET/CT. Materials and Methods: [11'C]CO2 produced by cyclotron was converted to [11C]CH3I via gas phase iodination. [11C]CH3I was bubbled into a reactor vessel contained 0.2ml of DMSO with 1mg precursor, demethyl-Raclopride, and 5μI of 8M NaOH. The reactor was heated to 700C for 5 minutes for labelling reaction and then the product was separated by HPLC. The HPLC eluent containing the product diluted by 80ml of water and passed through a plus C 18 cartridge. The cartridge was washed with 10 ml water, 2 times then eluted by I ml of ethanol. The ethanol was diluted with 10ml saline and the mixture passed through a 0.22μm filter to a sterilized vial. The final product was analysed by HPLC and had sterilization and pyrogen test. 6 patients of Parkinson's disease without therapy, 4 patients after piribedil therapy with mean age of 66.6±7.20 and mean disease duration 2.6±1.33 years and 4 volunteers with mean age of 69.75±2.63 took part in the test. All of them underwent [11C]raclopride PET/CT examination, with ten serial 1 minute, ten 2-minutes, and thereafter six 3.33-minutes time frames over the period of 50 minutes, providing a total of 26 time frames. After reconstruction, 16-26 frames were selected to calculate the bindings. The [11C]raclopride binding index was defined as an uptake ratio of striatum to cerebellum. Result: Total synthesis time from transfer [11C]CO, to synthesis finished is 40 min. The final yield without decay corrected is about 5%. The radiochemistry purity is more than 98%. The final product

  14. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer

    Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy. The medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed. Physicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The

  15. Mild synthesis of [N-methyl-11C]-isovaleroyl-(L)-carnitine. The usefulness of a tritium approach

    The title carnitine derivative was labelled both with [11C]methyl iodide and [3H]methyl iodide. The former was synthesized in order to improve the knowledge of the acyl carnitines fate in humans. The latter was synthesized, at approximately the same concentration level as that of the former, in order to optimize its radiosynthesis, taking advantage from the long half-life of the tritium

  16. Mild synthesis of [N-methyl-{sup 11}C]-isovaleroyl-(L)-carnitine. The usefulness of a tritium approach

    Angelini, G.; Carnevaletti, F.; Margonelli, A.; Corsi, G. [Istituto di Chimica Nucleare - C.N.R., C.P. 10, Rome (Italy); Ragni, P. [Istituto di Chimica Nucleare -- C.N.R., C.P. 10 -- 00016 Monterotondo Stazione, Roma, (Italy); Fazio, F.; Todde, S. [Istituto di Neuroscienze e Bioimmagini - C.N.R., H.S. Raffaele, Milan (Italy); Tinti, O. [Sigma-Tau, Industrie Farmaceutiche Riunite S.p.A., Pomezia, Rome (Italy)

    1999-02-01

    The title carnitine derivative was labelled both with [{sup 11}C]methyl iodide and [{sup 3}H]methyl iodide. The former was synthesized in order to improve the knowledge of the acyl carnitines fate in humans. The latter was synthesized, at approximately the same concentration level as that of the former, in order to optimize its radiosynthesis, taking advantage from the long half-life of the tritium.

  17. Hot reactions in the systems 11C/H2O(l), 11C/H2O-NH3(l) and 13N/H2O(g)

    The chemical reactions of hot 11C with liquid water and a water ammonia mixture of mass ratio 3:1 and of 13N with water vapour were studied at T = 295 K. 11C was generated by the nuclear processes 16O(p,α,pn)11C and 14N(p,α)11C. 13N was produced via the 16O(p,α)13N nuclear reaction. The proton radiation dose was varied from D* = 2.8x10-3 to 0.28 eV per target molecule for the system 11C/H2O(l), from D* = 2.2 to 32 eV for the system 11C/H2O-NH3(l) and from D* = 0.13 to 6.2 eV for the system 13N/H2O(g), in order to follow radiolytic changes of the reaction products. Products of the system 11C/H2O(l) were 11CO2 (98-100% radiochemical yield) and 11CO (max. 1.5%). For the system 11C/H2O-NH3(l) six products (11CO2, 11CO, H11COOH, 11CH2O, 11CH3OH and 11CH4) were observed at radiation doses up to D* = 32 eV. In the system 13N/H2O(g) five products were detected: 13NO2, 13NO, 13NN, 13NNO and some 13NH3. 13NO is the main product at lowest doses with radiochemical yields exceeding 45%. With increasing radiolysis 13NO is changed to 13NO2. At higher doses 13NN becomes the main product. The system 11C/H2O-NH3(l) seems to bear some importance for the production of labelled precursors for the synthesis of radiopharmaceuticals. The interesting products 11CH2O and 11CH3OH are still formed under intensive irradiation which is necessary for the production of high radioactivities for nuclear medical application. (orig./RB)

  18. 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)

    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.

  19. Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD)

    Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I1R and I2R). I2Rs are associated with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomography (PET) probes for I2Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I2Rs by PET. We labeled a selective I2R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with 11C and performed the first imaging of I2Rs by PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Methods: [11C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [11C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated. Results: [11C]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 [11C]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 I2R. The radioactivity levels and VT values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control. Conclusion: [11C]FTIMD showed specific binding to I2Rs in rat brains with a high density of I2R.

  20. An efficient synthesis of 2-[carbonyl-11C]acetamido-2-deoxy-D-glucopyranose (N-[carbonyl-11C]acetyl-D-glucosamine)

    A rapid chemical synthesis of 2-[carbonyl-11C]acetamido-2-deoxy-D-glucopyranose (N-[carbonyl-11C]acetyl-D-glucosamine) starting from [11C]carbon dioxide is described. The total time required for the synthesis, the radiochemical yield, and purity of the titled sugar are ca. 60 min, 49.5% (based on [carbonyl-11C] acetic acid), and >98%, respectively. (author)

  1. Short-lived positron emitter labeled radiotracers - present status

    The preparation of labelled compounds is important for the application of positron emission transaxial tomography (PETT) in biomedical sciences. This paper describes problems and progress in the synthesis of short-lived positron emitter (11C, 18F, 13N) labelled tracers for PETT. Synthesis of labelled sugars, amino acids, and neurotransmitter receptors (pimozide and spiroperidol tagged with 11C) is discussed in particular

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

    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.

  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

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

    In this study, we compared the ability of [11C]CIC, [11C]MeDAS and [11C]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 [11C]CIC, [11C]MeDAS and [11C]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 [11C]CIC make this tracer less suitable for in vivo PET imaging. [11C]PIB showed good uptake in the white matter in the cerebrum, but [11C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [11C]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 [11C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [11C]CIC and [11C]PIB. (orig.)

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

    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. PMID:26958085

  6. Cryogenic molecular separation system for radioactive 11C ion acceleration

    A 11C molecular production/separation system (CMPS) has been developed as part of an isotope separation on line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive 11C ion beams. In the ISOL system, 11CH4 molecules will be produced by proton irradiation and separated from residual air impurities and impurities produced during the irradiation. The CMPS includes two cryogenic traps to separate specific molecules selectively from impurities by using vapor pressure differences among the molecular species. To investigate the fundamental performance of the CMPS, we performed separation experiments with non-radioactive 12CH4 gases, which can simulate the chemical characteristics of 11CH4 gases. We investigated the separation of CH4 molecules from impurities, which will be present as residual gases and are expected to be difficult to separate because the vapor pressure of air molecules is close to that of CH4. We determined the collection/separation efficiencies of the CMPS for various amounts of air impurities and found desirable operating conditions for the CMPS to be used as a molecular separation device in our ISOL system

  7. A new visualization technique for the study of the accumulation of photoassimilates in wheat grains using [11C]CO2

    Non-invasive real-time visualization of the accumulation of photoassimilates in the grains of an ear of wheat using [11C]CO2 and positron emitting tracer imaging system (PETIS) was studied. [11C]CO2 was supplied to the center of a fully expanded leaf of a wheat plant for an initial 10 min, and the transportation of 11C-labeled photoassimilates into the grains of the ear was monitored for 120 min using the PETIS. Each grain was clearly identified in the obtained animation. The 11C-labeled photoassimilates arrived at the ear from the [11C]CO2-absorbing leaf within 53 min from the time of supplying [11C]CO2. After that, grains appeared on the image one by one from the basal part and full images of the grains appeared within 20 min. The time course of the accumulation of photoassimilates into each grain showed a different profile. Furthermore, the PETIS data suggested that the photo-condition of the ear plays an important role in the transportation of photoassimilates in wheat. PETIS can be used to visualize the dynamics of the substances in a living plant in real time and can exhibit the time course analysis of substances, such as the transportation, distribution, and accumulation

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

    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)

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

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

  10. Transition metal mediated [(11) C]carbonylation reactions: recent advances and applications.

    Kealey, Steven; Gee, Antony; Miller, Philip W

    2014-04-01

    [(11) C]Carbon monoxide is undoubtedly a highly versatile radiolabelling synthon with many potential applications for the synthesis of positron emission tomography (PET) tracer molecules and functional groups, but why has it not found more applications in the PET radiolabelling arena? Today, (11) CO radiolabelling is still primarily viewed as a niche area; however, there are signs that this is beginning to change as some of the technical and chemistry challenges of producing, handling and reacting (11) CO are overcome. This mini review covers the more recent developments of (11) CO-labelling chemistry and is focused on palladium and rhodium-mediated carbonylation reactions that are growing in importance and finding wider application for carbon-11 PET radiotracer development. PMID:24425679

  11. Assessment of cerebral P-glycoprotein expression and function with PET by combined [11C]inhibitor and [11C]substrate scans in rats

    Introduction: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood–brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer’s or Parkinson’s disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [11C]elacridar and [11C]tariquidar to visualize Pgp density in rat brain with PET. Methods: Rats underwent a first PET scan with [11C]elacridar (n = 5) or [11C]tariquidar (n = 6) followed by a second scan with the Pgp substrate (R)-[11C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3 mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution (VT) of radiotracers in different brain regions. Results: Brain PET signals of [11C]elacridar and [11C]tariquidar were very low (∼ 0.5 standardized uptake value, SUV). There was a significant negative correlation between VT and K1 (i.e. influx rate constant from plasma into brain) values of [11C]elacridar or [11C]tariquidar and VT and K1 values of (R)-[11C]verapamil in different brain regions which was consistent with binding of [11C]inhibitors to Pgp and efflux of (R)-[11C]verapamil by Pgp. Conclusion: The small Pgp binding signals obtained with [11C]elacridar and [11C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain

  12. In vivo evaluation of [{sup 11}C]SA4503 as a PET ligand for mapping CNS sigma{sub 1} receptors

    Kawamura, Kazunori; Ishiwata, Kiichi E-mail: ishiwata@pet.tmig.or.jp; Tajima, Hisashi; Ishii, Shin-Ichi; Matsuno, Kiyoshi; Homma, Yoshio; Senda, Michio

    2000-04-01

    The potential of the {sup 11}C-labeled selective sigma{sub 1} receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([{sup 11}C]SA4503) was evaluated in vivo as a positron emission tomography (PET) ligand for mapping sigma{sub 1} receptors in rats. SA4503 is known to have a high affinity (IC{sub 50} 17.4 nM) and a higher selectivity (sigma{sub 1}/sigma{sub 2}=103) for the sigma{sub 1} receptor. A high and increasing brain uptake of [{sup 11}C]SA4503 was found. Pre-, co- and postinjection of cold SA4503 significantly decreased uptake of [{sup 11}C]SA4503 in the brain, spleen, heart, lung, and kidney in which sigma receptors are present as well as in the skeletal muscle. In the blocking study with one of four sigma receptor ligands including haloperidol, (+)-pentazocine, SA4503, and (-)-pentazocine (in the order of their affinity for sigma{sub 1} receptor subtype), SA4503 and haloperidol significantly reduced the brain uptake of [{sup 11}C]SA4503 to approximately 30% of the control, but the other two benzomorphans did not. A high specific uptake of [{sup 11}C]SA4503 by the brain was also confirmed by ex vivo autoradiography (ARG) and PET. Ex vivo ARG showed a higher uptake in the vestibular nucleus, temporal cortex, cingulate cortex, inferior colliculus, thalamus, and frontal cortex, and a moderate uptake in the parietal cortex and caudate putamen. Peripherally, the blocking effects of the four ligands depended on their affinity for sigma{sub 1} receptors. No {sup 11}C-labeled metabolite was detected in the brain 30 min postinjection, whereas approximately 20% of the radioactivity was found as {sup 11}C-labeled metabolites in plasma. These results have demonstrated that the {sup 11}C-labeled sigma{sub 1} receptor ligand [{sup 11}C]SA4503 has a potential for mapping sigma{sub 1} receptors in the central nervous system and peripheral organs.

  13. Imaging of Carrageenan-Induced Local Inflammation and Adjuvant-Induced Systemic Arthritis with [11C]PBR28 PET

    Shao, Xia; Wang, Xueding; English, Sean J; Desmond, Timothy; Sherman, Phillip S; Quesada, Carole A; Piert, Morand R

    2013-01-01

    Introduction [11C]PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models. Methods Acute inflammation was induced by local Carrageenan-injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [11C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak 11C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [11C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures. Results LPS-stimulated macrophages displayed dose-dependent increased [11C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of Carrageenan-treated paws was significantly increased compared to controls. Also, the [11C]PBR28 uptake ratio of Carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [11C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips. Conclusions Based on our initial data, [11C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving

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

    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.

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

    Introduction: We reinvestigated the synthesis of [N-methyl-11C]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-11C]vorozole. Methods: Norvorozole was alkylated with [11C]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 (13C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-11C]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-11C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-11C]vorozole binds to aromatase. [N-methyl-11C]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-11C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

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

    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.

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

    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

  18. [11C]quinidine and [11C]laniquidar PET imaging in a chronic rodent epilepsy model: Impact of epilepsy and drug-responsiveness

    Introduction: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [11C]quinidine and [11C]laniquidar. Methods: Metabolism and brain kinetics of both [11C]quinidine and [11C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into “responders” and “non-responders”. Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar. Results: [11C]quinidine was metabolized rapidly, whereas [11C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [11C]quinidine and [11C]laniquidar brain concentrations. In the epileptic subgroup “non-responders”, brain uptake of [11C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [11C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. Conclusions: We confirmed that both [11C]quinidine and [11C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [11C]quinidine between drug-resistant and drug-sensitive animals

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

    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......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...

  20. Comparison of the binding of the irreversible monoamine oxidase tracers, [{sup 11}C]clorgyline and [{sup 11}C]l-deprenyl in brain and peripheral organs in humans

    Fowler, Joanna S. E-mail: fowler@bnl.gov; Logan, Jean; Wang, Gene-Jack; Volkow, Nora D.; Telang, Frank; Ding Yushin; Shea, Colleen; Garza, Victor; Xu Youwen; Li Zizhong; Alexoff, David; Vaska, Paul; Ferrieri, Richard; Schlyer, David; Zhu Wei; John Gatley, S

    2004-04-01

    The monoamine oxidase A and B (MAO A and B) radiotracers [{sup 11}C]clorgyline (CLG) and [{sup 11}C]L-deprenyl (DEP) and their deuterium labeled counterparts (CLG-D and DEP-D) were compared to determine whether their distribution and kinetics in humans are consistent with their physical, chemical and pharmacological properties and the reported ratios of MAO A:MAO B in post-mortem human tissues. Irreversible binding was consistently higher for DEP in brain, heart, kidneys and spleen but not lung where CLG >DEP and not in thyroid where there is no DEP binding. The generally higher DEP binding is consistent with its higher enzyme affinity and larger free fraction in plasma while differences in regional distribution for CLG and DEP in brain, heart, thyroid and lungs are consistent with different relative ratios of MAO A and B in humans.

  1. Improved automated synthesis and preliminary animal PET/CT imaging of 11C-acetate

    To study a simple and rapid automated synthetic technology of 11C-acetate (11C- AC), automated synthesis of 11C-AC was performed by carboxylation of MeMgBr/tetrahydrofuran (THF) on a polyethylene loop with 11C-CO2, followed by hydrolysis and purification on solid-phase extraction cartridges using a 11C-Choline/Methionine synthesizer made in China. A high and reproducible radiochemical yield of above 40% (decay corrected) was obtained within the whole synthesis time about 8 min from 11C-CO2. The radiochemical purity of 11C-AC was over 95%. The novel, simple and rapid on-column hydrolysis-purification procedure should adaptable to the fully automated synthesis of 11C-AC at several commercial synthesis module. 11C-AC injection produced by the automated procedure is safe and effective, and can be used for PET imaging of animals and humans. (authors)

  2. Synthesis of [11C]salicylic acid and related compounds and their biodistribution in mice

    For in vivo measurement of the hydroxyl radical (%s·OH), we synthesized [11C]salicylic acid, [11C]O-acetylsalicylic acid and [11C]2-methoxybenzoic acid by carboxylation of 2-bromomagnesiumanisol using [11C]CO2. The radiochemical yield of [11C]salicylic acid, [11C]O-acetylsalicylic acid and [11C]2-methoxybenzoic acid calculated from trapped [11C]CO2 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 11C 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

  3. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    McLeod, C; Bagust, A; Boland, A; Hockenhull, J; Dundar, Y; Proudlove, C; Davis, H; Green, J; Macbeth, F; Stevenson, J; Walley, T; Dickson, R

    2009-06-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of erlotinib for the treatment of relapsed non-small cell lung cancer (NSCLC), according to its licensed indication, based upon the evidence submission from Roche Products to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence includes one randomised controlled trial (RCT) (BR21) investigating the effect of erlotinib versus placebo, which demonstrates that erlotinib significantly increases median overall survival, progression-free survival and response rate compared with placebo. The majority of patients in the trial experienced non-haematological drug-related adverse effects. Currently there are no trials that directly compare erlotinib with any other second-line chemotherapy agent. For the purposes of indirect comparison, the manufacturer's submission provides a narrative discussion of data from 11 RCTs investigating the use of docetaxel. From these data the manufacturer concludes that erlotinib has similar clinical efficacy levels to docetaxel but results in fewer serious haematological adverse events; however, it is difficult to compare the results of BR21 with those of the docetaxel trials or with current UK clinical practice because, for example, the BR21 patient population is younger than that expected to present in UK clinical practice and almost half of the BR21 participants received erlotinib as third-line chemotherapy, with third-line chemotherapy being rare in the UK. The manufacturer's submission included a three-state model comparing erlotinib with docetaxel, reporting an incremental cost-effectiveness ratio (ICER) of 1764 pounds per quality-adjusted life-year (QALY) gained for erlotinib compared with docetaxel. Rerunning the manufacturer's economic model with varied parameters and assumptions increases the ICER to in excess of 52

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

    Jensen, Lars Henrik

    2016-01-01

    . 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...... erlotinib was negative, but suggested improved progression free survival in cholangiocarcinoma patients when added to gemcitabine and oxaliplatin. There is no clinical, radiological or molecular marker to guide therapy, but genomic profiling and basket or umbrella trials may be useful in identifying the...

  5. PET study using [11C]FTIMD with ultra-high specific activity to evaluate I2-imidazoline receptors binding in rat brains

    Introduction: We recently developed a selective 11C-labeled I2-imidazoline receptor (I2R) ligand, 2-(3-fluoro-4-[11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). [11C]FTIMD showed specific binding to I2Rs in rat brains having a high density of I2R, as well as to I2Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [11C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I2R in rat brains, we synthesized [11C]FTIMD with ultra-high specific activity and evaluated its binding. Methods: [11C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide, which was produced by iodination of [11C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated. Results: [11C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470±1660 GBq/μmol at end of synthesis, n=11) for injection. In the PET study, distribution volume (VT) values in all the brain regions investigated whether I2R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29–45% decrease). Differences in VT values between control and BU224-pretreated rats using [11C]FTIMD with ultra-high specific activity were greater than those using [11C]FTIMD with normal specific activity (17–34% decrease) in all brain regions investigated. Conclusion: Quantitative PET using [11C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I2R expression in the brain.

  6. Pharmacokinetic Analysis of 11C-PBR28 in the Rat Model of Herpes Encephalitis: Comparison with (R)-11C-PK11195.

    Parente, Andrea; Feltes, Paula Kopschina; Vállez García, David; Sijbesma, Jurgen W A; Moriguchi Jeckel, Cristina M; Dierckx, Rudi A J O; de Vries, Erik F J; Doorduin, Janine

    2016-05-01

    (11)C-PBR28 is a second-generation translocator protein (TSPO) tracer with characteristics supposedly superior to the most commonly used tracer for neuroinflammation, (R)-(11)C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of (11)C-PBR28 in rodent models of neuroinflammation have been published yet. Therefore, this study aimed to evaluate (11)C-PBR28 as a tool for detection and quantification of neuroinflammation in preclinical research and to compare its imaging properties with (R)-(11)C-PK11195. The herpes simplex encephalitis (HSE) model was used for induction of neuroinflammation in male Wistar rats. Six or 7 d after virus inoculation, a dynamic (11)C-PBR28 or (R)-(11)C-PK11195 PET scan with arterial blood sampling was obtained. Pharmacokinetic modeling was performed on the PET data and analyzed using volumes of interest and a voxel-based approach. Volume-of-interest- and voxel-based analysis of (11)C-PBR28 images showed overexpression of TSPO in brain regions known to be affected in the HSE rat model. (11)C-PBR28 was metabolized faster than (R)-(11)C-PK11195, with a metabolic half-life in plasma of 5 and 21 min, respectively. Overall, (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in detecting neuroinflammation. The binding potential (BPND) of (11)C-PBR28 was significantly higher (P < 0.05) in the medulla (176%), pons (146%), midbrain (101%), hippocampus (85%), thalamus (73%), cerebellum (54%), and hypothalamus (49%) in HSE rats than in control rats, whereas (R)-(11)C-PK11195 showed a higher BPND only in the medulla (32%). The BPND in control animals was not significantly different between tracers, suggesting that the nonspecific binding of both tracers is similar. (11)C-PBR28 was more sensitive than (R)-(11)C-PK11195 in the detection of TSPO overexpression in the HSE rat model, because more brain regions with significantly increased tracer uptake could be found, irrespective of the data

  7. [11C]-metformin distribution in the liver and small intestine using dynamic PET in mice demonstrates tissue-specific transporter dependency

    Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen;

    2016-01-01

    ) 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 PET with C11-labelled metformin ([11C]-metformin) in mice to investigate the role of...

  8. Automated synthesis of [11C]choline, a positron-emitting tracer for tumor imaging

    (β-Hydroxyethyl)tri([11C]methyl)ammonium ([11C]choline) is a tracer very effective in imaging various human tumors using positron emission tomography (PET). We have constructed a computer-controlled [11C]choline synthetic apparatus which carries out the whole process of synthesis and product purification automatically. The setup is simple and the process quick. In 20 min, 11 GBq of [11C]choline (chloride) is obtainable from 26 GBq of [11C]CO2. The final product is a sterile and pyrogen-free [11C]choline 'injection'

  9. Binding kinetics of 11C-N-methyl piperidyl benzilate (11C-NMPB) in a rhesus monkey brain using the cerebellum as a reference region

    The binding kinetics of' 11C-N-methyl piperidyl benzilate (11C-NMPB) in rhesus monkey brain were studied using animal positron emission tomography (PET) (SHR2000). This study is intended to assess the validity of the method using the cerebellum as a reference region, and to evaluate the effects of anesthesia on 11C -NMPB binding. Two monkeys, anesthetized with ketamine, received intravenous 11C-NMPB alone (370-760 MBq, 11C-NMPB accumulated densely in the striatum and cerebral cortex with time. In contrast, the tracer accumulation significantly decreased with increased doses of nonradioactive NMPB. In the cerebellum, on the other hand, the accumulation of 11C-NMPB remained low and the tracer was slowly eliminated from the brain following the injection. 11C-NMPB binding in the cerebellum was barely affected by the increased dose of nonradioactive NMPB. We thus concluded that the specific 11C-NMPB binding was negligible in the cerebellum, and performed simplified evaluation of 11C-NMPB binding in each brain region by a graphical method using the cerebellum as a reference region. PET was conducted 26 times, in total both in ketamine-anesthetized and awake monkeys (n=3 each). Measurements of 11C-NMPB binding showed good run-to-run reproducibility within individual animals. When 11C-NMPB binding was compared between ketamine-treated and awake animals, a significant increase in 11C-NMPB binding was observed in the striatum but not in other brain regions of ketamine-treated animals. (author)

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

    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 [11C]tariquidar and [11C]elacridar with the Pgp substrate radiotracer (R)-[11C]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 [11C]tariquidar (n = 7), [11C]elacridar (n = 6) and (R)-[11C]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. [11C]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 (AUC0-60) were 38.8 ± 2.2 min and 25.0 ± 5.3 min (p = 0.016, Wilcoxon matched pairs test). [11C]Elacridar and (R)-[11C]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 [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil. Among the tested radiotracers, [11C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [11C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. (orig.)

  11. 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

    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.)

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

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]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 [11C]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 (11C]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

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

    Galynker, I; Schlyer, D J; Dewey, S L; Fowler, J S; Logan, J; Gatley, S J; MacGregor, R R; Ferrieri, R A; Holland, M J; Brodie, J; Simon, E; Wolf, A 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-[11C]methyl]buprenorphine ([11C]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 [11C]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 (Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]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. PMID:8782244

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

    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.

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

    Purpose: The purpose of this work was to define the optimal margins for gadolinium-enhanced T1-weighted magnetic resonance imaging (Gd-MRI) and T2-weighted MRI (T2-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 ([11C]MET-PET) findings. Methods and Materials: Computed tomography (CT), MRI, and [11C]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 T2-MRI of the CTV (CTV-T2) were compared with the extent of [11C]MET-PET (CTV--[11C]MET-PET) uptake by using CT--MRI or CT--[11C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T2 (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T2, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [11C]MET-PET and the relationship between CTV-T2 (x mm) and CTV-- [11C]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-T2 (20 mm) (96.4%) was significantly higher than that of the other CTV-T2 (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T2 (x = 20 mm). Conclusions: It is necessary to use a margin of at least 2 cm for CTV-T2 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 T2-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

  16. 11C-Acetate PET imaging for renal cell carcinoma

    In this study, we investigated the effectiveness of positron emission tomography (PET) with 11C-acetate (AC) for evaluation of renal cell carcinoma. Enrolled in the study were 20 patients with suspected renal tumour, one of whom had three renal lesions. In all, 22 renal lesions were evaluated. Following administration of 350 MBq (10 mCi) of AC, whole-body PET images were obtained. Based on these PET findings, kidney lesions were scored as positive or negative. The PET results were correlated with the CT findings and histological diagnosis after surgery. In 18 patients, 20 tumours were diagnosed as renal cell carcinoma. Lesions in the remaining two patients were diagnosed as complicated cyst without malignant tissue. Of the 20 renal cell carcinomas. 14 (70%) showed positive AC PET findings; 6 were negative. The two patients with complicated cyst had negative AC PET findings. Of the 20 renal cell carcinomas, 19 were clear-cell carcinoma and 1 was a papillary cell carcinoma. This papillary cell carcinoma showed high AC uptake. AC demonstrates marked uptake in renal cell carcinoma. These preliminary data show that AC is a possible PET tracer for detection of renal cancer. (orig.)

  17. Comparative evaluation of two serotonin transporter ligands in the human brain: [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine

    Takano, Akihiro; Suhara, Tetsuya; Sudo, Yasuhiko; Inoue, Makoto; Ichimiya, Tetsuya; Yasuno, Fumihiko [Brain Imaging Project, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan); CREST, Japan Science and Technology Corporation, Kawaguchi (Japan); Hashimoto, Kenji [Welfide Corporation, Iruma (Japan); Zhang, Ming-Rong; Suzuki, Kazutoshi [Brain Imaging Project, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan)

    2002-10-01

    Serotonin (5-HT) is considered to be an important transmitter underlying mood and behaviour. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. A number of ligands have been developed to visualise the 5-HT transporter in vivo, but only a few have successfully visualised specific binding in vivo. In this study, we comparatively evaluated two ligands for 5-HT transporter, [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine, in the human brain. Brain uptake of [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine was measured with PET in 15 healthy volunteers. Second PET scans were performed after pretreatment with the potent 5-HT reuptake inhibitor clomipramine. Data were analysed as regional brain uptake as well as whole brain uptake. In six healthy volunteers uptake of the two ligands was also measured in the lung since it is one of the high-uptake organs in the body. In the brain, high accumulation was observed in the thalamus and striatum, the regions known to contain high densities of 5-HT transporter, for both [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine. The average ratio of thalamus to cerebellum uptake at 90 min after the tracer injection was approximately 1.6 for [{sup 11}C](+)McN5652 and 1.7 for [{sup 11}C]cyanoimipramine, while the ratios obtained after pretreatment with clomipramine were approximately 1.2. However, the whole brain uptake of [{sup 11}C](+)McN5652 was approximately twice that of [{sup 11}C]cyanoimipramine, while the lung uptake of [{sup 11}C](+)McN5652 was approximately half that of [{sup 11}C]cyanoimipramine. Both [{sup 11}C](+)McN5652 and [{sup 11}C]cyanoimipramine showed sufficient specific binding for performance of a quantitative analysis in the brain. [{sup 11}C](+)McN5652 could be superior because of its higher distribution to the brain. (orig.)

  18. Comparative evaluation of two serotonin transporter ligands in the human brain: [11C](+)McN5652 and [11C]cyanoimipramine

    Serotonin (5-HT) is considered to be an important transmitter underlying mood and behaviour. Abnormalities of the 5-HT transporter have been suggested in mood disorders, since it is one of the major binding sites of antidepressants. A number of ligands have been developed to visualise the 5-HT transporter in vivo, but only a few have successfully visualised specific binding in vivo. In this study, we comparatively evaluated two ligands for 5-HT transporter, [11C](+)McN5652 and [11C]cyanoimipramine, in the human brain. Brain uptake of [11C](+)McN5652 and [11C]cyanoimipramine was measured with PET in 15 healthy volunteers. Second PET scans were performed after pretreatment with the potent 5-HT reuptake inhibitor clomipramine. Data were analysed as regional brain uptake as well as whole brain uptake. In six healthy volunteers uptake of the two ligands was also measured in the lung since it is one of the high-uptake organs in the body. In the brain, high accumulation was observed in the thalamus and striatum, the regions known to contain high densities of 5-HT transporter, for both [11C](+)McN5652 and [11C]cyanoimipramine. The average ratio of thalamus to cerebellum uptake at 90 min after the tracer injection was approximately 1.6 for [11C](+)McN5652 and 1.7 for [11C]cyanoimipramine, while the ratios obtained after pretreatment with clomipramine were approximately 1.2. However, the whole brain uptake of [11C](+)McN5652 was approximately twice that of [11C]cyanoimipramine, while the lung uptake of [11C](+)McN5652 was approximately half that of [11C]cyanoimipramine. Both [11C](+)McN5652 and [11C]cyanoimipramine showed sufficient specific binding for performance of a quantitative analysis in the brain. [11C](+)McN5652 could be superior because of its higher distribution to the brain. (orig.)

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

    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.

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

    N-(4-fluorobut-2-yn-1-yl)-2β-carbomethoxy-3β-(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 [11C]PR04.MZ ([11C]-1) has been developed using GMP compliant equipment. An adult female Papioanubis baboon was studied using a test-retest protocol with [11C]-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 [11C]-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. [11C]-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.

  1. Radiosynthesis of [11C]SNAP-7941—the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1)

    The melanin concentrating hormone (MCH) system is a new target to treat human disorders. Our aim was the preparation of the first PET-tracer for the MCHR1. [11C]SNAP-7941 is a carbon-11 labeled analog of the published MCHR1 antagonist SNAP-7941. The optimum reaction conditions were 2 min reaction time, ≤25 °C reaction temperature, and 2 mg/mL precursor (SNAP-acid) in acetonitrile, using [11C]CH3OTf as methylation agent. [11C]SNAP-7941 was prepared in a reliable and feasible manner with high radiochemical yields (2.9±1.6 GBq; 11.5±6.4% EOB, n=15). - Graphical Abstract: Radiosynthesis of [11C]SNAP-7941. Highlights: ► Synthesis of the first PET-tracer for the MCHR1 [11C]SNAP-7941. ► High radiochemical incorporation yields 2.9±1.6 GBq; 11.5±6.4% EOB. ► Preparation and characterization of a suitable labeling precursor; SNAP-acid.

  2. Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab.

    Brand, Toni M; Dunn, Emily F; Iida, Mari; Myers, Rebecca A; Kostopoulos, Kellie T; Li, Chunrong; Peet, Chimera R; Wheeler, Deric L

    2011-09-01

    The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab, and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib, and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical successes, however many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in steady-state expression of EGFR, HER2, and HER3 receptors as well as increased signaling through the MAPK and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation, and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared to vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increase rates of apoptosis. The work presented herein suggests that 1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and 2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing

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

    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.

  4. Synthesis of carbon-11 labelled calcium channel antagonists

    A useful synthetic approach to carbon-11 labelled 1,4-dihydropyridines is described. Carbon-11 labelled calcium channel antagonists 11C-Nifedipine, 11C-Nisoldipine, 11C-nitrendipine and 11C-CF3-Nifedipine were synthesized by a modified Hantzsch method using protected carboxy functions. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the corresponding potassium salts and subsequent methylation with 11CH3I produced the labelled compounds in very good chemical and radiochemical yields (94%). (author)

  5. Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib.

    Truong, Duy Hieu; Tran, Tuan Hiep; Ramasamy, Thiruganesh; Choi, Ju Yeon; Lee, Hee Hyun; Moon, Cheol; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2016-04-01

    To improve the solubility and oral bioavailability of erlotinib, a poorly water-soluble anticancer drug, solid self-emulsifying drug delivery system (SEDDS) was developed using solid inert carriers such as dextran 40 and Aerosil® 200 (colloidal silica). The preliminary solubility of erlotinib in various oils, surfactants, and co-surfactants was determined. Labrafil M2125CS, Labrasol, and Transcutol HP were chosen as the oil, surfactant, and co-surfactant, respectively, for preparation of the SEDDS formulations. The ternary phase diagram was evaluated to show the self-emulsifying area. The formulations were optimized using the droplet size and polydispersity index (PDI) of the resultant emulsions. Then, the optimized formulation containing 5% Labrafil M2125CS, 65% Labrasol, and 30% Transcutol was spray dried with dextran or Aerosil® and characterized for surface morphology, crystallinity, and pharmacokinetics in rats. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) exhibited the amorphous form or molecular dispersion of erlotinib in the formulations. The pharmacokinetic parameters of the optimized formulations showed that the maximum concentration (C max) and area under the curve (AUC) of erlotinib were significantly increased, compared to erlotinib powder (p < 0.05). Thus, this SEDDS could be a promising method for enhancing the oral bioavailability of erlotinib. PMID:26238806

  6. Erlotinib-associated Near-fatal Interstitial Pneumonitis in A Patient with Relapsed Lung Adenocarcinoma

    Chun-Liang Chou

    2010-02-01

    Full Text Available Erlotinib (Tarceva® is a human epidermal growth factor receptor (EGFR tyrosinekinase inhibitor used for treatment of locally advanced or metastatic non-small cell lung cancer(NSCLC after failure of at least one prior chemotherapy regimen. Interstitial lung disease,associated with gefitinib (Iressa® use, has been reported in approximately 1% ofpatients worldwide. However, the adverse pulmonary effects of erlotinib remain poorly documented.Reviewed English language publications in MEDLINE and PubMed suggest thatthis report is to be the first case report in English of a histologically-confirmed case of nearfatalinterstitial pneumonitis with acute lung injury, associated with erlotinib, in East Asianpatients. Physicians are hereby encouraged to promptly evaluate new or worsening pulmonarysymptoms so that they can detect early radiographic signs of pulmonary toxicity inpatients on erlotinib. If toxicity is confirmed, erlotinib should be discontinued and thepatient treated appropriately. The case presented suggests that the outcome of erlotinib-associatedpulmonary toxicity with acute respiratory failure may be favorable with adequateearly management.

  7. Effects of cocaine on [11C]norepinephrine and [11C]β-CIT uptake in the primate peripheral organs measured by PET

    The toxic properties of cocaine are related to both the central and peripheral effects. To identify possible lethal mechanisms and the accumulation of cocaine in various organs, the effects of cocaine on [11C] norepinephrine and cocaine congener [11C]β-CIT uptake in Cynomolgus monkeys were measured by positron emission tomography (PET). Cocaine (5 mg/kg) noticeably inhibited [11C] norepinephrine uptake in the heart. The uptake of [11C]β-CIT in the heart and lung was reduced by pretreatment with cocaine. There was a significant uptake in the liver which was increased following cocaine pretreatment. The results of this study confirm that cocaine blocks the neuronal uptake of norepinephrine in sympathetic nerve terminals in the myocardium. The effect of cocaine on [11C]β-CIT uptake indicates that the binding sites in the heart and lung are saturable, while the uptake mechanism in the liver is different from those of the heart and lung. (author)

  8. The influence of mass of [11C]-laniquidar and [11C]-N-desmethyl-loperamide on P-glycoprotein blockage at the blood–brain barrier

    Introduction: An earlier report suggested that mass amount of PET tracers could be an important factor in brain uptake mediated by P-glycoprotein. Thereby, this study investigated the influence of mass dose of laniquidar, desmethyl-loperamide and loperamide on the P-glycoprotein-mediated brain uptake of, respectively, [11C]-laniquidar and [11C]-N-desmethyl-loperamide ([11C]-dLop). Methods: Wild-type (WT) mice were injected intravenously with solutions of 5.6 MBq [11C]-laniquidar (either no carrier added or 60 mg/kg laniquidar added) or with 5.0–7.4 MBq [11C]-dLop (either no carrier added or 3 mg/kg desmethyl loperamide). Mice were killed, and brain and blood were collected, weighted and counted for radioactivity. Mdr1a(−/−) knockout mice were incorporated as the control group. Results: Injection of 11C-laniquidar (no carrier added) in WT mice resulted in a statistical significant lower brain uptake (0.7±0.2 %ID/g) compared to the carrier-added formulation (60 mg/kg laniquidar) (3.1±0.3 %ID/g) (P=.004), while no statistical difference could be observed between formulations of [11C]-dLop. The [11C]-laniquidar and [11C]-dLop blood concentrations were not significantly different between the tested formulations in WT mice. In control animals, no effect of mass amount on brain uptake of both tracers could be demonstrated. Conclusions: These results demonstrate the bivalent character of laniquidar, acting as a substrate at low doses and as a blocking agent for P-glycoprotein transport in the brain at higher doses. In comparison, no difference was observed in [11C]-dLop uptake between carrier- and no-carrier-added formulations, which confirms that desmethyl-loperamide is a substrate of P-glycoprotein at the blood–brain barrier.

  9. Evaluation of [11C]SA5845 and [11C]SA4503 for imaging of sigma receptors in tumors by animal PET

    Sigma receptors are expressed in a wide variety of tumor cell lines, and are expressed in proliferating cells. A radioligand for the visualization of sigma receptors could be useful for selective detection of primary tumors and their metastases, and for non-invasive assessment of tumor proliferative status. To this end we evaluated two sigma receptor ligands, [11C]SA5845 and [11C]SA4503. In an in vitro study, AH109A hepatoma showed moderate densities of sigma1 and sigma2 receptors, and VX-2 carcinoma showed a high density of sigma2 receptors: Bmax (fmol/mg protein) for sigma1 vs. sigma2, 1,700 vs. 1,200 for AH109A hepatoma and 800 vs. 10,000 for VX-2 carcinoma. In a cell growth assay in vitro, neither SA5845 nor SA4503 (11C]SA5845 and [11C]SA4503 in AH109A tissues was accumulated over the first 60 minutes; however, the uptake of both tracers increased by co-injection with haloperidol as a sigma receptor ligand. On the other hand, in the PET studies of rabbits, the uptake of [11C]SA5845 in the VX-2 carcinoma was relatively higher than that of [11C]SA4503, because of a much higher density of sigma2 receptors compared to sigma1 receptors in the VX-2 tissue, and the uptake of both tracers in the VX-2 tissue was decreased by carrier-loading and pre-treatment with haloperidol ([11C]SA5845, 53% and 26%, respectively; [11C]SA4503, 41% and 22%, respectively at 30 minutes after injection). Therefore, [11C]SA5845 and [11C]SA4503 may be potential ligands for PET imaging of sigma receptor-rich tumors. (author)

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

    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)

  11. Further investigation on the radiosynthesis of α-[11C]methyl-tryptophan

    Improved procedures for the radiosynthesis of α-[11C]-methyl-tryptophan and α-[11C]methyl-tryptophan methyl ester were studied. Following α-deprotonation of tryptophan methyl ester benzaldimine with LDA, 60 - 80% of no carrier added [11C]iodomethane was incorporated in 5 minutes at 27 - 30 oC. After HPLC purification, radiochemically pure α-[11C]methyl-tryptophan or its methyl ester was produced with minimum chemical contamination form tryptophan. The [11C]methyl-tryptophan synthesized, however, was found to be a racemate. (Author)

  12. Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice

    Introduction: Oseltamivir phosphate (Tamiflu) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this study was to evaluate [11C]oseltamivir and [11C]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for measuring their amounts in living brains. Methods: Whole-body biodistribution of [11C]oseltamivir and [11C]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice. Results: Between 1 and 60 min after injection of [11C]oseltamivir and [11C]Ro 64-0802, 0.20-0.06% and 0.39-0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25-0.05 for [11C]oseltamivir and 0.38-0.02 for [11C]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [11C]oseltamivir and [11C]Ro 64-0802 in the brains after [11C]oseltamivir injection. Conclusion: This study determined the distribution and metabolism of [11C]oseltamivir and [11C]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system

  13. Biodistribution and metabolism of the anti-influenza drug [{sup 11}C]oseltamivir and its active metabolite [{sup 11}C]Ro 64-0802 in mice

    Hatori, Akiko; Arai, Takuya; Yanamoto, Kazuhiko; Yamasaki, Tomoteru; Kawamura, Kazunori; Yui, Joji; Konno, Fujiko; Nakao, Ryuji; Suzuki, Kazutoshi [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences (NIRS), Inage-ku, Chiba 263-8555 (Japan); Zhang Mingrong [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences (NIRS), Inage-ku, Chiba 263-8555 (Japan)], E-mail: zhang@nirs.go.jp

    2009-01-15

    Introduction: Oseltamivir phosphate (Tamiflu) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this study was to evaluate [{sup 11}C]oseltamivir and [{sup 11}C]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for measuring their amounts in living brains. Methods: Whole-body biodistribution of [{sup 11}C]oseltamivir and [{sup 11}C]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice. Results: Between 1 and 60 min after injection of [{sup 11}C]oseltamivir and [{sup 11}C]Ro 64-0802, 0.20-0.06% and 0.39-0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25-0.05 for [{sup 11}C]oseltamivir and 0.38-0.02 for [{sup 11}C]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [{sup 11}C]oseltamivir and [{sup 11}C]Ro 64-0802 in the brains after [{sup 11}C]oseltamivir injection. Conclusion: This study determined the distribution and metabolism of [{sup 11}C]oseltamivir and [{sup 11}C]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system.

  14. In vivo imaging of astrocytosis in Alzheimer's disease: an 11C-L-deuteriodeprenyl and PIB PET study

    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 11C-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, 11C-labelled Pittsburgh Compound B (PIB) retention was determined. Results show a significantly higher 11C-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.)

  15. [{sup 14}C]Serotonin uptake and [O-methyl-{sup 11}C]venlafaxine kinetics in porcine brain

    Smith, D.F. E-mail: dfsmith@inet.uni2.dk; Hansen, S.B.; Oestergaard, L.; Gee, A.D.; Danielsen, E.; Ishizu, K.; Bender, D.; Poulsen, P.H.; Gjedde, A

    2001-08-01

    As part of our program of developing PET tracers for neuroimaging of psychotropic compounds, venlafaxine, an antidepressant drug, was evaluated. First, we measured in vitro rates of serotonin uptake in synaptosomes prepared from selected regions of porcine brain. Then, we determined the pharmacokinetics of venlafaxine, [O-methyl-{sup 11}C]-labeled for PET. Synaptosomal studies showed that the active uptake of [{sup 14}C]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphe region, and thalamus, and lowest rates in cortex and cerebellum. PET studies showed that the unidirectional rate of uptake of [O-methyl-{sup 11}C]venlafaxine from blood to brain was highest in the hypothalamus, raphe region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological conditions, the capillary permeability-surface area (PS) product for [O-methyl-{sup 11}C]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the apparent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitations of blood-brain transfer were observed, giving PS-products for water that were only ca. 50% higher than those of venlafaxine. Thus, under normal physiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited.

  16. Synthesis of L-[β-11C]amino acids using immobilized enzymes

    L-[β-11C]-3,4-dihydroxyphenylalanine(L-[β-11C]DOPA) and L-[β-11C]-5-hydroxytryptophan(L-[β-11C]-5-HTP) were synthesized in one step with immobilized thermostable enzymes (alanine racemase, D-amino acid oxidase, and β-tyrosinase or tryptophanase) on an aminopropyl-CPG carrier in a single column and by passing D,L-[3-11C]alanine through the column with coenzymes and other substrates. L-[β-11C]DOPA and L-[β-11C]-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

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

    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, [11C]3MPICA. We report here the in vivo evaluation of [11C]3MPICA in rats. Biodistribution analysis revealed that [11C]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%, P11C]3MPICA does not appear to be a promising PET radiotracer for in vivo use

  18. 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

    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.

  19. Synthesis and in vivo evaluation of [{sup 11}C]SA6298 as a PET sigma{sub 1} receptor ligand

    Kawamura, Kazunori; Ishiwata, Kiichi E-mail: ishiwata@pet.tmig.or.jp; Tajima, Hisashi; Ishii, Shin-Ichi; Shimada, Yuhei; Matsuno, Kiyoshi; Homma, Yoshio; Senda, Michio

    1999-11-01

    The potential of a {sup 11}C-labeled selective sigma{sub 1} receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([{sup 11}C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma{sub 1} receptors in the central nervous system and peripheral organs. [{sup 11}C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [{sup 11}C]CH{sub 3}I, with the decay-corrected radiochemical yield of 39{+-}5% based on [{sup 11}C]CH{sub 3}I and with the specific activity of 53{+-}17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [{sup 11}C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [{sup 11}C]SA6298 by these organs except for the small intestine, but significant displacement of [{sup 11}C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (-)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma{sub 1} receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [{sup 11}C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [{sup 11}C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma{sub 1} receptors. The saturable brain uptake of [{sup 11}C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a

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

    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.

  1. Strategy for improved [11C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [11C]DAA1106

    Introduction: The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [11C]DAA1106 ([11C]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 [11C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [11C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [11C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [11C]CH3I trapped. Evaluation of [11C]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 [11C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [11C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/μmol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [11C]DAA1106. In vivo microPET [11C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 μmol) 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 [11C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model

  2. The 5-HT2A receptor and serotonin transporter in Asperger’s Disorder: a PET study with [11C]MDL 100907 and [11C]DASB

    Girgis, Ragy R.; Slifstein, Mark; Xu, Xiaoyan; Frankle, W. Gordon; Anagnostou, Evdokia; Wasserman, Stacey; Pepa, Lauren; Kolevzon, Alexander; Abi-Dargham, Anissa; Laruelle, Marc; Hollander, Eric

    2011-01-01

    Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [11C]MDL 100907 and [11C]DASB to characterize the 5-HT2A receptor and serotonin transporter in Asperger’s Disorder. 17 individuals with Asperger’s Disorder (age = 34.3 ± 11.1 yr) and 17 healthy controls (age = 33.0 ± 9.6 yr) were scanned with [11C]MDL 100907. Of the 17 patients, eight (a...

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

    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.)

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

    R,S-N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methox y)-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 11C-labelled analogue as an in vivo tracer for VEGFR-2 expression in solid tumours. [11C]PAQ was synthesized by an N-methylation of desmethyl-PAQ using [11C]methyl iodide. The tracer's pharmacokinetic properties and its distribution in both subcutaneous and intraperitoneal tumour models were evaluated with positron emission tomography (PET). [18F]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 [18F]FDG and correlated well with variations in VEGFR-2 expression determined ex vivo by immunohistochemical analysis. These results suggest that [11C]PAQ has potential as a noninvasive PET tracer for in vivo imaging of VEGFR-2 expression in angiogenic ''hot spots''. (orig.)

  5. Enhancement of radiation sensitivity by erlotinib and celecoxib in A549 human lung cancer cell line

    Objective: To investigate the role of epidermal growth factor receptor and cyclooxygenase-2 pathways in the erlotinib and celecoxib enhanced radiation sensitivity in A549 human lung cancer cell line. Methods: IC20 of erlotinib and celecoxib on in A549 human lung cancer cells was measured by MTT assay, Clonogenic assays were used to evaluate the antitumor effects of the drugs and X-irradiation. Flow cytometry was used to assess the apoptosis and cell cycle alteration, and Western blot was used for the detection of Akt and phospho-Akt.Results Both erlotinib and celecoxib could inhibit the proliferation of A549 cells in vitro in a dose-dependent manner and their values of IC20 were (5.15 ± 0.14) and (40.32 ± 1.26) μmol/L, respectively. For radiation survival,the values of Dq, D0, SF2 of the combination of two drugs were lower than those of either drug (t=6.62, P<0.05). The SER of celecoxib, erlotinib and their combination were 1.299, 1.503 and 2.217, respectively. Flow cytometry assay showed that both celecoxib and erlotinib could enhance radiation-induced G0/G1 arrest, reduce the cell number in S phase, and enhance radiation-induced apoptosis, especially for the combination of drugs. Western blot assay showed that the expressions of Akt protein were similar in all groups. However, pAkt expression was suppressed by erlotinib and celecoxib, but promoted by radiation. pAkt had the lowest expression in the radiated cells with the treatment of two drugs (t=4.89, P<0.05). Conclusions: The erlotinib and/or celecoxib could enhance radiosensitivity probably by increasing cell apoptosis and reducing the number of S-phase cells with low radiosensitivity. (authors)

  6. Measurement of short-term 11C-thymidine activity in human head and neck tumours using positron emission tomography (PET)

    Tumour uptake of 11C-thymidine labeled in the methyl position was assessed after intravenous injection in 13 patients with head and neck tumours. This activity was compared to other tracers such as C15O, 13NH3 and C15O2. In every single case a 'positive' tumour image after injection of 11C-thymidine was obtained. Time-activity curves showed the initial activity to be followed by a rapid decrease over the first 10-15 min with an apparent plateau thereafter. A similar level of uptake was found in normal salivary gland regions and myocardium, while higher activities were noted in liver and kidney parenchyma. It is suggested that both blood flow and cellular metabolism can influence 11C-thymidine imaging in this class of human tumours. (orig.)

  7. Optimization of [11C]DASB-synthesis: Vessel-based and flow-through microreactor methods

    The intention for the present study was to implement a microfluidic set-up for N-11C-methylations in a flow-through microreactor device with [11C]DASB as model-compound and [11C]CH3I and [11C]CH3OTf, respectively, as 11C-methylation agents. Due to an observed “aging” effect of the 11C-methylation agents' solution, this goal was not achieved. Nevertheless, based on these observations, the time consumption for the vessel-based routine production of [11C]DASB was reduced (34±1 min) and RCY was increased to 45.1±4.6% (EOB; 5.2±0.95 GBq EOS). - Highlights: ► Aging effect of 11C-methylation agents observed. ► Microfluidic set-up for remote 11C-methylations questionable. ► Vessel-based approach was ameliorated. ► Radiochem. yield of [11C]DASB was increased to 45.1±4.6% (EOB; 5.2±0.95 GBq EOS).

  8. Non-HPLC methods for the production of 18F, 11C and 68Ga PET tracers

    Full text: The most popular PET radionuclides in routine clinical use are 11C and 18F, although other radionuclides, such as 68Ga, continue to make headlines. This is due to their well established chemistry, their utility for labeling low molecular weight compounds, and their ease of production in modern PET cyclotrons or via commercially available generators. Their relatively short half lives, along with the global trend toward Good Manufacturing Practice in PET drug production has necessitated the development of aseptic, robust and rapid labeling methodologies. This is achieved by the use of automated radiochemistry systems, which, in turn, has allowed radiosynthesis scale-up and multiple dose preparation. Major impediments to routine production of a number of useful 11C, 18F and 68Ga PET tracers, and to new tracer development, remain: 1) the necessity of thorough system clean up in between consecutive runs; and 2) inconsistent yields and prolonged synthesis time when using HPLC methods for final product separation and purification. To address these issues, new radiochemistry applications have been developed for the radiochemistry modules: a) for 18F: FLT Lite, F-MISO Lite, F-Choline Lite, and FET Lite; b) for 11C: Acetate, Methyl Iodide, Methionine, Choline; c) for 68Ga: DOTA-Peptides. These methods utilize sterile disposable kits, and allow for the PET tracers to be purified and isolated with SPE cartridges only, thus eliminating the need for HPLC separation. The processes and the radiochemical yields obtained with these methods will be presented, and their utility discussed

  9. 'Serial review on clinical PET tracers'. Dopamine D2 receptor imaging by positron emission tomography with [11C]N-methylspiperone and [11C]raclopride

    Dopamine D2 receptor binding is one of postsynaptic functions of dopaminergic neurotransmission system, and it can be estimated by positron emission tomography (PET) with [11C]raclopride and [11C]N-methylspiperone. The dopaminergic neurotransmission system is of central interest in pathophysiology of neuropsychiatric disorders, e.g., Parkinson's disease and schizophrenia. Measurement of binding potential (BPND) of [11C]raclopride to dopamine D2 receptors is useful for differential diagnosis of Parkinson's disease from other neurodegenerative diseases. Effects of antipsychotic drugs have widely been considered to be mediated by blockade of dopamine D2 receptors, and occupancy of dopamine D2 receptor by antipsychotic drug can be calculated from BPND of [11C]raclopride at baseline and drug challenge studies. Measurement of dopamine D2 receptor occupancy is useful for evaluation of effects of antipsychotic drug. It can also be applied for optimal dose finding of new antipsychotic drug in clinical trials. (author)

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

    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...

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

    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.

  12. Re-evaluation of in vivo selectivity of [11C]SA4503 to σ1 receptors in the brain: Contributions of emopamil binding protein

    Introduction: Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) was shown to be a promising PET ligand for mapping σ1 receptors, and was applied to human subjects. However, an in vitro study indicated that SA4503 also binds to the emopamil binding protein (EBP), vertebral Δ8-Δ7 sterol isomerase. To our knowledge, no information is available about the possibility of [11C]SA4503 binding to EBP in the brain in vivo. Methods: To confirm the selectivity of [11C]SA4503, we carried out an in vivo blocking experiment using high-affinity EBP and σ1 selective blocker. Results: The brain uptake of [11C]SA4503 was dose-dependently decreased by SA4503 and the high-affinity σ1 blockers haloperidol, ifenprodil, and trifluperidol. On the other hand, the effects of the high-affinity EBP blockers tamoxifen and trifluoperazine were negligible. Conclusions: Our results confirmed the σ1-selective binding of [11C]SA4503 in the brain.

  13. [11C]SMe-ADAM, an imaging agent for the brain serotonin transporter: synthesis, pharmacological characterization and microPET studies in rats

    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 [11C]methyl iodide to obtain the potential positron emission tomography (PET) radioligand [11C]S Me-Adam. The radiochemical yield was 27±5%, and the specific radioactivity was 26-40 GBq/μmol 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 [11C]SMe-ADAM uptake in the thalamus was significantly decreased by pretreatment with fluoxetine to 38±11% of the control value. Furthermore, no metabolites of [11C]SMe-ADAM could be detected in the SERT-rich regions of the rat brain. It is concluded that [11C]SMe-ADAM may be a suitable PET ligand for SERT imaging in the living brain

  14. Radiosynthesis and in vivo evaluation of [{sup 11}C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A

    Plisson, Christophe, E-mail: Christophe.2.plisson@gsk.com [GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN (United Kingdom); Salinas, Cristian [GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN (United Kingdom); Weinzimmer, David; Labaree, David; Lin, Shu-Fei; Ding, Yu-Shin [Yale University PET Center, Yale University School of Medicine, PO Box 208048 New Haven, CT (United States); Jakobsen, Steen [Aarhus PET Centre, Aarhus Sygehus, Norrebrogade 44, DK-8000 Aarhus C (Denmark); Smith, Paul W. [GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN (United Kingdom); Eiji, Kawanishi [Medicinal Chemistry Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505 (Japan); Carson, Richard E. [Yale University PET Center, Yale University School of Medicine, PO Box 208048 New Haven, CT (United States); Gunn, Roger N.; Rabiner, Eugenii A. [GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN (United Kingdom)

    2011-08-15

    Introduction: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [{sup 11}C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. Methods: A procedure was developed for labeling MP-10 with carbon-11. [{sup 11}C]MP-10 was evaluated in vivo both in the pig and baboon brain. Results: Alkylation of the corresponding desmethyl compound with [{sup 11}C]methyl iodide produced [{sup 11}C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [{sup 11}C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [{sup 11}C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [{sup 11}C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [{sup 11}C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V{sub T}) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP{sub ND}) as the outcome measure of specific binding. Quantification of [{sup 11}C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP{sub ND} estimates consistent with those obtained by the two-tissue compartment model. Conclusion: We demonstrated that [{sup 11}C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the

  15. Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.

    Wang, Zhongliang; Du, Tingting; Dong, Xiaorong; Li, Zhenyu; Wu, Gang; Zhang, Ruiguang

    2016-06-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment for non-small cell lung cancer patients, but acquired resistance limit the efficiency of this treatment. As a homeostatic cellular recycling mechanism, autophagy has been proposed to participate in the EGFR-TKI resistance. However, the role of autophagy in lung cancer treatment and the underlying mechanisms have not been clarified. In this study, we found the sensitivity to erlotinib, a well-used EGFR-TKI, was correlated with basal autophagy level. Erlotinib was able to induce autophagy not only in TKI-sensitive, but also TKI-resistant cancer cells. Inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis. In this process, CCAAT/enhancer binding protein homologous protein (CHOP) acted as an executioner. Downregulation of CHOP with siRNA blocked the autophagy inhibition and erlotinib co-treatment induced apoptosis and prevented cancer cells from this co-treatment-induced cell death. Our findings suggest that autophagy inhibition overcomes erlotinib resistance through modulation of ER stress mediated apoptosis. PMID:27035631

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

    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.

  17. Solid state support for the synthesis of [1-11C]-putrescine

    A novel solid state support was demonstrated using [11C]-HCN for the radiosynthesis of [1-11C]-putrescine by the Michael addition reaction to acrylonitrile. The silica gel support allowed near quantitative trapping of the [11C]-HCN and its efficient use under anhydrous conditions. The absence of water during the addition reaction eliminated by-product formation and reduced the overall synthesis and purification time required for the preparation of the radiopharmaceutical. A radiochemical yield of 53 ± 4 was achieved for purified product within 40 min of EOB. The process can be automated for the routine synthesis of [1-11C]-putrescine radiopharmaceutical. (author)

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

    Antoni, Gunnar; Lubberink, Mark; Estrada, Sergio; Axelsson, Jan; Carlson, Kristina; Lindsjö, Lars; Kero, Tanja; Roland Långström, Bengt; Granstam, Sven-Olof; Rosengren, Sara; Vedin, Ola; Wassberg, Cecilia; Wikström, Gerhard; Westermark, Per; Sörensen, Jens

    2013-01-01

    -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...... patients 15-25 min after injection and was not seen in any volunteer. A significant difference in (11)C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with (11...

  19. The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo.

    Hume, W Ewan; Shingaki, Tomotaka; Takashima, Tadayuki; Hashizume, Yoshinobu; Okauchi, Takashi; Katayama, Yumiko; Hayashinaka, Emi; Wada, Yasuhiro; Kusuhara, Hiroyuki; Sugiyama, Yuichi; Watanabe, Yasuyoshi

    2013-12-15

    In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [(11)C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [(11)C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations. PMID:24238901

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

    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.

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

    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

  2. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1

    Prados, Michael D.; Lamborn, Kathleen R.; Chang, Susan; Burton, Eric; Butowski, Nicholas; Malec, Mary; Kapadia, Ami; Rabbitt, Jane; Page, Margaretta S.; Fedoroff, Ann; Xie, Dong; Kelley, Sean K.

    2006-01-01

    The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmacokinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eighty-three patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%–71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted. PMID:16443950

  3. Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient

    Yukari Tsubata

    2012-01-01

    Full Text Available We herein describe a case of drug-induced interstitial lung disease (ILD following treatment with erlotinib. The plasma trough concentration of erlotinib at the time of the ILD diagnosis was extremely elevated compared with the plasma maximum concentration on day 1. We hypothesized that this phenomenon was associated with the pharmacodynamic interaction with a concomitant drug. The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of erlotinib. Oncologists should be aware of the possibility of ILD induced by erlotinib, especially for patients with co-morbidities.

  4. 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

    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

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

    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.

  6. Desorption and catalytic study of vanadium modified MCM-41 silica by 11C radiolabeled methanol

    Complete text of publication follows. Vanadium modified MCM-41 (V-MCM-41) materials were prepared by solid state reduction technique with V2O5 and catalytically tested in ethylacetate oxidation. In the recent study, 11C-labeling methanol is introduced as a probe molecule for characterization of the state of various catalytic active sites, which were obtained after the V-MCM-41 treatment in oxidative (V-MCM-41o) or reductive (VMCM- 41r) atmosphere. Solid state vanadium modified mesoporous MCM-41 silica is characterised by XRD, N2 physisorption, FTIR and UV-Vis spectroscopies. Novel consecutive 11C- and 12C-methanol adsorption technique was used for the elucidation of the contribution of various vanadium species in methanol conversion. The radiodetectors are placed in front of the reactor to follow the methanol desorption at different temperatures as well as for radio-GC analysis (including FID coupled on-line with radiodetector) of methanol conversion. The rates of 11C-methanol desorption was negligible for V-MCM-41o, while a sharp increase is observed for V-MCM-41r in the temperature range of 160-180 deg C, indicating the presence of various types of catalytic active sites for both materials. Radio-GC results also reveal different catalytic behaviour for these vanadium modifications. On V-MCM- 41o, at lower temperature (250-280 deg C) a small amount of dimethyl ether (DME) was registered. The selectivity to CH4, CO, CO2, HCHO and methylal was strongly increased between 280-360 deg C. On V-MCM-41r, no DME and only a negligible amount of methylal were detected. The process was carried out exclusively to HCHO, and similarly to V-MCM- 41o, at higher temperatures - to CO formation. The desorption and catalytic measurements reveal that the variation in the pretreatment medium provides the formation of catalytic centers with different redox and acidic activity. While the products of methanol decomposition (CH4, CO, HCHO, CO2) are typical of the presence of redox sites

  7. Synthesis of 1-[11c]methylpiperidin-4-yl propionate ([11c]pmp) for in vivo measurements of acetylcholinesterase activity

    Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP), an in vivo substrate for acetylcholinesterase, is reported. An improved preparation of 4-piperidinyl propionate (PHP), the immediate precursor for radiolabeling, was accomplished in three steps from 4-hydroxypiperidine by (a) protection of the amine as the benzyl carbamate, (b) acylation with propionyl chloride, and (c) deprotection of the carbamate by catalytic hydrogenation. The final product was obtained in an overall 82% yield. Reaction of the free base form of PHP with [11C]methyl trifluoromethanesulfonate at room temperature in N,N-dimethylformamide, followed by high performance liquid chromatography (HPLC) purification, provided [11C]PMP in 57% radiochemical yield, >99% radiochemical purity, and >1500 Ci/mmol at the end of synthesis. The total synthesis time from end-of-bombardment was 35 min. [11C]PMP can thus be reliably prepared for routine clinical studies of acetylcholinesterase in human brain using positron emission tomography

  8. Effects of cocaine on [{sup 11}C]norepinephrine and [{sup 11}C]{beta}-CIT uptake in the primate peripheral organs measured by PET

    Suhara, Tetsuya; Farde, L.; Halldin, C.; Karlsson, P. [Karolinska Hospital, Stockholm (Sweden); Nagren, K.

    1996-02-01

    The toxic properties of cocaine are related to both the central and peripheral effects. To identify possible lethal mechanisms and the accumulation of cocaine in various organs, the effects of cocaine on [{sup 11}C] norepinephrine and cocaine congener [{sup 11}C]{beta}-CIT uptake in Cynomolgus monkeys were measured by positron emission tomography (PET). Cocaine (5 mg/kg) noticeably inhibited [{sup 11}C] norepinephrine uptake in the heart. The uptake of [{sup 11}C]{beta}-CIT in the heart and lung was reduced by pretreatment with cocaine. There was a significant uptake in the liver which was increased following cocaine pretreatment. The results of this study confirm that cocaine blocks the neuronal uptake of norepinephrine in sympathetic nerve terminals in the myocardium. The effect of cocaine on [{sup 11}C]{beta}-CIT uptake indicates that the binding sites in the heart and lung are saturable, while the uptake mechanism in the liver is different from those of the heart and lung. (author).

  9. Exacerbation of radiation fibrosis with erlotinib. Another pattern of radiation recall phenomenon

    A 79-year-old woman with advanced lung cancer presented with worsened radiation fibrosis after administration of erlotinib. After radiation therapy 7 months previously, she had radiation fibrosis that had been stable for months. On the 19th day after administration of erlotinib, low-grade fever and mild dyspnea developed accompanied by new pulmonary opacity in the area of the radiation fibrosis, which improved without therapy. We surmise that this is a manifestation of the radiation recall phenomenon, and discontinuation of the drug should be considered with discretion. (author)

  10. In vivo [11C]dihydrotetrabenazine binding in rat striatum: sensitivity to dopamine concentrations

    Introduction: The sensitivity of the in vivo binding of [11C]dihydrotetrabenazine ([11C]DTBZ) and [11C]methylphenidate ([11C]MPH) to their respective targets - vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter - after alterations in endogenous levels of dopamine was examined in the rat brain. Methods: In vivo binding of [11C]DTBZ and [11C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography. Results: Repeated dosing with α-methyl-p-tyrosine (AMPT) at doses that significantly (-75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [11C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [11C]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment. Conclusion: These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous L-DOPA.

  11. Synthesis of [11C]citalopram and brain distribution studies in rats

    The study of serotonin uptake sites in the living human brain by PET with [11C]citalopram may be valuable in investigating the anatomic locus and the therapeutic role of depression and prevention of suicide. For this purpose, the authors have synthesized [11C]citalopram. In vivo biodistribution in rats has been determined

  12. In vivo [{sup 11}C]dihydrotetrabenazine binding in rat striatum: sensitivity to dopamine concentrations

    Kilbourn, Michael R. [Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States)], E-mail: mkilbour@umich.edu; Butch, Elizabeth R.; Desmond, Timothy; Sherman, Phillip [Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Harris, Paul E. [Department of Medicine, Columbia University Medical College, New York, NY 10032 (United States); Frey, Kirk A. [Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States)

    2010-01-15

    Introduction: The sensitivity of the in vivo binding of [{sup 11}C]dihydrotetrabenazine ([{sup 11}C]DTBZ) and [{sup 11}C]methylphenidate ([{sup 11}C]MPH) to their respective targets - vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter - after alterations in endogenous levels of dopamine was examined in the rat brain. Methods: In vivo binding of [{sup 11}C]DTBZ and [{sup 11}C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography. Results: Repeated dosing with {alpha}-methyl-p-tyrosine (AMPT) at doses that significantly (-75%) depleted brain tissue dopamine levels resulted in increased (+36%) in vivo [{sup 11}C]DTBZ binding to VMAT2 in the striatum. The increase in binding could be completely reversed via treatment with L-DOPA/benserazide to restore dopamine levels. There were no changes in the total number of VMAT2 binding sites, as measured using in vitro autoradiography. No changes were observed for in vivo [{sup 11}C]MPH binding to the dopamine transporter in the striatum following AMPT pretreatment. Conclusion: These results indicate that large reductions in dopamine concentrations in the rat brain can produce modest but significant changes in the binding of radioligands to VMAT2, which can be reversed by replenishment of dopamine using exogenous L-DOPA.

  13. Effects of smoking on the lung accumulation of [11C]McN5652

    The lung is one of the key organs for determining the distribution of drugs in the human body. Various factors influence the accumulation of drugs. In this study, we investigated the effects of smoking on drug distribution to the lung using radiolabeled drugs. We measured the lung uptake of [11C](+)McN5652, a radioligand for serotonin transporter (5-HTT), and inactive enantiomer [11C](-)McN5652 in 19 healthy men (12 nonsmokers and 7 smokers) using positron emission tomography. Pretreatment study was performed by the administration of clomipramine (50 mg), a potent 5-HTT inhibitor. The mean lung uptake of [11C](+)McN5652 and [11C](-)McN5652 was significantly higher in smokers than in nonsmokers. The lung uptake of [11C](+)McN5652 decreased after pretreatment with clomipramine, whereas that of [11C](-)McN5652 was not affected by clomipramine. Lung uptake of [11C](-)McN5652 was influenced by smoking, possibly because the probable nonspecific binding accumulation was changed as [11C](-)McN5652 was reported to have negligible affinity to 5-HTT. Smoking might be one of the important factors when distribution of radioligands is considered. (author)

  14. PET imaging of dopamine transporters in the human brain using [{sup 11}C]-{beta}-CPPIT, a cocaine derivative lacking the 2{beta}-ester function

    Schoenbaechler, Roland D.; Gucker, Pascale M.; Arigoni, Michele; Kneifel, Stefan; Vollenweider, Franz X.; Buck, Alfred; Burger, Cyrill; Berthold, Thomas; Bruehlmeier, Matthias; Schubiger, P. August; Ametamey, Simon M. E-mail: simon-mensah.ametamey@psi.ch

    2002-01-01

    The compound 3{beta}-(4'-chlorophenyl)-2{beta}-(3'-phenylisoxazol-5'-yl)tropane (CPPIT or RTI 177) is a 2{beta}-heterocyclic substituted cocaine congener with high in vitro selectivity and affinity for the dopamine transporter relative to serotonin and norepinephrine transporters. The aim of the present study was to evaluate the in vivo selectivity of [{sup 11}C]-{beta}-CPPIT and to determine whether [{sup 11}C]-{beta}-CPPIT may be a suitable alternative to existing DAT PET radioligands. [{sup 11}C]-{beta}-CPPIT was prepared by N-alkylation of the free amine with [{sup 11}C]methyl iodide. In mouse brain, the striatal binding of [{sup 11}C]-{beta}-CPPIT was reduced significantly by preinjecting the dopamine reuptake antagonist GBR 12909 (5 mg/kg). By contrast, radioactivity uptake in the brain was not affected significantly by the preinjection of citalopram (5 mg/kg) and desipramine (5 mg/kg), inhibitors for the serotonin and norepinephrine transporters, respectively. No effect was also observed by pretreatment with ketanserin (2.5 mg/kg) a compound with high affinity for the 5-HT{sub 2A}-receptor and the vesicular monoamine transporter. In a PET study with six healthy volunteers high striatal uptake was observed. The distribution pattern of [{sup 11}C]-{beta}-CPPIT was similar to the known distribution of the dopamine transporter in the human brain. Compared to {sup 123}I labeled {beta}-CIT, the rate of metabolic degradation of [{sup 11}C]-{beta}-CPPIT was almost twofold slower suggesting that bioisosteric heterocyclic substitution of the ester group at the 2{beta}-position of the tropane ring does have an influence on the rate of metabolism of [{sup 11}C]-{beta}-CPPIT. The rank order of the distribution volumes obtained via the one-tissue compartment model is also similar to the reported distribution of DAT. These preliminary results suggest that [{sup 11}C]-{beta}-CPPIT may be a useful PET radioligand for the visualization and quantification of

  15. PET imaging of dopamine transporters in the human brain using [11C]-β-CPPIT, a cocaine derivative lacking the 2β-ester function

    The compound 3β-(4'-chlorophenyl)-2β-(3'-phenylisoxazol-5'-yl)tropane (CPPIT or RTI 177) is a 2β-heterocyclic substituted cocaine congener with high in vitro selectivity and affinity for the dopamine transporter relative to serotonin and norepinephrine transporters. The aim of the present study was to evaluate the in vivo selectivity of [11C]-β-CPPIT and to determine whether [11C]-β-CPPIT may be a suitable alternative to existing DAT PET radioligands. [11C]-β-CPPIT was prepared by N-alkylation of the free amine with [11C]methyl iodide. In mouse brain, the striatal binding of [11C]-β-CPPIT was reduced significantly by preinjecting the dopamine reuptake antagonist GBR 12909 (5 mg/kg). By contrast, radioactivity uptake in the brain was not affected significantly by the preinjection of citalopram (5 mg/kg) and desipramine (5 mg/kg), inhibitors for the serotonin and norepinephrine transporters, respectively. No effect was also observed by pretreatment with ketanserin (2.5 mg/kg) a compound with high affinity for the 5-HT2A-receptor and the vesicular monoamine transporter. In a PET study with six healthy volunteers high striatal uptake was observed. The distribution pattern of [11C]-β-CPPIT was similar to the known distribution of the dopamine transporter in the human brain. Compared to 123I labeled β-CIT, the rate of metabolic degradation of [11C]-β-CPPIT was almost twofold slower suggesting that bioisosteric heterocyclic substitution of the ester group at the 2β-position of the tropane ring does have an influence on the rate of metabolism of [11C]-β-CPPIT. The rank order of the distribution volumes obtained via the one-tissue compartment model is also similar to the reported distribution of DAT. These preliminary results suggest that [11C]-β-CPPIT may be a useful PET radioligand for the visualization and quantification of dopamine transporters in man

  16. 11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

    11C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl] -4-(3-methoxy-methylpyridin-2- yl)-piperazine (11C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of 11C-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 11C-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 11C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of 11C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged 11C-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 11C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min-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. 11C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of 11C-ORM-13070 was in the same range as that of other 11C-labelled brain receptor tracers. An injection of 500 MBq of 11

  17. radiosynthesis of 11C-meta-(-) hydroxyephedrine and micro PET imaging

    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-methyl-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-methyl-iodine as the N-methylation agents. 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 the precursor was separated 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%/g of adrenals was increased. Micro PET imaging showed that the heart can be visualized at 10 and 30 min postinjection, but the uptake of myocardium was decreased and the washout was speeded after co-injection of the precursor. The chemical and radiochemical purity of 11C-(-) HED can be improved by using 3% EthOH in 0.24 moL/L NaH2PO4 and then switching to 10% EthOH in 0.24 moL/L NaH3PO4 as the HPLC mobile phase. (authors)

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

    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.

  19. Development of [11C]-α-aminoisobutyric acid and [18F]-haloperidol as substrate-specific radiotracers

    In light of the emergence of positron emission tomography (PET), two new substrate-specific radiotracers have been synthesized and evaluated as potential agents for the study of specific physiological processes: [1-11C]-α-aminoisobutyric acid ([1-11C]-AIB), a transport system-specific radiotracer for tumor localization and for the assessment of amino acid transport in vivo; and [18F]-haloperidoll, a receptor-binding radiotracer for the assessment of brain dopamine receptors in vivo. AIB, a non-metabolized amino acid, accumulates in cells, particularly malignant cells, via the A type, or ''alanine-preferring'', amino acid transport system [1-11C]-AIB in normal and in treated and untreated tumor-bearing rats, in tumor-bearing dogs, and in a tumor-bearing patient indicate rapid blood clearance and, concomitantly, rapid tissue localization, with slow net redistribution. Generally, there was selective localization in the kidney, in the liver, and in the pancreas, as well as in various tumors. The canine tumors and the human tumor were well visualized by external scintigraphy, especially when utilizing PET. [18F]-Haloperidol, a dopamine receptor-binding neuroleptic of the butyrophenone series widely used in the management of schizophrenia was prepared via the Balz-Schiemann reaction. As the haloperdol dose administered to mice was increased from 0.01 to 1000 μg/kg, the relative concentration (μCi found per gm tisue sample/μCi injected per gm body mass) of [18F]-haloperidol at 1 hr decreased from 30 to 1.0 in the striatum and from 8.0 to 1.0 in the cerebellum. The decrease in striatum radioactivity reflects competition between labeled and unlabeled haloperidol for dopamine receptors

  20. An improved automated synthesis and in vivo evaluation of PET radioligand for serotonin re-uptake sites. [11C]McN5652X

    Carbon-11 labeled serotonin (5-HT) re-uptake inhibitor, [11C]McN5 652X ((6S,10bR)-trans-( + )-1,2,3,5,6,10b-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline), has recently been reported to be favorable for studying human 5-HT re-uptake site by positron emission tomography (PET) because of its rapid and high specific binding characteristics as radioligands. [11C]McN5652X has been synthesized by S-methylation of the corresponding des-methyl precursor A with [11C]iodomethane. One serious disadvantage of this procedure, however, is the lack of stability of A. The improved method for the synthesis of A has been desired. We have found that the decomposition of A is significantly reduced by adding a protecting agent for SH groups, dithiothreitol (DTT), into the reaction medium immediately after the demethylation of McN5652X. By using this stabilized precursor A, we have developed an automated procedure giving [11C]McN5652X with 98.6±0.4% radiochemical purity in high specific activity (181.3±7.4GBq/μmol). Preclinical evaluation of the produ ct was carried out by injecting the solution of [11C]McN5652X obtained by this procedure into mice. [11C]McN5652X showed the high accumulation into mouse thalamus, striatum and cerebral cortex, organs known to have high level of 5-HT receptor density, after intravenous injection. Human PET studies also showed the high uptakes of this radioligand into the thalamus, striatum and midbrain

  1. Synthesis and preliminary evaluation of [{sup 11}C]-(-)-phenylephrine as a functional heart neuronal PET agent

    Rosario, Renato B. del; Jung, Y.-W.; Caraher, John; Chakraborty, Pulak K.; Wieland, Donald M

    1996-07-01

    The in vivo behavior of (-)-[{sup 11}C]phenylephrine (PHEN) is compared with the structurally similar but monoamine oxidase (MAO)-resistant analog (-)-[{sup 11}C]-m-hydroxyephedrine (HED), which is an established heart neuronal marker. The chiral synthesis of PHEN has been achieved by direct methylation of (-)-m-octopamine with either {sup 11}CH{sub 3}I or CF{sub 3}SO{sup 11}{sub 3}CH{sub 3}. These synthetic methods produced PHEN with a specific activity ranging from 500-1000 Ci/mmol, in a radiochemical yield of >50% (EOS) and with an enantiomeric purity of 94-96%. Biodistribution studies indicate the initial uptake of PHEN in rat heart is approximately half that of HED. Following PHEN injection, radioactivity egresses from the rat heart rapidly, with 50% washout occurring from 5 to 60 min. HED washout over this interval was less than 20%. The heart neuronal selectivity determined by desipramine blockade of the amine neuronal transporter was 75-77% compared to 92-95% for HED. Ring-labeled (-)-[{sup 3}H]phenylephrine gave tissue-to-blood concentration ratios and heart clearance times very similar to PHEN. Rats pretreated with the MAO A inhibitor clorgyline showed higher levels of activity in the heart at 15 and 60 min. Tandem PET studies with PHEN and HED in the closed-chest dog provided excellent heart images with both tracers.

  2. Bilberry extract, its major polyphenolic compounds, and the soy isoflavone genistein antagonize the cytostatic drug erlotinib in human epithelial cells.

    Aichinger, G; Pahlke, G; Nagel, L J; Berger, W; Marko, D

    2016-08-10

    Erlotinib (Tarceva®) is a chemotherapeutic drug approved for the treatment of pancreatic cancer and non-small cell lung cancer. Its primary mode of action is the inhibition of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Recently, RTK-inhibiting polyphenols have been reported to interact synergistically with erlotinib. Furthermore some anthocyanidins and anthocyanin-rich berry extracts have been reported to inhibit tyrosine kinases, including the EGFR, which raises the question of potential interactions with erlotinib. Polyphenol-rich preparations such as berry- or soy-based products are commercially available as food supplements. In the present study we tested a bilberry extract, its major anthocyanin and potential intestinal degradation products, as well as genistein, with respect to possible interactions with erlotinib. Cell growth inhibition was assessed using the sulforhodamine B assay, while interactions with EGFR phosphorylation were analyzed by SDS-PAGE/western blotting with subsequent immunodetection. Genistein, bilberry extract, delphinidin-3-O-glucoside and delphinidin were found to antagonize erlotinib whereas phloroglucinol aldehyde was found to enhance cytostatic effects of the drug on human epithelial A431 cells. Genistein also antagonized the EGFR inhibitory effects of erlotinib, whereas bilberry anthocyanins showed no significant interactions in this regard. Our data indicate that different polyphenols are potentially able to impair the cytostatic effect of erlotinib in vitro. Genistein interacts via the modulation of erlotinib-mediated EGFR inhibition whereas bilberry anthocyanins modulated the growth-inhibitory effect of erlotinib without affecting EGFR phosphorylation, thus indicating a different mechanism of interference. PMID:27485636

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

    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.

  4. Expression of CD11c in periprosthetic tissues from failed total hip arthroplasties.

    Chamaon, Kathrin; Barber, Henriette; Awiszus, Friedemann; Feuerstein, Bernd; Lohmann, Christoph H

    2016-01-01

    In this work, we characterize integrin CD11c (αXß2) expression in periprosthetic tissues of 45 hip revisions. Tissues were retrieved from 23 ceramic-on-ultra-high molecular weight polyethylene (UHMWPE), 20 metal-on-UHMWPE, and 2 metal-on-metal total hip arthroplasties (THAs). Capsular tissue retrieved during primary THA from 19 patients served as controls. We identified a system to identify important immunohistochemical markers that are expressed in aseptic loosening. We focused on CD11c, CD68 and CD14. We observed that the CD11c molecule possesses four different cellular patterns in the periprosthetic tissues. Three of them are associated with the occurrence of UHMWPE abrasive material. Double staining with CD14 and CD68 was used for a more detailed analysis of the CD11c expressing cells. We observed that all forms of CD11c positive cells are CD68 positive however, only two forms of CD11c expressing cells are positive for CD14. Providing cellular diversity of CD11c expression in periprosthetic tissue, our results provide a contribution toward the further understanding of different cellular mechanisms to foreign body material. PMID:26255872

  5. Asymmetric radiosynthesis of α-[11C]methyl-l-tryptophan for PET studies

    Asymmetric radiosynthesis of α-[11C]methyl-l-tryptophan has been achieved using the enantioselective [11C]methylation of the enolate of either 8-(phenylsulfonyl) or 8-acetyl substituted derivatives of dimethyl (2S.3aR, 8aS)-(+)-hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate. Reaction of the enolates generated by treatment with LDA at -78 deg. C, with [11C]methyl iodide at -78 deg. C gave in 5 min incorporation of the radiolabel of 86% for 8-phenylsulfonyl derivative and 63% for 8-acetyl derivative. The hexahydropyrrolo[2,3-b]indoles were then decyclized to the fully protected α-[11]methyl-l-tryptophan by treatment with trifluoroacetic acid. Removal of all the protecting groups, including the phenylsulfonyl, was achieved by reaction with 10 N NaOH at 210 deg. C in a sealed vial. Neutralization of the alkali with 10 N H2SO4 followed by purification by HPLC gave α-[11C]methyl-l-tryptophan with an overall radiochemical yield of 20% (uncorrected for decay) relative to the amounts of [11C]CH3I from 8-phenylsulfonyl derivative, and 9% (relative to [11C]CH3I; uncorrected for decay) from 8-acetyl derivative in a preparation time of 40 min after [11C]methyl iodide was introduced into the reaction mixture

  6. Fast synthesis of 11C-Raclopride and its initial PET study on animal model

    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-Raclopride, 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-Raclopride 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-Raclopride 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 D2R 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. (authors)

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

    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

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

    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).

  9. Utilidad de 11C-metionina PET/CT en neurooncología

    Ignacio Casas Parera; Jorge L. Igirio Gamero; Yamila Blumenkrantz; Gabriel Bruno; Alejandra Báez; José G. Tafur Canabal; Mariana Báez; Valeria Kuchkaryan

    2013-01-01

    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...

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

    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.

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

    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

  12. [11C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography

    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 ([11C]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, [11C]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 [11C]CURB was irreversibly bound to FAAH. Conclusions: The

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

    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

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

    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 [11C](+)-PHNO ([11C](+)-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 [3H]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 [11C](+)-PHNO and [3H]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for 11C and 3H. The specific binding ratio {SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum)} was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [11C](+)-PHNO and [3H]raclopride SBRs responded indistinguishably in terms of both ED50 and Hill slope (e.g., (-)-NPA ED50 values are 0.027 and 0.023 mg/kg for [11C](+)-PHNO and [3H]raclopride, respectively). In response to AMPH challenge, [11C](+)-PHNO and [3H]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [11C](+)-PHNO- and [3H]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 applicability of the D2 two-state model, as described by in vitro binding experiments

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

    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

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

    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.

  17. The synthesis of (R)- and (S)-[N-methyl-11C]β, β-difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo

    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-11C]β,β-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of β,β-difluoroamphetamine were prepared from trans-β-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-β,β-difluoroamphetamine (3) were then each labelled with carbon-11 (t1/2=20.4 min) by N-methylation of the corresponding homochiral β,β-difluoroamphetamine with [11C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [11C]carbon dioxide in 15-16% decay-corrected radiochemical yield, with a radiochemical purity of >99% and specific radioactivity of 50-150 GBq μmol-1 at end of synthesis

  18. PET-examination and metabolite evaluation in monkey of [{sup 11}C]NAD-299, a radioligand for visualisation of the 5-HT{sub 1A} receptor

    Sandell, Johan E-mail: Johan.E.Sandell@ks.se; Halldin, Christer; Chou Yuanhwa; Swahn, Carl-Gunnar; Thorberg, Seth-Olov; Farde, Lars

    2002-01-01

    NAD-299 is a selective 5-HT{sub 1A} receptor antagonist that is currently developed as a putative antidepressant drug. [{sup 11}C]NAD-299 was examined in the cynomolgus monkey brain with positron emission tomography (PET). After radioligand injection high accumulation of radioactivity was observed in the frontal and temporal cortex and the raphe nuclei, regions known to contain a high density of 5-HT{sub 1A} receptors. Peak equilibrium appeared already at about 10 min after i.v. injection. Pre-treatment with a high dose of the antagonist WAY-100635 reduced the amount of radioactivity in the cortex and the raphe to the level of the cerebellum. A strong pre-treatment effect could also be achieved using pindolol, a partial agonist at the 5-HT{sub 1A}-receptors. The appearance of labeled metabolites in monkey plasma was measured with HPLC. At 45 minutes after injection 49% (range 27-55%, n=5) of radioactivity in monkey plasma represented unchanged radioligand. [{sup 11}C]NAD-299 was metabolized to more polar labeled metabolites of which one has the same chromatographic mobility as the descyclobutyl analogue of NAD-299 (NAD-272). The results indicate that [{sup 11}C]NAD-299 has potential as a PET radioligand for studies of 5-HT{sub 1A} receptors in the primate brain.

  19. Improved and semi-automated GMP-compliant radiosynthesis of [11C]docetaxel

    [11C]Docetaxel (Taxotere) has been synthesized via an improved synthesis route, which involves a more efficient intermediate removal of the excess 1,2,2,2-tetrachloroethyl chloroformate. Furthermore, the purification and formulation into a human applicable solution of [11C]docetaxel was developed. 1,2,2,2-Tetrachloroethyl chloroformate is used for the synthesis of the intermediate [11C]tert-butyl-1,2,2,2-tetrachloroethyl carbonate that in the final reaction step reacts with the precursor, the primary amine of docetaxel, yielding [11C]docetaxel. The purified and isolated product was obtained in 10±2% overall decay-corrected radiochemical yield. The total synthesis time was 67 min and the specific activity was 9-17 GBq/μmol (N=7)

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

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

    2013-01-01

    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......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...... 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...

  1. Capturing [11C]CO2 for use in aqueous applications

    We present a simple method for trapping [11C]CO2 gas and releasing it into a buffered solution using an ion-exchange cartridge. Sodium hydroxide cartridges captured >99% of [11C]CO2 following NaOH activation. A sodium bicarbonate solution eluted >99% of trapped radioactivity. Trapping [11C]CO2 directly in small volumes of several solutions was less effective than cartridge methods. The recommended methods allow for fast and simple production of highly concentrated carbon-11 containing aqueous solutions for use in filling phantoms, calibrating detectors, or (bio)geochemical experiments. - Highlights: • An ion exchange resin can trap [11C]CO2 gas and release it with saturated bicarbonate. • Elution from cartridge requires as little as 300 µL volume, with eluant at pH=10. • SPE trap-and-release provided better results than trapping in solution

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

    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

  3. Clinical impact of 11C-methionine PET on expected management of patients with brain neoplasm

    We retrospectively examined the clinical efficacy of 11C-methionine positron emission tomography (11C-MET PET) in patients with brain neoplasm, especially whether the 11C-MET PET changed the clinical management and whether the change was beneficial or detrimental. This study reviewed 89 11C-MET PET scans for 80 patients (20 scans for initial diagnosis of brain tumor and 69 scans for differentiating tumor recurrence from radiation necrosis). Final diagnosis and the effect on the intended management were obtained from the questionnaire to the referring physicians or directly from the medical records. The diagnostic sensitivity, specificity, and accuracy for the 11C-MET PET were evaluated. Regarding the management impact, the rate of scans that caused changes in intended management was also evaluated. Moreover, the occurrence of scans having detrimental diagnostic impact (DDI) and beneficial diagnostic impact (BDI) were evaluated. Sensitivity, specificity, and accuracy of 11C-MET PET was 87.8, 80.0, and 85.9%. The intended management was changed in 50.0% of the scans. DDI and BDI were observed in 4.3 and 36.2% of the total relevant scans, respectively. 11C-MET PET can provide useful information in initial diagnosis and differentiating tumor recurrence from radiation necrosis. The intended management was changed in half of the scans. Since a few cases did not receive the requisite treatment due to false-negative results of 11C-MET PET, management decision should be made carefully, especially in the case of a negative scan. (orig.)

  4. The role of 11C-acetate PET imaging for diagnosis of renal cancer

    Objective: To evaluate the relationship between 11C-acetate and 18F-fluorodeoxyglucose (FDG) for the detection of renal neoplasm and to determine the feasibility of 11C-acetate used as a complement of 18F-FDG. Methods: Twenty-nine patients with 25 primary lesions underwent 11C-acetate (111-655 MBq intravenous injection) PET imaging (early imaging after injection instantly, and delayed imaging 10 min latter), and among them 22 patients underwent 18F-FDG PET imaging within one week. Twenty-five primary and three metastatic lesions were confirmed histologically. One metastasis was proved by CT and clinical follow-up. Thirteen renal clear cell carcinoma and six transitional cell carcinoma lesions had pathologic grading. Results: Among all human organs, pancreas showed persistent highest uptake of 11C-acetate. Activity in bowel was due to the pancreatic excretion. High accumulation was also observed in renal cortex initially but was cleared rapidly, while most primary lesions of renal cell carcinoma showed radioactive hot areas in delayed images. Compared with 18F-FDG (30.8% positively), 11C-acetate was more sensitive in detecting primary lesions of renal cell carcinoma (76.9% positively). However, 18F-FDG was an effective tracer in the diagnosis of transitional cell carcinoma, since 5 (5/5) of them were all visualized while only 2 (2/6) were demonstrated in 11C-acetate imaging. One renal angiomyolipoma was both positive in early and delayed imaging of 11C-acetate, but urethritis was negative. Conclusions: 11C-acetate is more sensitive than 18F-FDG for the detection of well differentiated renal cell carcinoma, especially for grade I - Il. Therefore, 1lC-acetate imaging can be used as a complement for 18F-FDG. (authors)

  5. [11C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure

    The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [11C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. Methods: A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [14C]-Acetoacetate, a non-positron (β −) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [11C]-acetoacetate (β +) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n = 15) and treated Dox(+) (n = 6) rats. The uptake rate (K1) and myocardial clearance rate (k2or kmono) were extracted. Results: [14C]-Acetoacetate in the blood was increased in Dox(+), from 2 min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t-test, p < 0.05). PET kinetic analysis of [11C]-acetoacetate showed that rate constants K1, k2 and kmono were decreased in Dox(+) (p < 0.05) combined with a reduction of 24% of the left ventricular ejection fraction (p < 0.001). Conclusion: Radioactive acetoacetate ex vivo analysis [14C], and in vivo kinetic [11C] studies provided evidence that [11C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [11C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [11C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [11C]-acetoacetate in cardiac pathophysiology

  6. [11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

    Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø; Alstrup, Aage Kristian Olsen; Bender, Dirk

    2014-01-01

    Boc-protected precursor. The isolated [11C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[11C]-O-methylreboxetine ([11C]MeNER). RESULTS: The radiolabeling technique yielded [11C]NS8880 in low (<10%) but still useful......INTRODUCTION: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8...... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...

  7. [11C]β-CIT, a cocaine analogue. Preparation, autoradiography and preliminary PET investigations

    β-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) is a cocaine analogue with a high affinity for the dopamine transporter. [11C]β-CIT was prepared by N-methylation of nor-β-CIT with [11C]methyl iodide. The total radiochemical yield of [11C]β-CIT was 40-50% with an overall synthesis time of 35-40 min. The radiochemical purity was > 99% and the specific radioactivity at the time of injection was about 1000 Ci/mmol (37 GBq/μmol). Autoradiographic examination of [11C]β-CIT binding in human brains post-mortem demonstrated a high level of specific binding in the striatum. PET examination of [11C]β-CIT in a Cynomolgus monkey showed a marked accumulation of radioactivity in the striatum. The ratio of radioactivity in the striatum-to-cerebellum approached 5 after 87 min. In a displacement experiment, radioactivity in the striatum but not in the cerebellum, was markedly reduced after injection of unlabelled cocaine. [11C]β-CIT has a potential as ligand for PET examination of cocaine effects in man. (author)

  8. Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer

    Introduction: Up-regulation of the type 2 cannabinoid receptor (CB2R) has been reported in (neuro)inflammatory diseases. In this study, we report the preclinical evaluation of [11C]NE40 as positron emission tomography (PET) radioligand for visualization of the CB2R. Methods: The selectivity of NE40 for CB2R and its toxicity and mutagenicity were determined. [11C]NE40 was evaluated by biodistribution and autoradiography studies in normal rats and a microPET study in normal mice, rats and a rhesus monkey. Specific in vivo binding of [11C]NE40 to human CB2R (hCB2R) was studied in a rat model with hCB2R overexpression. Results: [11C]NE40 shows specific CB2R binding in the spleen and blood of normal rats and high brain uptake in rhesus monkey. [11C]NE40 showed specific and reversible binding to hCB2R in vivo in a rat model with local hCB2R overexpression. Conclusions: [11C]NE40 shows favorable characteristics as radioligand for in vivo visualization of the CB2R and is a promising candidate for hCB2R PET imaging.

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

    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.

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

    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.

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

    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)

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

    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. 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. 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

  13. Synthesis of carbon-11 labelled (R)-carnitine

    A route to 11C-labelled (R)-carnitine, based on the methylation of the dimethyl derivative is described. Furthermore, a five-step synthesis for the enantiomerically pure precursor is outlined. (author)

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

    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.

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

    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

  16. Synthesis of opiate receptor radioligand 11C-carfentanil and its biodistribution in rats

    Objective: To establish an automatic synthesis method for 11C-carfentanil (CFN) as an novel opiate receptor radioligand and study its biodistribution in rats. Methods: 11C-Triflate-CH3 was bubbled into 0.5 mg precursor desmethyl-CFN (which was dissolved in 0.15 ml DMSO) to generate 11C-CFN in a V-tube at room temperature. Sep-Pak C2 column was used for purification of 11C-CFN, which was eluted by 3 ml binary system aqueous solution, 10 ml water thrice, and then I ml ethanol. The biodistribution (% ID/g) of 11C-CFN in SD rats was studied. SPSS 13.0 was used for statistical analysis. Non-normal distribution data were analyzed using nonparametric test. Results: The synthesis time for 11C-CFN was 20 min (end of bombardment, EOB). The synthesis yield was (35.5±2.2) % on average (n=12, uncorrected)with the radiochemical purity over 98%. Biodistribution study in rats showed that the tracer had a high brain uptake, rapid blood clearance, and a metabolic pathway via liver and kidney. The highest tracer uptake was in thalamus (4.26±0.89) % ID/g and striatum (4.05±1.08) % ID/g at 5 min after injection, followed by cerebral cortex (2.63±0.89) %ID/g, pons (2.26±0.57) % ID/g, hippocampus (2.17±0.55) %ID/g and cerebellum (2.15±0.39) %ID/g. Conclusions: The automatic synthesis of 11C-CFN is fast and reliable, and this radioligand can be used for opiate receptor imaging. (authors)

  17. 11C-acetate PET imaging in patients with multiple sclerosis.

    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.

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

    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.

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

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

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The 18F-labeled amyloid tracer, [18F]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 [ 11C ]Pittsburgh compound B (PIB) and [ 18F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ 11C ]PIB and [ 18F ]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 [ 18F ]FACT studies without partial volume correction, while significant differences were observed in [ 11C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ 18F ]FACT studies as well as [ 11C ]PIB. Relatively lower uptakes of [ 11C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ 18F ]FACT. Relatively higher uptake of [ 11C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ 18F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ 11C ]PIB and [ 18F ]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic

  1. 11C-Colchicine distribution in tissues of colchicine -sensitive and -resistant neuroblastoma xenografts

    Mehta, B.M.; Levchenko, A.; Broussard, E. [Memorial Sloan Kettering Cancer Center, NY (United States)] [and others

    1995-05-01

    Multidrug resistance (MDR), a major obstacle in chemotherapy of cancer is thought to be due to the overexpression of a membrane P-glycoprotein (Pgp). P-glycoprotein acts as an energy activated efflux pump, reducing the effective drug concentrations from the MDR tumors. Our earlier studies using neuroblastoma cell lines BE(2)-C (-sensitive), and BE(2)-C/CHCb (-resistant) to colchicine (CHC), showed that uptake of 3H-CHC as well as 14C-CHC in sensitive tumors was twice as much as in resistant tumors. In view of this finding we synthesized 11C-CHC to study the distribution in xenografted animals, since 11C-CHC can be used a a Positron Emission Tomography (PET) tracer in humans. Two groups of Balb/c nude mice (5 animals each) xenografted with BE(2)-C and BE(2)-C/CHCb cells (10 x 10{sup 6} cells per animal) were injected iv retroorbitally with 200 {mu}Ci/100 {mu}l of 11C-CHC per animal. One hour after injection animals were sacrificed by cervical dislocation and blood, tissues and tumors were excised to determine the amount of radioactivity. 11C-CHC biodistribution compared well with 3H-CHC and 14C-CHC distribution. Tumor uptake in sensitive was 1.21 {plus_minus} 0.84% ID/g compared to 0.76 {plus_minus} 0.43% ID/g in resistant tumors. Tumor to blood ratios is sensitive and resistant tumors were 1.62 {plus_minus} 0.41 and 0.69 {plus_minus}0.30 respectively. 11C-Isocolchicine, a byproduct of 11C-CHC synthesis, on the other hand had only 25% uptake as compared to 11C-CHC in both sensitive and resistant tumors. We interpret these results to mean that 11C-CHC behaves similarly to other forms of CHC as a marker of the MDR phenotype. In the future, we plan to use 11C-CHC for identification of MDR status of tumors in vivo using PET scanning.

  2. Ammonia oxidation is not required for growth of Group 1.1c soil Thaumarchaeota.

    Weber, Eva B; Lehtovirta-Morley, Laura E; Prosser, James I; Gubry-Rangin, Cécile

    2015-03-01

    Thaumarchaeota are among the most abundant organisms on Earth and are ubiquitous. Within this phylum, all cultivated representatives of Group 1.1a and Group 1.1b Thaumarchaeota are ammonia oxidizers, and play a key role in the nitrogen cycle. While Group 1.1c is phylogenetically closely related to the ammonia-oxidizing Thaumarchaeota and is abundant in acidic forest soils, nothing is known about its physiology or ecosystem function. The goal of this study was to perform in situ physiological characterization of Group 1.1c Thaumarchaeota by determining conditions that favour their growth in soil. Several acidic grassland, birch and pine tree forest soils were sampled and those with the highest Group 1.1c 16S rRNA gene abundance were incubated in microcosms to determine optimal growth temperature, ammonia oxidation and growth on several organic compounds. Growth of Group 1.1c Thaumarchaeota, assessed by qPCR of Group 1.1c 16S rRNA genes, occurred in soil, optimally at 30°C, but was not associated with ammonia oxidation and the functional gene amoA could not be detected. Growth was also stimulated by addition of organic nitrogen compounds (glutamate and casamino acids) but not when supplemented with organic carbon alone. This is the first evidence for non-ammonia oxidation associated growth of Thaumarchaeota in soil. PMID:25764563

  3. Synthesis of [11C-methyl]-(-)-OSU6162, its regional brain distribution and some pharmacological effects of (-)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography

    The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6162, ((S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine) was performed by an alkylation with [11C]methyl iodide of the thio anion (-)-OSU1281, followed by a selective oxidation to the corresponding methyl sulfone, [11C-methyl]-(-)-OSU6162. The total radiochemical yield calculated from the produced [11C]carbon dioxide to final product was about 25% and the time of synthesis was in the range of 40 min from end of bombardment. The synthesis of the precursor, (-)-OSU1281, was performed from (-)-3PPP in a three-step synthesis. The regional brain distribution of (-)-OSU6162 radiolabelled with 11C was studied in rhesus monkeys by means of positron emission tomography, PET. [11C-Methyl]-(-)-OSU6162 was rapidly and uniformly distributed to gray matters of the brain, and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses of 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [11C-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88), supporting competition with dopamine for selective binding to dopamine receptors

  4. Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

    Palner, Mikael; McCormick, Patrick; Gillings, Nicolas; Begtrup, Mikael; Wilson, Alan A; Knudsen, Gitte M

    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 ...

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

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

    2012-01-01

    nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All......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...... subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes...

  6. Test-retest variability of quantitative [11C]PIB studies in Alzheimer's disease

    The aim of this study was to assess the test-retest variability of [11C]PIB studies in patients with Alzheimer's disease (AD) and healthy controls using several tracer kinetic models and to assess the suitability of the cerebellum as reference tissue. [11C]PIB studies with arterial sampling were performed in eight AD patients and eight healthy controls. Retest scans were performed in six controls and six AD patients. Data were analysed using plasma input and reference tissue models, together with simple ratios. Test-retest variability was best (∝3%) for SRTM2, a parametric method based on the simplified reference tissue model. Highest values (∝10%) were found for plasma input models. Cerebellar VT values did not differ significantly between AD and controls. Parametric SRTM2 with the cerebellum as reference tissue is the method of choice for quantitative analysis of [11C]PIB PET studies. (orig.)

  7. N-[11C]methylpiperidine esters as acetylcholinesterase substrates: an in vivo structure-reactivity study

    A series of simple esters incorporating the N-[11C]methylpiperidine structure were examined as in vivo substrates for acetylcholinesterase in mouse brain. 4-N-[11C]Methylpiperidinyl esters, including the acetate, propionate and isobutyrate esters, are good in vivo substrates for mammalian cholinesterases. Introduction of a methyl group at the 4-position of the 4-piperidinol esters, to form the ester of a teritary alcohol, effectively blocks enzymatic action. Methylation of 4- N-[11C]methylpiperidinyl propionate at the 3-position gives a derivative with increased in vivo reactivity toward acetylcholinesterase. Esters of piperidinecarboxylic acids (nipecotic, isonipecotic and pipecolinic acid ethyl esters) are not hydrolyzed by acetylcholinesterase in vivo, nor do they act as in vivo inhibitors of the enzyme. This study has identified simple methods to both increase and decrease the in vivo reactivity of piperidinyl esters toward acetylcholinesterase

  8. Synthesis of (2-[11C]Methoxy)rotenone, a marker of mitochondrial complex I activity

    Recent studies suggest that defects in the function of the complexes of the electron transport chain might be involved in the pathology of neurological diseases such as mitochondrial encephalopathies, Parkinson's Huntington's and Alzheimer's disease. Rotenone is a potent reversible competitive inhibitor of complex I (NADH-CoQ reductase). To study the possible involvement of complex I in such diseases, we synthesized (2-[11C]methoxy)rotenone by [11C]alkylation of 2-O-desmethyl rotenone methyl enol ether followed by hydrolysis of the enol ether to the ketone using aqueous trifluoroacetic acid. (2-[11C]Methoxy)rotenone was purified by high pressure liquid chromatography (silica gel) and was obtained in 7-10% yields decay corrected to end of bombardment in synthesis times typically shorter than 48 min. Radiochemical purities were over 95% and specific activities averaged 1000 Ci/mmol at end of synthesis

  9. [11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies.

    Gulyás, Balázs; Halldin, Christer; Vas, Adám; Banati, Richard B; Shchukin, Evgeny; Finnema, Sjoerd; Tarkainen, Jari; Tihanyi, Károly; Szilágyi, Géza; Farde, Lars

    2005-03-15

    Vinpocetine, a synthetic derivative of the Vinca minor alkaloid vincamine, is a widely used drug in neurological practice. We tested the hypothesis that vinpocetine binds to peripheral benzodiazepine binding sites (PBBS) and is therefore a potential ligand of PBBS. Positron emission tomography (PET) measurements in two cynomolgous monkeys showed that pretreatment with vinpocetine markedly reduced the brain uptake of [11C]PK11195, a known PBBS radioligand. On the other hand, whereas pretreatment with PK11195 increased the brain uptake of [11C]vinpocetine due to the blockade of PBBS in the periphery, it significantly reduced the binding potential (BP) values of [11C]vinpocetine in the whole brain and in individual brain structures to PK11195. These findings indicate that, whereas the two ligands have different affinities to PBBS, vinpocetine is a potent ligand of PBBS, which in turn suggests that the pharmacological activity of vinpocetine may involve the regulation of glial functions. PMID:15760643

  10. Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results

    Major depressive disorder (MDD) has been related to both a dysfunctional γ-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GABAA-benzodiazepine receptor in depressed patients or in relation to antidepressant treatment. Eleven depressed outpatients were compared, before and after treatment with citalopram, with nine age-matched healthy controls. The subjects were scanned using the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (VT) and binding potential (BPND) values. Plasma GABA levels were determined and a dexamethasone-corticotropin releasing hormone (DEX-CRH) test was performed. In MDD, parametric voxel-by-voxel Logan plots showed bilateral reduced [11C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected ≤0.001). In the temporal area, [11C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [11C]FMZ binding in the right insula. Following treatment with citalopram, voxel-based analysis revealed reduced binding in the right lateral temporal gyrus and dorsolateral prefrontal cortex. The bilateral reduction in limbic parahippocampal and right temporal [11C]FMZ binding found in MDD indicates decreased GABAA-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABAA binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition. (orig.)

  11. Biodistribution and radiation dosimetry of [11C]DASB in baboons

    Objective: The serotonin transporter has been implicated in a variety of conditions including mood disorders and suicidal behavior. In vivo human brain studies with positron emission tomography and the serotonin transporter antagonist [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) are ongoing in several laboratories with the maximum administered activity based on dosimetry collected in rodents. We report on the biodistribution and dosimetry of [11C]DASB in the baboon as this species may be a more reliable surrogate for human dosimetry. Methods: Four baboon studies (two studies in each of two baboons) were acquired in an ECAT ACCEL camera after the bolus injection of 183±5 MBq/2.3±1.0 nmol of [11C]DASB. For each study, six whole-body emission scans were collected in 3D mode over 6/7 bed positions for 2 h. Regions of interest were drawn on brain, lungs, liver, gallbladder, spleen, kidneys, small intestine and bladder. Since no fluid was removed from the animal, total body radioactivity was calculated using the injected dose calibrated to the ACCEL image units. Results: Uptake was greatest in lungs, followed by the urinary bladder, gallbladder, brain and other organs. The ligand was eliminated via the hepato-billiary and renal systems. The largest absorbed dose was found in the lungs (3.6x10-2 mSv/MBq). The absorbed radiation doses in lungs and gallbladder were four and nine times larger than that previously estimated from rat studies. Conclusion: Based on our baboon biodistribution and dose estimates, the lungs are the critical organs for administration of [11C]DASB. In the United States, the absorbed dose to the lungs would limit [11C]DASB administered with the approval of a Radioactive Drug Research Committee to 1400 MBq (37 mCi) in the adult male and 1100 MBq (30 mCi) in the adult female

  12. Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.

    Ding, Lin; Liu, Tianju; Wu, Zhe; Hu, Biao; Nakashima, Taku; Ullenbruch, Matthew; Gonzalez De Los Santos, Francina; Phan, Sem H

    2016-07-01

    Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation. PMID:27206766

  13. Pharmacokinetics and biodistribution of 11C-HupA in the normal animal

    Objective: Hula is one of the potential drugs which can be used to treat Alzheimer's disease (Ad). The aim of this study was to explore the pharmacokinetics and biodistribution of Hula in vivo by using 11C-Hula. Methods: A total of 25 Sd rats were studied. They were divided into 5 groups (5 rats in each group). All had intravenous injection of 22 MBq (in 0.2 ml) 11C-Hula through tail vein. Dynamic imaging Was acquired from 5 to 90 minutes after injection. Venous blood and organ activities were collected at 5, 15, 30, 60. and 90 minutes after injection. Percentage activity of injected dose per gram of tissue (%ID/g) was calculated to characterize the biodistribution of tracer in different brain regions: frontal,apical, temporal, occipital, cerebellum, hippocampus, striatum, thalamencephalon, and brain stem, Variance analysis using SPSS 11.5 software was performed and compared among the study groups. Results: 11C-HupA was characteristic for its quick clearance from blood, with half time T1/2 of (14.61 ± 1.77) min, and clearance rate (CL) of (0.12 ± 0.01) ml · min -1· kg-1. Metabolism was through liver, and excretion through kidney. Pharmacokinetics of 11C-HupA in rats corresponded to a one-compartment model. with an activity curve (area under curve, AUC)0-8 integral of (167.57 ± 12.39) ml · min-1 · kg-1. There was significant difference of 11C-HupA distribution in different brain regions, being greater in cerebral cortex, hippocampus, hypothalamus and brain stem. Conclusions: Pharmacokinetic study of 11C-HupA in brain was fast. convenient and showed high specificity and sensitivity. Its ability to quantitatively evaluate brain function and its characteristic distribution in mice provided some evidence for monitoring therapy in AD patients. (authors)

  14. 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

    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.).

  15. Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

    Brand, Toni M; Dunn, Emily F.; Iida, Mari; Myers, Rebecca A.; Kostopoulos, Kellie T.; Li, Chunrong; Peet, Chimera R.; Wheeler, Deric L

    2011-01-01

    The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resis...

  16. Erlotinib-mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4

    Orcutt, Kevin P.; Parsons, Arlene D.; Sibenaller, Zita A.; Scarbrough, Peter M.; Zhu, Yueming; Sobhakumari, Arya; Wilke, Werner W.; Kalen, Amanda L.; Goswami, Prabhat; Miller, Francis J.; Spitz, Douglas R.; Simons, Andrean L.

    2011-01-01

    Redox regulation of EGFR signaling helps protect cells against oxidative stress. In this study, we investigated whether the cytotoxicity of an EGFR tyrosine kinase inhibitor, erlotinib (ERL), was mediated by induction of oxidative stress in human head and neck cancer (HNSCC) cells. ERL elicited cytotoxicity in vitro and in vivo while increasing a panel of oxidative stress parameters which were all reversible by the antioxidant N-acetyl cysteine. Knockdown of EGFR using siRNA similarly increas...

  17. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma

    Sathornsumetee, Sith; Desjardins, Annick; Vredenburgh, James J.; McLendon, Roger E; Marcello, Jennifer; Herndon, James E.; Mathe, Alyssa; Hamilton, Marta; Jeremy N Rich; Norfleet, Julie A.; Gururangan, Sridharan; Friedman, Henry S.; Reardon, David A.

    2010-01-01

    Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The pri...

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

    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/m2 to 825 mg/m2 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

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

    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.

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

    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

  1. Extraction of left ventricular myocardial mass from dynamic 11C-acetate PET

    Harms, Hans; Tolbod, Lars Poulsen; Hansson, Nils Henrik; Kero, Tanja; Orndahl, LH; Kim, Won Yong; Bouchelouche, Kirsten; Wiggers, Henrik; Frøkiær, Jørgen; Sørensen, Jens

    resonance (CMR) scan. The aim of this study was to explore the feasibility of estimating myocardial mass directly from a dynamic 11C-acetate PET scan. Methods: 21 subjects underwent a 27-min 11C-acetate PET scan on a Siemens Biograph TruePoint 64 PET/CT scanner. In addition, 10 subjects underwent a dynamic...... wall was defined automatically using obtained parametric images and myocardial mass was derived from the volumes of the obtained myocardial segments. LV myocardial mass derived from CMR was used as gold standard reference. Results: A good agreement between LV mass derived using PET and CMR was found...

  2. 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

    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

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

    Introduction: [11C]Loperamide and [11C]N-desmethyl-loperamide ([11C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [11C]loperamide metabolism is N-demethylation to [11C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [11C]loperamide and [11C]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 [11C]loperamide or [11C]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 [11C]loperamide and its main radiometabolite, [11C]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 [11C]loperamide and the radiometabolite [11C]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 [11C]dLop and its radiometabolites in either wild-type or knockout mice, except to increase the low plasma [11C]dLop concentration. The least polar radiometabolite of [11C]dLop was identified with LC-MSn as the N-hydroxymethyl analog of [11C]dLop and this also behaved as a P-gp substrate. Conclusion: In this study, ketoconazole (50 mg/kg, ip) proved partially effective for inhibiting the N-demethylation of [11C]loperamide in mouse in vivo but had relatively

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

    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

  5. Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential

    Cantero, Jon; Tarrats, Antoni; Fernández, Marco Antonio; Sumoy, Lauro; Rodolosse, Annie; McSorley, Stephen J.

    2016-01-01

    CD11c is an α integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naïve mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including γδ T cells and invariant natural killer T (iNKT) cells. However, in women, only γδ T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-γ secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential. PMID:27119555

  6. In vivo imaging of astrocytosis in Alzheimer's disease: an {sup 11}C-L-deuteriodeprenyl and PIB PET study

    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.)

  7. Alterations in the translocation of photosynthesis products in soy bean varieties stressed by salt administration: Application of the radionuclides 11C and 14C

    In the soy bean varities ''Lee'' and ''Jackson'' possessing different sensitivity to salt the influence of NaCl salinification of the culture medium of different intensity and duration on the net rate of photosynthesis and assimilate translocation was investigated. The two radioactive isotopes 11C and 14C proved to be suitable indicators for tracing the assimilate transport. By means of the short-lived isotope 11C (Tsub(1/2)=20.3 min) short-time kinetics of assimilate transport by the roots were established, and 14C helped to strike the balance of assimilate distribution in the total plant. For the implementation of the experiments it was necessary to average extensive experimental set-ups. For the labelling of individual leaf organs under laboratory conditions an inexpensive furnigation system was constructed. A special device was built for in-vivo measurement of leaf-to-root translocation using 11C. Stressing by salt administration had a differentiated effect on photosynthesis and assimilate translocation, which depended both on the intensity and duration of the salt administration. (orig./MG)

  8. Synthesis and preliminary biological evaluation of MMP inhibitor radiotracers [11C]methyl-halo-CGS 27023A analogs, new potential PET breast cancer imaging agents

    A series of [11C]methyl-halo-CGS 27023A analogs (2-F, 1a; 4-F, 1b; 2-Cl, 1c; 3-Cl, 1d; 4-Cl, 1e; 2-Br, 1f; 3-Br, 1g; 4-Br, 1h; 4-I, 1i), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The precursors halo-CGS 27023A analogs (2-F, 6a; 4-F, 6b; 2-Cl, 6c; 3-Cl, 6d; 4-Cl, 6e; 2-Br, 6f; 3-Br, 6g; 4-Br, 6h; 4-I, 6i) for radiolabeling were obtained in four steps from starting material amino acid D-valine with moderate to excellent chemical yields. Precursors were labeled by [11C]methyl triflate through 11C-O-methylation method at the aminohydroxyl position under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compounds in 40-60% radiochemical yields (decay corrected to end of bombardment), in 20-25 min synthesis time

  9. Imaging the serotonin transporter with positron emission tomography: initial human studies with [{sup 11}C]DAPP and [{sup 11}C]DASB

    Houle, S.; Ginovart, N.; Hussey, D.; Meyer, J.H.; Wilson, A.A. [Vivian Rakoff PET Centre, Centre for Addiction and Mental Health and University of Toronto (Canada)

    2000-11-01

    Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio)benzylamine (DAPP) and N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [{sup 11}C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [{sup 11}C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans. (orig.)

  10. Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB

    Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio)benzylamine (DAPP) and N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [11C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [11C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans. (orig.)

  11. Productions and interests of the radiopharmaceuticals labelled by 11C, 13N, 15O, and 18F

    As medical diagnosis methods based on the use of short-life radioelements such as carbon-11, nitrogen-13, oxygen-15 and fluorine-18 have been developed, these four radio-isotopes are notably adapted to external detection by tomography. Besides, due to their short period, their radioactive concentration per mass unity is very high. In the first part of this research thesis, the author presents the characteristics of these four radio-isotopes, describes the operation of cyclotrons and the principles, benefits, drawbacks, and types of positron emission tomography. The second part addresses the production of the radionuclides and precursors, the production of radiopharmaceutical products (haemoglobin, sugars, amino acids, fatty acids, steroid marking, and drug marking). The third part reports some studies illustrating the pharmaceutical interest of these radioelements

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

    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

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

    Cantore, Mariangela; Benadiba, Marcel; Elsinga, Philippus; Kwizera, Chantal; Dierckx, Rudi; Colabufo, Nicola A.; Luurtsema, Geert

    2016-01-01

    Abstract 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

  14. Some radiopharmaceuticals derived from carbon-eleven labelled phosgene

    This thesis deals with some applications of the short lived cyclotron produced radioisotope carbon-11 (half life 20.4 min.) For medical use. Both chemical manipulation of highly radioactive gamma emitting material in order to prepare suitable 11C-labelled radiopharmaceuticals and two clinical studies are discussed. The first chapter comprises a general introduction concerning the application of the ''tracer principle'' to the short lived positron emitting radionuclides 18F, 11C, 13N and 15O in medicine. Chapter two deals with the synthesis of 11COCl2. This product is a useful new 11C-synthon with many potential applications. In chapter three the synthesis of 11C-urea from 11C-phosgene for medical use is described. The method uses the reaction of 11COCl2 with aqueous ammonia. Chapter four deals with the synthesis of 11C-barbituric acids and 11C-hydantoins and presents a clinical study on epilepsy, using 2-11C-5,5-diphenylhydantoin (11C-DPH). Patients having intractable epilepsy and patients having no epilepsy were given intravenously a single dose of 11C-DPH after which the accumulation of the radioactivity in the brain was followed by positron emission tomography. No regional concentration differences could be found near epileptic foci. There was a faint indication that there are some differences in uptake for whole brain between the two categories of patients. (Auth.)

  15. Angular distributions of four neutron groups from the 10B(d, n)11C reaction

    Paris, C.H.; Endt, P.M.

    1954-01-01

    Measurements are described of the angular distributions of the four most energetic neutron groups from the 10B(d, n)11C reaction at a deuteron energy of 0.6 MeV. Neutrons were detected by their recoil protons in nuclear emulsions. The angular distributions have been analyzed in terms of a stripping

  16. Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET

    Sørensen, M.; Munk, O.L.; Ørntoft, N.W.;

    2016-01-01

    the liver with simultaneous measurements of hepatic blood perfusion and 11C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with...

  17. Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET

    Sørensen, Michael; Munk, Ole Lajord; Oerntoft, Nikolaj;

    2016-01-01

    liver with measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal and hepatic venous blood. In three pigs (seven experiments) bile was collected from a catheter in the common hepatic duct (CHD). PET data were analyzed by a two-tissue compartmental model with...

  18. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

    Marner, Lisbeth; Gillings, Nic; Madsen, Karine; Erritzoe, David; Baaré, William F C; Svarer, Claus; Hasselbalch, Steen G; Knudsen, Gitte M

    2010-01-01

    the low inter-and intrasubject variation, use of the present method will enable detection of a 15% difference in striatum with only 7-13 subjects in a 2-sample test and with only 4-5 subjects in a paired test. The citalopram challenge did not discernibly alter [(11)C]SB207145 binding. In conclusion...

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

    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...

  20. Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184

    Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation. Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Brain uptake of [11C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. [11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium. (orig.)

  1. Charge topology of the coherent dissociation of relativistic {sup 11}C and {sup 12}N nuclei

    Artemenkov, D. A.; Bradnova, V.; Zaitsev, A. A.; Zarubin, P. I., E-mail: zarubin@lhe.jinr.ru; Zarubina, I. G.; Kattabekov, R. R.; Kornegrutsa, N. K.; Mamatkulov, K. Z.; Rukoyatkin, P. A.; Rusakova, V. V. [Joint Institute for Nuclear Research (Russian Federation); Stanoeva, R. [South–West University (Bulgaria)

    2015-09-15

    The charge topology of coherent-dissociation events is presented for {sup 11}C and {sup 12}N nuclei of energy 1.2 GeV per nucleon bombarding nuclear track emulsions. This topology is compared with respective data for {sup 7}Be, {sup 8,10}B, {sup 9,10}C, and {sup 14}N nuclei.

  2. Synthesis of ( sup 11 C)citalopram and brain distribution studies in rats

    Ram, S.; Krishnan, K.R.R.; Bissette, G.; Knight, D.L.; Coleman, R.E. (Duke Univ., Durham, NC (USA). Medical Center)

    1991-01-01

    Citalopram (1-(3-dimethylamino)propyl-1-(p-fluoro-phenyl)-5-phthalancarbonitrile) is a selective serotonin uptake inhibitor, and this prototype drug possesses high affinity for serotonin uptake sites and is used in the treatment of depression. We have synthesized ({sup 11}C)citalopram by alkylation. The procedure involves the reaction of ({sup 11}C)iodomethane with desmethylcitalopram in acetone in the presence of sodium hydroxide base at 65{sup o}C for 8-10 min, and followed by purification by column, which contained, in series silica gel and basic alumina produces pure ({sup 11}C)citalopram with a specific activity of 150-434 Ci/mmol (at EOS). The radiochemical yields were 18% to 66% (at EOB), with a radiochemical purity range 92% to 99%. In vivo biodistribution of ({sup 11}C)citalopram in Sprague-Dawley rats brain clearly differentiates regions of high (frontal cortex, substantia niagra and hypothalamus) and low (cerebellum) uptake corresponding to the known distribution of serotonin uptake in rats and primates. These results demonstrate that this ligand is suitable for study of serotonin uptake sites by P.E.T., and may be useful as a biochemical diagnostic imaging tool in various psychiatric disorders. Further studies with this ligand are in progress. (author).

  3. Charge topology of coherent dissociation of $^{11}$C and $^{12}$N relativistic nuclei

    Artemenkov, D A; Zaitsev, A A; Zarubin, P I; Zarubina, I G; Kattabekov, R R; Kornegrutsa, N K; Mamatkulov, K Z; Rukoyatkin, P A; Rusakova, V V; Stanoyeva, R Z

    2014-01-01

    The charge topology of the events of coherent dissociation of $^{11}$C and $^{12}$N of an energy of 1.2~A~GeV in nuclear track emulsion is presented and its compared is given with the appropriate data on the nuclei $^{7}$Be, $^{8,10}$B, $^{9,10}$C and $^{14}$N.

  4. 11C-methane production in small volume, high pressure gas targets

    The parameters affecting the production of 11C-methane, in situ, in small volume, high-pressure gas targets include target chamber size and material. The results are based on experiments that varied the target gas composition, the target material and geometry. Methane production yields were typically 65% of the yields of 11CO2 in the same target chamber. (orig.)

  5. Synthesis and distribution kinetics of 11C-chlorpromazine in animals

    A study on animals of the fast distribution kinetics of 11C-chlorpromazine hydrochloride administered intravenously shows, in both rabbits and monkeys, a very early radioactivity build-up in the brain and lungs (immediately after injection). The lung and brain activities develop and decrease during the experimental period (about 60 min) whereas that of the liver increases. Quantitative results obtained on mice after removal of the organs and counting of the activity obtained by intravenous injection of 11C-chlorpromazine hydrochloride prove that the radioactivity observed is indeed an accumulation and is not due to passage of the blood flow, the blood activity remaining low throughout. No tumor fixation of 11C-chlorpromazine was observed in the mice under our experimental conditions. A quantitative kinetics study of 11C-chlorpromazine in vivo is not easy to pursue in animals such as rabbits or monkeys, and even less so in mice, in view of the size of the animal and the resolution of the gamma camera collimator. But this, we think, is relatively unimportant as the aim of this work is to prepare for the application to humans of this new pharmacokinetics method

  6. Visual assessment of [11C]PIB PET in patients with cognitive impairment

    The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-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 (κ = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p 11C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings. (orig.)

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

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

    Vesicular monoamine transporter type 2 abundance quantified using the radiotracer [11C]-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 [11C]-DTBZ in humans. Five baboon studies were acquired using a Siemens ECAT camera. After transmission scanning, 165-210 MBq of [11C]-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 [11C]-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.)

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

    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.)

  10. The Analysis of Erlotinib on Brain Metastases in Patients with Non-small-cell Lung Cancer

    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

  11. Amino acid uptake in the skeletal muscle measured using [11C]methylaminoisobutyrate (MEAIB) and PET

    An amino acid analogue, [11C]MeAIB, recently introduced for oncological positron emission tomography (PET) studies, is a highly selective substrate for insulin-sensitive amino acid transport system A. The aim of this study was to study the uptake kinetics of [11C]MeAIB in skeletal muscle in the fasting state and during insulin stimulation. Two dynamic PET studies were carried out in 11 healthy subjects, once in the fasting state and once during euglycaemic hyperinsulinaemia (serum insulin 67±12 mU l-1). Graphical analysis was used to calculate the fractional [11C]MeAIB uptake rate (Ki). Amino acid uptake was estimated by multiplying Ki by the serum amino acid concentration. After tracer injection, rapid uptake in muscle tissue was detected both in the fasting state and during insulin stimulation and femoral muscles were clearly visualised in both studies. In the graphical analysis, the volume of distribution of [11C]MeAIB plotted against normalised plasma time yielded a linear curve (the slope of which = Ki). The fractional [11C]MeAIB uptake rate (Ki) in the femoral muscle regions increased from 0.0070±0.0018 min-1 (mean±SD) in the fasting state to 0.0079±0.0020 min-1 (P-1 (P-1 (P=0.0001) during hyperinsulinaemia. The calculated skeletal muscle total amino acid uptake and the uptake of the six amino acids typically using system A were similar in the fasting state and during insulin clamp (17.1±3.2 vs 17.7±3.7 μmol kg-1 min-1, NS, and 5.0±1.3 vs 5.0±1.4 μmol kg-1 min-1, NS, respectively). The uptake rates correlated with perfusion both in the fasting state and during hyperinsulinaemia (P11C]MeAIB PET appears to be a feasible method for measurement of amino acid uptake in human skeletal muscle. As a tracer that is not metabolised in the tissues, [11C]MeAIB provides simple modelling and robust data analysis and thus provides a means to investigate amino acid uptake into muscle tissue in various disease conditions known to affect protein metabolism. (orig.)

  12. Utilidad de 11C-metionina PET/CT en neurooncología

    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.

  13. Quantification of (R)-[{sup 11}C]PK11195 binding in rheumatoid arthritis

    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.)

  14. Synthesis of 2-[11C]cyano-isonicotinic acid hydrazide

    Isonicotinic acid hydrazide (isoniazid), a drug used in treating tuberculosis has been labelled with carbon-11 at the 2-position. The labelling synthesis starts with methyl isonicotinate treated with dimethyl sulfate. The resulting salt solution is loaded onto silica gel and dried, followed by treatment with carbon-11 labelled hydrocyanic acid. Work-up gave the labelled compound with an average 32% radiochemical yield. Subsequent treatment with hydrazine hydrate yielded isoniazid

  15. Development and evaluation of muscarinic cholinergic receptor ligands n-[11c]ethyl-4-piperidyl benzilate and n-[11c]propyl-4-piperidyl benzilate: a PET study in comparison with n-[11c]methyl-4-piperidyl benzilate in the conscious monkey brain

    The muscarinic cholinergic receptor ligands N-[11C]ethyl-4-piperidyl benzilate (4-EPB) and N-[11C]propyl-4-piperidyl benzilate (4-PPB) were developed and evaluated in comparison with N-[11C]methyl-4-piperidyl benzilate (4-MPB) in the conscious monkey brain using positron emission tomography (PET). Time-activity curves of [11C]4-EPB, unlike [11C]4-MPB, showed peaks within 91 min in regions rich in muscarinic receptors. [11C]4-PPB showed no specific binding even in the regions rich in these receptors. These observation demonstrated that increases in [11C]alkyl chain length could alter the kinetic properties of receptor ligands for PET

  16. Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy.

    He, Yongju; Su, Zhigui; Xue, Lingjing; Xu, Hui; Zhang, Can

    2016-05-10

    Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG2C18-L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl-l-glutamyl2-histidyl-hexahydrobenzoic acid, HHG2C18) was used to construct a pH-sensitive lipid bilayer (HHG2C18-L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH2). Erlotinib and DOX were separately incorporated into HHG2C18-L and MSN-NH2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG2C18-L(E+D)). We confirmed that M-HHG2C18-L(E+D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH2, erlotinib released faster than DOX during the cellular transport. Additionally, HHG2C18-L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH2, leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E+D)) and simultaneous DRUG coadministration. M-HHG2C18-L(E+D) with sequential staggered drug release and pH-sensitive charge conversional properties

  17. Synthesis and biological evaluation of [11C]SB366791: A new PET-radioligand for in vivo imaging of the TRPV1 receptor

    Introduction: The transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor, a non-selective cation channel, is known for its key role in pain nociception and neurogenic inflammation. TRPV1 expression has been demonstrated in diverse tissues and an essential role for TRPV1 in various disorders has been suggested. A TRPV1-specific PET-radioligand can serve as a useful tool for further in vivo research in animals and directly in humans. In this study, we report the synthesis and biological evaluation of a carbon-11 labelled analogue of N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) which was reported as a specific high-affinity antagonist for TRPV1. Methods: The new tracer was evaluated with respect to log D and biodistribution in control, pretreated and TRPV1−/− mice. The percentage of radiometabolites of [11C]SB366791 was determined in mouse plasma and brain. Results: [11C] SB366791 was obtained in good yield (69% ± 11%; isolated amounts 3034–5032 MBq) and high specific activity (390 ± 215 GBq/μmol). The tracer was efficiently cleared from blood and all major organs via hepatobiliary and renal pathways. Initial brain uptake was high (1.6% ID) and wash-out from brain was rapid. The retention of [11C] SB366791 in the trigeminal nerve of control mice was prominent. The in vitro binding affinity of SB366791 was determined to be 280 ± 56 nM and 780 ± 140 nM for human and rat TRPV1, respectively. Conclusions: [11C] SB366791 has favourable biodistribution characteristics in mice. However the obtained low binding affinity for TRPV1 may not be sufficient to use the current compound as PET tracer.

  18. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the 18F-labeled Pittsburgh compound B (PIB) derivative [18F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [18F]FMM and [11C]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 [18F]FMM PET 85 min after injection, 60-min dynamic [11C]PIB PET, and cognitive testing. [18F]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. [18F]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 [11C]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 18F]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 [11C]PIB PET. (orig.)

  19. Synthesis of the racemate and individual enantiomers of [11C]methylphenidate for studying presynaptic dopaminergic neutron with positron emission tomography

    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 [11C]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/μmole (at EOB). (author)

  20. Synthesis of the racemate and individual enantiomers of [[sup 11]C]methylphenidate for studying presynaptic dopaminergic neutron with positron emission tomography

    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. Reproducibility of repeated measures of deuterium substituted [{sup 11}C]L-deprenyl ([{sup 11}C]L-deprenyl-D2) binding in the human brain

    Logan, Jean E-mail: jlogan@bnl.gov; Fowler, Joanna S.; Volkow, Nora D.; Wang, Gene-Jack; MacGregor, Robert R.; Shea, Colleen

    2000-01-01

    The purpose of this study was to assess the reproducibility of repeated positron emission tomography (PET) measures of brain monoamine oxidase B (MAO B) using deuterium-substituted [{sup 11}C]L-deprenyl ([{sup 11}C]L-deprenyl-D2) in normal subjects and to validate the method used for estimating the kinetic constants from the irreversible 3-compartment model applied to the tracer binding. Five normal healthy subjects (age range 23-73 years) each received two PET scans with [{sup 11}C]L-deprenyl-D2. The time interval between scans was 7-27 days. Time-activity data from eight regions of interest and an arterial plasma input function was used to calculate {lambda}k{sub 3}, a model term proportional to MAO B, and K{sub 1}, the plasma to brain transfer constant that is related to blood flow. Linear (LIN) and nonlinear least-squares (NLLSQ) estimation methods were used to calculate the optimum model constants. A comparison of time-activity curves for scan 1 and scan 2 showed that the percent of change for peak uptake varied from -18.5 to 15.0% and that increases and decreases in uptake on scan 2 were associated with increases and decreases in the value of the arterial input of the tracer. Calculation of {lambda}k{sub 3} showed a difference between scan 1 and scan 2 in the global value ranging between -6.97 and 4.5% (average -2.1{+-}4.7%). The average percent change for eight brain regions for the five subjects was -2.84{+-}7.07%. Values of {lambda}k{sub 3} for scan 1 and scan 2 were highly correlated (r{sup 2}=0.98; p<0.0001; slope 0.955). Similarly, values of K{sub 1} showed a significant correlation between scan 1 and scan 2 (r{sup 2}=0.61; p<0.0001; slope 0.638) though the values for scan 2 were generally lower than those of scan 1. There was essentially no difference between the values of model constants calculated using the NLLSQ or LIN methods. Regional brain uptake of [{sup 11}C]L-deprenyl-D2 varied between scan 1 and scan 2, driven by the differences in arterial

  2. Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer's disease

    Amyloid imaging with 18F-labelled radiotracers will allow widespread use of this technique, facilitating research, diagnosis and therapeutic development for Alzheimer's disease (AD). The purpose of this analysis was to compare data on cortical Aβ deposition in subjects who had undergone both 11C-PiB (PiB) and 18F-florbetaben (FBB) PET imaging. We identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370 MBq of PiB and 300 MBq of FBB under separate research protocols. PiB and FBB images were coregistered so that placement of regions of interest was identical on both scans and standard uptake value ratios (SUVR) using the cerebellar cortex as reference region were calculated between 40 and 70 min and between 90 and 110 min after injection for PiB and FBB, respectively. Significantly higher SUVR values (p 18F radiotracer for imaging AD pathology in vivo. (orig.)

  3. Biodistribution and radiation dosimetry of [{sup 11}C]DASB in baboons

    Belanger, Marie-Jose [Department of Psychiatry, Columbia University College of Physicians and Surgeons New York, NY 10032 (United States); Division of Brain Imaging, Department of Neuroscience, New York State Pyschiatric Institute, New York, NY 10032 (United States); Simpson, Norman R. [Department of Radiology, Columbia University College of Physicians and Surgeons and Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032 (United States); Wang, Theodore [Department of Radiology, Columbia University College of Physicians and Surgeons and Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032 (United States); Division of Brain Imaging, Department of Neuroscience, New York State Pyschiatric Institute, New York, NY 10032 (United States)] [and others

    2004-11-01

    Objective: The serotonin transporter has been implicated in a variety of conditions including mood disorders and suicidal behavior. In vivo human brain studies with positron emission tomography and the serotonin transporter antagonist [{sup 11}C]DASB ([{sup 11}C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) are ongoing in several laboratories with the maximum administered activity based on dosimetry collected in rodents. We report on the biodistribution and dosimetry of [{sup 11}C]DASB in the baboon as this species may be a more reliable surrogate for human dosimetry. Methods: Four baboon studies (two studies in each of two baboons) were acquired in an ECAT ACCEL camera after the bolus injection of 183{+-}5 MBq/2.3{+-}1.0 nmol of [{sup 11}C]DASB. For each study, six whole-body emission scans were collected in 3D mode over 6/7 bed positions for 2 h. Regions of interest were drawn on brain, lungs, liver, gallbladder, spleen, kidneys, small intestine and bladder. Since no fluid was removed from the animal, total body radioactivity was calculated using the injected dose calibrated to the ACCEL image units. Results: Uptake was greatest in lungs, followed by the urinary bladder, gallbladder, brain and other organs. The ligand was eliminated via the hepato-billiary and renal systems. The largest absorbed dose was found in the lungs (3.6x10{sup -2} mSv/MBq). The absorbed radiation doses in lungs and gallbladder were four and nine times larger than that previously estimated from rat studies. Conclusion: Based on our baboon biodistribution and dose estimates, the lungs are the critical organs for administration of [{sup 11}C]DASB. In the United States, the absorbed dose to the lungs would limit [{sup 11}C]DASB administered with the approval of a Radioactive Drug Research Committee to 1400 MBq (37 mCi) in the adult male and 1100 MBq (30 mCi) in the adult female.

  4. (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET

    In order to investigate [11C]nicotine binding and metabolism in the living human brain by PET, routine protocols were developed for the preparation and purification of (S)-and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. (S)- and (R)-[11C]nicotine were prepared by N-methylation with [11C]methyl iodide of the appropriate secondary amine, which was liberated in situ by 2,2,6,6,-tetramethylpiperidine (TMP) from its corresponding biscamsylate-salt. (R/S)-[11C]Cotinine was prepared by N-methylation of the amide precursor using tetrabutylammonium hydroxide as a phase transfer catalyst. Straight-phase semipreparative HPLC was in all purifications found to be superior to reversed-phase since the contamination by the norcompounds was eliminated. Reaction in acetonitrile for both (S)- and (R)-[11C]nicotine and (R/S)-[11C]cotinine with subsequent straight-phase HPLC purification resulted in 35-45% radiochemical yield with a total synthesis time of 30-35 min, a specific radioactivity of 1000-1500 Ci/mmol (37-55 GBq/μmol, EOS) and a radiochemical purity >99%. The uptake and distribution of these tracers in the human brain was studied in healthy volunteers by PET. The metabolite (R/S)-[11C]cotinine did not cross the blood-brain barrier to any significant degree. (author)

  5. Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study

    This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6). Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01235416

  6. Positron emission tomography (PET) study of the alterations in brain distribution of [11C]dethamphetamine in methamphetamine sensitized dog

    [11C]Methamphetamine ([11C]MAP) was synthesized by an automated on-line [11C]methylation system for positron emission tomography (PET) study. We newly produced a MAP sensitized dog by repeated MAP treatment and studied the brain distribution of [11C]MAP in the normal and the MAP sensitized dog. The maximal level of accumulation of [11C]MAP in the sensitized dog brain was 1.4 times higher than that in the control. No difference was found in the metabolism of MAP between the two conditions. The significant increase of [11C]MAP in the MAP sensitized brain indicates that subchronic MAP administration causes some functional change in uptake site of MAP

  7. Imaging Spectrum and Pitfalls of 11C-Methionine Positron Emission Tomography in a Series of Patients with Intracranial Lesions

    Matsuda, Hiroshi; Kubota, Kazoo

    2016-01-01

    11C-methionine (Met) positron emission tomography (PET) is one of the most commonly used PET tracers for evaluating brain tumors. However, few reports have described tips and pitfalls of 11C-Met PET for general practitioners. Physiological 11C-Met uptake, anatomical variations, vascular disorders, non-tumorous lesions such as inflammation or dysplasia, benign brain tumors and patient condition during 11C-Met PET examination can potentially affect the image interpretation and cause false positives and negatives. These pitfalls in the interpretation of 11C-Met PET images are important for not only nuclear medicine physicians but also general radiologists. Familiarity with the spectrum and pitfalls of 11C-Met images could help prevent unfavorable clinical results caused by misdiagnoses. PMID:27134530

  8. Comparison of microglia and infiltrating CD11c+ cells as antigen presenting cells for T cell proliferation and cytokine response

    Wlodarczyk, Agnieszka; Løbner, Morten; Cédile, Oriane;

    2014-01-01

    BACKGROUND: Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells...... (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. METHODS: In this work we compared the antigen presenting capacity of CD11c+ and CD11c- microglia subsets with infiltrating CD11c......+ APC, which include DC. The microglial subpopulations (CD11c- CD45dim CD11b+ and CD11c+ CD45dim CD11b+) as well as infiltrating CD11c+ CD45high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR...

  9. Maintenance erlotinib in advanced nonsmall cell lung cancer: cost-effectiveness in EGFR wild-type across Europe

    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

  10. EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.

    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.

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

    Nahimi, Adjmal; Jakobsen, Steen; Munk, Ole;

    2015-01-01

    of 11C-yohimbine. With the lowest steady-state distribution volume (VT), determined in the corpus callosum, we calculated the binding potential (receptor availability) of the radioligand in other regions. Results: The linear regressions yielded similar estimates of the kinetic parameters. The...... cortical values of VT ranged from 0.82 mL cm−3 in the right frontal cortex to 0.46 mL cm−3 in the corpus callosum, with intermediate VT values in subcortical structures. Binding potentials averaged 0.6–0.8 in the cortex and 0.2–0.5 in subcortical regions. Conclusion: The maps of 11C-yohimbine binding to α2...

  12. Cerebral monoamine oxidase A inhibition in tobacco smokers confirmed with PET and [11C]Befloxatone

    The inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand [11C]befloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of [11C]befloxatone binding potential (BP) in cortical areas (average reduction, -60%) and a similar trend in caudate and thalamus (-40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco. (authors)

  13. Synthesis of no-carrier-added alpha-[11C]methyl-L-tryptophan

    Described here is a synthesis of no-carrier-added alpha-[11C]methyl-L-tryptophan based on alkylation with 11CH3I of an anion generated by reacting the Schiff base of L-tryptophan methyl ester with di-isopropylamine. The synthesis requires approximately 30 min after the end of 11CO2 collection and gives alpha-[11C]methyl-L-tryptophan in a 20-25% radiochemical yield calculated at the end of the synthesis and without correction for radioactive decay. The specific activity of the final radiopharmaceutical, measured at the end of the synthesis, was around 2000 Ci/mmol. Data confirming the stereospecificity of the synthesis are also presented

  14. N-[11C]-methyl-hydroxyfasudil is a potential biomarker of cardiac hypertrophy

    Introduction: Pathologic cardiac hypertrophy is one of the leading causes of sudden death from cardiac disease and involves a complex network of bio-signaling mechanisms. To date, the clinical detection and pathologic progression of hypertrophy remains elusive. Here we tested whether imaging Rho kinase activity would serve an accurate proxy for detecting hypertrophy. Specifically, we examine the use of the N-[11C]-methylated derivative of hydroxyfasudil, a Rho kinase inhibitor, as a biomarker for accurate identification of cardiomyocyte hypertrophy. Methods: Both transformed and primary neonatal cardiomyocytes were treated with isoproterenol to induce β-adrenergic receptor stimulation and hypertrophy. Phenotypic hypertrophy was verified using cytochemical evaluation of cell and nuclear size. Western blot and activity assays were used to detect ERK 1/2 mTOR and Rho kinase activation. N-[11C]-methyl-hydroxyfasudil binding was verified using in vitro binding assays with isoproterenol stimulated cells. Results: Isoproterenol induced a rapid and distinct activation of ERK 1/2, mTOR and Rho kinase with negligible cytotoxicity. Subsequent expansion in cell and nuclear size that is typically associated with hypertrophy was also observed. Enhanced retention of N-[11C]-methyl-hydroxyfasudil observed after ISO-induced Rho kinase activation in hypertrophic cells was prevented by pre-treatment with unlabeled hydroxyfasudil. Conclusions: N-[11C]-methyl-hydroxyfasudil is able to measure increased Rho kinase activity via specific binding in hypertrophied cardiomyocytes and demonstrates the potential for molecular imaging of altered Rho kinase activity in diseases such as cardiac hypertrophy

  15. Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation

    Linnman, Clas; Appel, Lieuwe; Fredrikson, Mats; Gordh, Torsten; Söderlund, Anne; Långström, Bengt; Engler, Henry

    2011-01-01

    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...

  16. [11C]d-threo-methylphenidate PET in patients with Parkinson's disease and essential tremor

    Twenty Parkinson's disease (PD) patients, 6 patients with essential tremor and 10 healthy controls were studied with the dopamine transporter ligand [11C]d-threo-methylphenidate ([11C]dMP) and positron emission tomography (PET) to assess dopamine terminal loss in relation to disease duration and motor disability. Dopamine transporter availability was expressed as [11C]dMP binding potential (BPdMP) in percentage of the mean of healthy controls. In PD patients (age at onset 57.7 ± 8.9 ys; disease duration 5.2 ± 3.3 ys; UPDRS motor score 24.2 ± 9.8; Hoehn and Yahr 2.1 ± 0.8; mean ± SD) BPdMP was reduced to 30 % (range: 11 - 55 %) in the putamen and 52 % (range: 14 - 96 %) in the caudate nucleus. BPdMP in the putamen closely correlated with the UPDRS motor score (r = -0.79, p dMP. Interestingly, when plotted over disease duration, PD patients with severe asymmetry of symptoms showed significantly lower BPdMP in the contralateral putamen (exponential fit: 34 % at onset) than the other PD patients (41 % at onset), indicating a different symptomatic threshold of these subgroups and an even closer correlation with the hypothetical 'true' disease duration. The exponential fit across all patients indicated a mean symptomatic threshold of 37 % contra- and 62 % ipsilateral, corresponding with an observed mean BPdMP of 51 % (average contra- and ipsilateral) in those patients with disease duration less than one year. No differences in BPdMP were observed between patients with essential tremor and healthy controls. [11C]dMP appears to be a useful and sensitive marker of dopaminergic dysfunction in PD and can be used to assess and monitor disease severity. (author)

  17. Towards the total synthesis of Stawamycin. Synthesis of C11-C21 fragment

    Dias Luiz C.; Jardim Luciana S. A.; Ferreira Andrea A.; Soarez Helena U.

    2001-01-01

    The carbocyclic (C11-C21) fragment of Stawamycin has been prepared by a sequence involving 11 steps (10% overall yield) from methyl (R)-(-)-3-hydroxy-2-methylpropionate. Key steps are Pd-catalyzed Stille coupling reaction between a vinyl iodide and a vinylstannane followed by an intramolecular Diels-Alder cycloaddition reaction to afford the desired adduct as the major isomer together with three other possible adducts in 78% overall yield.

  18. Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer

    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.

  19. Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer

    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/m2 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/m2 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

  20. Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas

    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.

  1. Auto-synthesis of 11C-gefitinib and micro PET/CT imaging for A549

    Gefitinib is an approved anticancer drug inhibiting epidermal growth factor receptor/tyrosine kinase (EGFR/TK) in non-small cell lung cancer (NSCLC). In this work, we aimed at developing an auto-synthesis method for 11C-Gefitinib with 11C-CH3-Triflate as methylation agent, and evaluating 11C-Gefinitib to explore its specific uptake with micro PET imaging, 11C-Gefitinib was synthesized by the reaction of 7-demethyl precursor with 11C-CH3-Triflate under base condition, and purified by HPLC. Micro PET/CT imaging was performed in A549 tumor-bearing mice. The results showed that it took 28 min for synthesis of 11C-Gefitinib with radiochemical yields of 30%-35% (with decay correction, n>5). The radiochemical purity was over 99%, and the specific activity was 55.5 GBq/μmol, respectively. Micro PET/CT imaging showed that the A549 tumor uptake of 11C-Gefitinib could be blocked by co-injection of non-radioactive Gefitinib (50 mg/kg), demonstrating the tumor specific accumulation of 11C-Gefitinib. It is concluded that 11C-Gefitinib can be served as PET imaging agent for the evaluation of Gefinitib therapy in NSCLC. (authors)

  2. Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-{sup 11}C-propyl]n-propylnorapomorphine

    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

  3. Radiosynthesis and ex vivo evaluation of (R)-(-)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

    Introduction: Several dopamine D2 agonist radioligands have been used with positron emission tomography (PET), including [11C-]-(-)-MNPA, [11C-]-(-)-NPA and [11C]-(+)-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 D2 and D3 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 D2/D3 selectivity. Methods: 2-Cl-[11C]-(-)-NPA and [11C]-(-)-NPA were synthesized by a two step N-acylation-reduction process using [11C]-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-[11C]-(-)-NPA and [11C]-(-)-NPA were produced in high specific activity and purity. 2-Cl-[11C]-(-)-NPA accumulated slower in the striatum than [11C]-(-)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[11C]-(-)-NPA (standard uptake value 0.72±0.24) was approximately half that of [11C]-(-)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[11C]-(-)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[11C]-(-)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake. Conclusion: Ex vivo experiments showed, despite a favorable D2/D3 selectivity, that 2-Cl-[11C]-(-)-NPA is inferior to [11C]-(-)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.

  4. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    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.

  5. 11C-Choline PET/pathology image coregistration in primary localized prostate cancer

    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 11C-choline PET/CT for delineation of gross tumour volume (GTV) in prostate cancer (PC). In 28 PC patients, 11C-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. 11C-Choline PET failed to distinguish tumour from nontumour tissue. (orig.)

  6. Efficiency Calibration for Measuring the 12C(n, 2n)11C Cross Section

    Eckert, Thomas; Gula, August; Vincett, Laurel; Yuly, Mark; Padalino, Stephen; Russ, Megan; Bienstock, Mollie; Simone, Angela; Ellison, Drew; Desmitt, Holly; Sangster, Craig; Regan, Sean; Fitzgerald, Ryan

    2015-11-01

    One possible inertial confinement fusion diagnostic involves tertiary neutron activation via the 12C(n, 2n)11C reaction. A recent experiment to measure this reaction cross-section involved coincidence counting the annihilation gamma rays produced by the positron decay of 11C. This requires an accurate value for the full-peak coincidence efficiency of the NaI detector system. The GEANT 4 toolkit was used to develop a Monte Carlo simulation of the detector system which can be used to calculate the required efficiencies. For validation, simulation predictions have been compared with the results of two experiments. In the first, full-peak coincidence positron annihilation efficiencies were measured for 22Na decay positrons that annihilate in a small plastic scintillator. In the second, a NIST-calibrated 68Ge source was used. A comparison of calculated with measured efficiencies, as well as 12C(n, 2n)11C cross sections are presented. Funded in part by a grant from the DOE through the Laboratory for Laser Energetics.

  7. Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole

    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 [11C]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 d of [11C]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 [11C]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

  8. {sup 11}C-Choline PET/pathology image coregistration in primary localized prostate cancer

    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.)

  9. Visualizing pancreatic {beta}-cell mass with [{sup 11}C]DTBZ

    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.

  10. Compact star clusters of the LMC HII region N11C

    Heydari-Malayeri, M; Rauw, G; Walborn, N R

    2000-01-01

    Based on imaging and spectroscopy obtained at the ESO NTT telescope and using an efficient image analysis algorithm, we study the core of the LMC OB association LH13, particularly the two compact stellar clusters Sk-6641 and HNT in the HII, region N11C. We resolve Sk-6641 into 15 components and for the first time the HNT cluster into 70 stars, and derive photometry for the members. Moreover, from medium resolution spectroscopy we determine the spectral types for sixteen stars in N11C. We compare the color-magnitude diagrams of the clusters with that of the field stars and discuss the cluster ages. With an age of ~100 Myr, the HNT cluster appears significantly older than the very young (< 5 Myr) Sk-6641 starburst. We suggest that most of the `field' O-stars in the core of N11C have actually been ejected from Sk-6641 through dynamical interactions in the compact cluster. The properties of the Sk-6641 and HNT clusters suggest that we are viewing different star formation regions lying at different distances al...

  11. [11C]Raclopride binding was reduced in vivo by sigma1 receptor ligand SA4503 in the mouse brain, while [11C]SA4503 binding was not by raclopride

    [11C]Raclopride is widely used as a representative dopamine D2-like receptor ligand in positron emission tomography (PET) studies, and [11C]1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride ([11C]SA4503) is a recently developed selective ligand for mapping sigma1 receptors in the brain. The striatal uptake of [11C]raclopride in mice was reduced by co-injection of an excess amount of SA4503, in spite of the fact that raclopride had no effect on the brain uptake of [11C]SA4503 as shown in a previous study. The blocking effect of SA4503 on the striatal uptake of [11C]raclopride was dose-dependent, but disappeared by 1 h or 6 h after intraperitoneal injection of SA4503. The brain uptake of [11C]SA4503 was not affected by a dopamine transporter inhibitor GBR 12909, nor was [11C]β-CIT-FP inhibited by SA4503. The IC50 values of raclopride for sigma1 and sigma2 receptor subtypes measured in vitro were 11800 nM and 4950 nM, respectively, suggesting that the affinity was too low for [11C]raclopride to bind in vivo to sigma receptors. On the other hand, the IC50 value of SA4503 for dopamine D2 receptors was 470 nM, that is approximate 1/25 of the affinity of raclopride for the dopamine D2 receptors. Therefore, possible explanations for the partial blocking effects of SA4503 on the striatal uptake of [11C]raclopride are: (1) an excess amount of SA4503 may reduce the [11C]raclopride uptake due to its low affinity for dopamine D2 receptors, or (2) SA4503 may enhance endogenous dopamine release, which results in the competitive inhibition of the [11C]raclopride uptake. These findings support that both [11C]raclopride and [11C]SA4503 are selective in vivo ligands for dopamine D2-like receptors and sigma1 receptors, respectively, in spite of the partial blocking effect of SA4503 on the striatal uptake of [11C]raclopride

  12. {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

    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

  13. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography

    [11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 +/- 0.92 to 0.26 +/- 0.13 in the thalamus (p less than 0.01) and from 1.8 +/- 0.33 to 0.16 +/- 0.065 in the frontal cortex (p less than 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35-70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35-70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible

  14. Multicompartmental analysis of (/sup 11/C)-carfentanil binding to opiate receptors in humans measured by positron emission tomography

    Frost, J.J.; Douglass, K.H.; Mayberg, H.S.; Dannals, R.F.; Links, J.M.; Wilson, A.A.; Ravert, H.T.; Crozier, W.C.; Wagner, H.N. Jr.

    1989-06-01

    (11C)-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of (11C)-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in t