Somatostatin-receptor imaging in the localization of endocrine tumors

International Nuclear Information System (INIS)

Lamberts, S.W.; Bakker, W.H.; Reubi, J.C.; Krenning, E.P.

1990-01-01

A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123 I-labeled Tyr3-octreotide, a somatostatin analogue, for tumor localization in 42 patients with carcinoid tumors, pancreatic endocrine tumors, or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. Primary tumors or metastases, often previously unrecognized, were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas, 8 of whom had more than one tumor, 10 temporal (tympanic or jugular), 9 carotid, and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. The 123 I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion

Clinical value of somatostatin receptor imaging in patients with suspected head and neck paragangliomas

Energy Technology Data Exchange (ETDEWEB)

Schmidt, Matthias; Dietlein, Markus; Weber, Kerstin; Moka, Detlef; Schicha, Harald [Klinik und Poliklinik fuer Nuklearmedizin, Universitaet zu Koeln, Joseph-Stelzmann-Strasse 9, 50924 Koeln (Germany); Fischer, Eva; Michel, Olaf; Stennert, Eberhard [Klinik und Poliklinik fuer Hals-, Nasen- und Ohrenheilkunde, Universitaet zu Koeln, Koeln (Germany)

2002-12-01

Paragangliomas or glomus tumours of the head and neck region are rare somatostatin receptor-expressing neuroendocrine tumours. Precise preoperative diagnosis is of special importance in order to adequately weigh the potential benefit of the operation against the inherent risks of the procedure. In this study, the clinical value of somatostatin receptor imaging was assessed in 19 patients who underwent somatostatin receptor scintigraphy because of known or suspected paraganglioma of the head and neck region. The results were compared with the results of computed tomography and/or magnetic resonance imaging, histology and clinical follow-up. [{sup 111}In-DTPA-D-Phe{sup 1}]-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 140-220 MBq {sup 111}In-octreotide. Whole-body and planar images as well as single-photon emission tomography images were acquired and lesions were graded according to qualitative tracer uptake. Somatostatin receptor imaging was positive in nine patients, identifying paragangliomas for the first time in three patients and recurrent disease in six patients. In one patient, a second, previously unknown paraganglioma site was identified. Negative results were obtained in ten patients. These patients included one suffering from chronic hyperplastic otitis externa, one with granuloma tissue and an organised haematoma, one with an acoustic neuroma, one with an asymmetric internal carotid artery, two with ectasia of the bulbus venae jugularis and one with a jugular vein thrombosis. In two patients with a strong family history of paraganglioma, individual involvement could be excluded. In only one patient did somatostatin receptor imaging and magnetic resonance imaging yield false negative results in respect of recurrent paraganglioma tissue. It is concluded that somatostatin receptor scintigraphy provides important information in patients with suspected paragangliomas of the head and neck region and has a strong impact on further

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

Science.gov (United States)

Stengel, Andreas; Taché, Yvette F

2017-01-01

Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function?

Directory of Open Access Journals (Sweden)

Elodie Urlacher

Full Text Available Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA and its receptor (Apime-ASTA-R; and C-type allatostatins (Apime-ASTC and Apime-ASTCC and their common receptor (Apime-ASTC-R. Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling.

Somatostatin Receptor Scintigraphy Findings in a Patient with Metastatic Gastrinoma and MEN 1 Syndrome

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Gözde Mütevelizade

2011-12-01

Full Text Available Liver metastases from neuroendocrine tumours frequently occur and significantly worsen their prognosis. Somatostatin receptor scintigraphy (SRS is a valuable method for the detection of somatostatin receptor-positive lesions like gastrinoma. In this case report, the importance of SRS to localize the primary tumor and the spread of disease is emphasized in a patient with neuroendocrine liver metastases. A 45-year-old man was admitted to hospital with multiple liver metastasis of neuroendocrine carcinoma. Somatostatin receptor scintigraphy showed multiple intense radiotracer uptakes in the liver and a focal tracer uptake at the right side of the upper abdominal region corresponding to duodenum or pancreas. Elevated serum gastrin levels confirmed the gastrinoma diagnosis. (MRT 2011;20:117-120

Somatostatin Receptor Scintigraphy (SRS) with 99m-Tc HYNIC-TOC

International Nuclear Information System (INIS)

Zarlenga, A.C.; Parma, P.; Arashiro, J.; Castiglia, S.; Obenaus, E.

2002-01-01

Background: This compound is a synthetic analogue of somatostatin by conjugating the Hydrazinocotinamide (Hynic) to Tyr 3 -Octreotide (Toc) radiolabeling via quelation with 99m Tc. Purpose: We have analyzed the feasibility in detecting neuroendocrine tumors (NET) by somatostatin receptor with 99m Tc Hynic-Toc. Methods: After comparative studies between 99m Tc Hynic-Toc and 111 In (pentetreotide) with excellent correlation, we have performed 48 scintigrams with 99m Tc Hynic-Toc. 35 patients with suspicions of NET were included (19 women, 16 men. Age range 22-75 y). We have performed planar images at 1,2,24 hs and tomographic images at 150 min after intravenous injection of 740 MBq 99m Tc Hynic-Toc. We compare the results with other diagnosis modalities and /or the histopathological findings after biopsy or surgery. Results: True Positive:17; True Negative:11; False Positive: 4; False Negative:3. Specificity=73.3%; Sensitivity=85%; Accuracy=80%; Not adverse effects were observed. Conclusions: 99m Tc Hynic-Toc is not limited availability of the isotope. It is a suitable radiopharmaceutical for in vivo evaluation to define tumor receptor status, staging, and for identification of patients who may benefit from therapy with somatostatin. The tumor uptake at 24 hs allows a better visualization of abdominal tumor sites. Tc Hynic-Toc is an alternative to 111 In-pentetreotide for imaging somatostatin receptor positive tumors. The study was offered to patients whom the scintigraphy with 111 In-pentetreotide offers a diagnosis alternative with high specificity and accessible cost

Somatostatin receptor imaging in intracranial tumours

International Nuclear Information System (INIS)

Schmidt, M.; Scheidhauer, K.; Voth, E.; Schicha, H.; Luyken, C.; Hildebrandt, G.; Klug, N.

1998-01-01

The somatostatin analogue [ 111 In-DTPA-d-Phe 1 ]-octreotide ( 111 In-octreotide) allows scintigraphic visualization of somatostatin receptor-expressing tissue. While it is well known that a large variety of tissues express somatostatin receptors and 111 In-octreotide scintigraphy has a clearly defined role in various neuroendocrine diseases, the clinical value of 111 In-octreotide scintigraphy in brain tumours is still under clinical investigation. In 124 patients with 141 brain lesions (63 meningiomas, 24 pituitary adenomas, 10 gliomas WHO class I and II, 12 gliomas WHO class III and IV, 11 neurinomas and 2 neurofibromas, 7 metastases and 12 other varieties: three non-Hodgkin B-cell lymphomas, two epidermoids, one abscess, one angioleiomyoma, one chordoma, one haemangiopericytoma, one osteosarcoma, one plasmacytoma and one pseudocyst), 111 In-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 110-220 MBq 111 In-octreotide. Planar images of the head in four views with a 128 x 128 matrix and single-photon emission tomographic images (64 x 64 matrix) were acquired, and lesions were graded according to qualitative tracer uptake. Fifty-nine of the 63 meningiomas showed moderate to intense tracer uptake. Nine of 24 pituitary adenomas were visible; the remaining 15 did not show any tracer uptake. None of the class I and II gliomas with an intact blood-brain barrier were detected whereas 11/12 class III and IV gliomas showed 111 In-octreotide uptake. None of the neurinomas or neurofibromas were positive. Five of seven metastases were classified as positive, as were the osteosarcoma, two of three non-Hodgkin B-cell lymphomas, one abscess, one angioleiomyoma, one chordoma and one haemangiopericytoma. The other varieties (one non-Hodgkin B-cell lymphoma, two epidermoids, one plasmacytoma and one pseudocyst) did not show 111 In-octreotide uptake. The results demonstrate that a large variety of intracranial lesions express somatostatin receptors and

Somatostatin receptor imaging in intracranial tumours

Energy Technology Data Exchange (ETDEWEB)

Schmidt, M.; Scheidhauer, K.; Voth, E.; Schicha, H. [Department of Nuclear Medicine, University of Koeln (Germany); Luyken, C.; Hildebrandt, G.; Klug, N. [Department of Neurosurgery, University of Kolen (Germany)

1998-07-01

The somatostatin analogue [{sup 111}In-DTPA-d-Phe{sup 1}]-octreotide ({sup 111}In-octreotide) allows scintigraphic visualization of somatostatin receptor-expressing tissue. While it is well known that a large variety of tissues express somatostatin receptors and {sup 111}In-octreotide scintigraphy has a clearly defined role in various neuroendocrine diseases, the clinical value of {sup 111}In-octreotide scintigraphy in brain tumours is still under clinical investigation. In 124 patients with 141 brain lesions (63 meningiomas, 24 pituitary adenomas, 10 gliomas WHO class I and II, 12 gliomas WHO class III and IV, 11 neurinomas and 2 neurofibromas, 7 metastases and 12 other varieties: three non-Hodgkin B-cell lymphomas, two epidermoids, one abscess, one angioleiomyoma, one chordoma, one haemangiopericytoma, one osteosarcoma, one plasmacytoma and one pseudocyst), {sup 111}In-octreotide scintigraphy was performed 4-6 and 24 h after i.v. injection of 110-220 MBq {sup 111}In-octreotide. Planar images of the head in four views with a 128 x 128 matrix and single-photon emission tomographic images (64 x 64 matrix) were acquired, and lesions were graded according to qualitative tracer uptake. Fifty-nine of the 63 meningiomas showed moderate to intense tracer uptake. Nine of 24 pituitary adenomas were visible; the remaining 15 did not show any tracer uptake. None of the class I and II gliomas with an intact blood-brain barrier were detected whereas 11/12 class III and IV gliomas showed {sup 111}In-octreotide uptake. None of the neurinomas or neurofibromas were positive. Five of seven metastases were classified as positive, as were the osteosarcoma, two of three non-Hodgkin B-cell lymphomas, one abscess, one angioleiomyoma, one chordoma and one haemangiopericytoma. The other varieties (one non-Hodgkin B-cell lymphoma, two epidermoids, one plasmacytoma and one pseudocyst) did not show {sup 111}In-octreotide uptake. The results demonstrate that a large variety of intracranial

DOTA-derivatives of octreotide dicarba-analogues with high affinity for somatostatin sst2,5 receptors

Science.gov (United States)

Pratesi, Alessandro; Ginanneschi, Mauro; Lumini, Marco; Papini, Anna M.; Novellino, Ettore; Brancaccio, Diego; Carotenuto, Alfonso

2017-02-01

In vivo somatostatin receptor scintigraphy is a valuable method for the visualization of human endocrine tumours and their metastases. In fact, peptide ligands of somatostatin receptors (sst’s) conjugated with chelating agents are in clinical use. We have recently developed octreotide dicarba-analogues, which show interesting binding profiles at sst’s. In this context, it was mandatory to explore the possibility that our analogues could maintain their activity also upon conjugation with DOTA. In this paper, we report and discuss the synthesis, binding affinity and conformational preferences of three DOTA-conjugated dicarba-analogues of octreotide. Interestingly, two conjugated analogues exhibited nanomolar affinities on sst2 and sst5 somatostatin receptor subtypes.

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

Directory of Open Access Journals (Sweden)

Andreas Stengel

2017-04-01

Full Text Available Corticotropin-releasing factor (CRF is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

Somatostatin receptor scintigraphy using (99m)Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

NARCIS (Netherlands)

Czepczynski, Rafal; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikolajczak, Renata; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Signore, Alberto

2007-01-01

Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin

Expression of the somatostatin receptor family mRNAs in lung cancer

International Nuclear Information System (INIS)

Wang Jing; Wang Liangang; Deng Jinglan; Wu Shengxi

2000-01-01

To investigate the characteristics of expression and distribution of 5 subtypes of somatostatin receptors (SSTR1-5) in lung cancer, in situ hybridization was used to examine the expression patterns of SSTR mRNAs in 21 cases of different pathologic types of lung cancer tissues with [α- 35 S]dATP labelled oligonucleotides of the 5 SSTR subtypes as probes. Additionally, Leica Q-500 image analysis processing system was employed for the semi-quantitatively analysis of the hybridization signals. Patterns of SSTR1-5 expression in lung cancer tissues were found as follows. SSTR2 was prominent in small cell lung cancer (SCLC), whereas in non-small cell lung cancer (NSCLC) including the adenous cancer (Ad) and the squamous cancer (Sq), the expression of SSTR1 mRNA was stronger than that of the other 4 types. the expression density of SSTR1-5 in the NSCLC was higher that the SCLC (p < 0.01). The expression patterns and densities of the SSTR subtypes showed heterogeneity in different pathologic types of lung cancer. The expressions of the SSTR mRNAs in both SCLC and NSCLC indicated the positive prospects for somatostatin analog (SSA)-oriented agents in the treatment of both types of the lung cancer

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)

2010-05-15

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

International Nuclear Information System (INIS)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Boerman, Otto C.

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Somatostatin receptor scintigraphy in endocrine ophthalmopathy; Somatostatin-Rezeptor-Szintigraphie bei endokriner Orbitopathie

Energy Technology Data Exchange (ETDEWEB)

Diaz, M. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany); Kahaly, G. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Muehlbach, A. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Bockisch, A. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany); Beyer, J. [3. Medizinische Klinik und Poliklinik, Innere Medizin - Endokrinologie, Univ. Mainz (Germany); Hahn, K. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Mainz (Germany)

1994-12-01

Somatostatin receptor scintigraphy with {sup 111}In-labeled octreotide proves to be a very sensitive diagnostic tool for evaluation of inflammative activity in endocrine ophthalmopathy (EO). The results of somatostatin receptor scintigraphy (SRS) in 40 patients with EO show a high orbital accumulation of {sup 111}In-octreotide in clinically active EO (4h-median/orbit-brain-ratio: 12.6; controls 4h-median: 5.8) Patients with clinically inactive EO (4h-median: 7.1) show a similar orbital accumulation of radioactivity compared to controls. 5 patients with active orbital myositis also revealed an even higher orbital accumulation of radioactivity (4h-median: 42.3). The diagnostic value of SRS lies in its ability to act as a measure of inflammation and an be useful as an activity parameter when planning therapeutic procedure as well as for EO follow-up. The results in patients with orbital myositis nevertheless do not permit a differential diagnosis with this method. The therapeutic value of {sup 111}In-octreotide in Graves` disease has yet to be established. (orig.) [Deutsch] Die Somatostatin-Rezeptor-Szintigraphie (SRS) mit dem {sup 111}Indium-markierten Somatostatinanalogon Octreotid stellt ein sensitives Verfahren zur Einschaetzung der entzuendlichen Aktivitaet bei endokriner Orbitopathie (EO) dar. Die Untersuchungen an 40 Patienten mit EO ergaben eine im Vergleich zur Kontrollgruppe signifikant hoehere orbitale Octreotidanreicherung bei klinisch aktiver Erkrankung (4h-Median/Orbita-Hirn-Quotient: 12,6; Kontrollgruppe 4h-Median: 5,8; p=0,0032). Patienten mit klinisch nicht aktiver Erkrankung (4h-Median: 7,1) unterschieden sich bezueglich der orbitalen Octreotidanreicherung nicht wesentlich von der Kontrollgruppe. Auch 5 Patienten mit florider orbitaler Myositis zeigten eine deutlich gesteigerte orbitale Aktivitaetsanreicherung (4h-Median: 42,3). Der diagnostische Nutzen der SRS liegt somit in ihrer Eigenschaft als Aktivitaets- und Entzuendungsparameter und kann mit

High sensitivity of the in vivo detection of somatostatin receptors by 111Indium (DTPA-Octreotide)-scintigraphy in meningioma patients

International Nuclear Information System (INIS)

Hildebrandt, G.; Luyken, C.; Klug, N.; Scheidhauer, K.; Schicha, H.; Dahms, P.; Krisch, B.

1994-01-01

The recent availability of isotope-labelled somatostatin analogues has allowed one to detect somatostatin receptors in normal tissue as well as in endocrine or non-endocrine cranial tumours. The purpose of the present study was to establish the value of somatostatin receptor scintigraphy using an 111 indium-labelled somatostatin analogue, octreotide, in the diagnostic work-up of meningioma patients. Twenty-two patients (16 women, 6 men, aged from 19-70 years) with newly diagnosed, residual or recurrent cranial meningiomas were examined. 111 indium-labelled DTPA-octreotide was injected i.v.. Planar and tomographic images were obtained with a gamma camera 4-6, and 24 hours after injection. In all of the meningiomas studies a high density of somatostatin receptor was detected by scintigraphy. No false negative test result was found. Due to this, a 100% predictive value of a negative test was calculated. However, when the tumours were taken in culture differing staining intensity could be seen in the light- and electron microscopic level even on individual cells of a single culture when silver intensified somatostatin-gold was used as ligand. We conclude, that in vivo somatostatin receptor scintigraphy may aid in the pre-operative differential diagnosis of skull base tumours

The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

Energy Technology Data Exchange (ETDEWEB)

Doerr, U.; Bihl, H. (Katharinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine); Frank-Raue, K.; Raue, F. (Heidelberg Univ. (Germany). Dept. of Internal Medicine); Sautter-Bihl, M.L.; Buhr, H.J. (Staedt. Klinikum, Karlsruhe (Germany). Dept. of Radiooncology and Nuclear Medicine); Guzman, G. (Katherinenhospital, Stuttgart (Germany). Dept. of Nuclear Medicine Inst. de Neurocirugia, Investigationes Cerebrales ' Dr Asenjo' Santiago (Chile). Dept. de Medicina Nuclear)

1993-06-01

In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with [sup 111]In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author).

The potential value of somatostatin receptor scintigraphy in medullary thyroid carcinoma

International Nuclear Information System (INIS)

Doerr, U.; Bihl, H.; Frank-Raue, K.; Raue, F.; Sautter-Bihl, M.L.; Buhr, H.J.; Guzman, G.; Inst. de Neurocirugia, Investigationes Cerebrales 'Dr Asenjo' Santiago

1993-01-01

In a prospective study, ten patients with recurrent medullary thyroid carcinoma (markedly elevated calcitonin levels) were investigated by means of somatostatin receptor scintigraphy (SRS) with 111 In-pentetreotide. Scintigraphically, 30 sites of pathological uptake were found, mostly located in the neck and upper mediastinum. So far, 18 suspected tumour sites underwent histological examination and 14 of them could be verified as metastases of medullary thyroid carcinoma (MTC). The remaining four putative tumour lesions turned out to be false positive scintigraphic findings caused by chronic inflammation and somatostatin receptor positive tumours other than MTC. We conclude that SRS is a promising imaging modality for localization of MTC recurrence and may thus make a contribution to better management of this patient group. (Author)

Pertussis toxin modifies the characteristics of both the inhibitory GTP binding proteins and the somatostatin receptor in anterior pituitary tumor cells

International Nuclear Information System (INIS)

Mahy, N.; Woolkalis, M.; Thermos, K.; Carlson, K.; Manning, D.; Reisine, T.

1988-01-01

The effects of pertussis toxin treatment on the characteristics of somatostatin receptors in the anterior pituitary tumor cell line AtT-20 were examined. Pertussis toxin selectively catalyzed the ADP ribosylation of the alpha subunits of the inhibitory GTP binding proteins in AtT-20 cells. Toxin treatment abolished somatostatin inhibition of forskolin-stimulated adenylyl cyclase activity and somatostatin stimulation of GTPase activity. To examine the effects of pertussis toxin treatment on the characteristics of the somatostatin receptor, the receptor was labeled by the somatostatin analog [125I]CGP 23996. [125I]CGP 23996 binding to AtT-20 cell membranes was saturable and within a limited concentration range was to a single high affinity site. Pertussis toxin treatment reduced the apparent density of the high affinity [125I]CGP 23996 binding sites in AtT-20 cell membranes. Inhibition of [125I]CGP 23996 binding by a wide concentration range of CGP 23996 revealed the presence of two binding sites. GTP predominantly reduced the level of high affinity sites in control membranes. Pertussis toxin treatment also diminished the amount of high affinity sites. GTP did not affect [125I]CGP 23996 binding in the pertussis toxin-treated membranes. The high affinity somatostatin receptors were covalently labeled with [125I] CGP 23996 and the photoactivated crosslinking agent n-hydroxysuccinimidyl-4-azidobenzoate. No high affinity somatostatin receptors, covalently bound to [125I]CGP 23996, were detected in the pertussis toxin-treated membranes. These results are most consistent with pertussis toxin uncoupling the inhibitory G proteins from the somatostatin receptor thereby converting the receptor from a mixed population of high and low affinity sites to only low affinity receptors

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system

DEFF Research Database (Denmark)

Ádori, Csaba; Glück, Laura; Barde, Swapnali

2015-01-01

Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is n......Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites...... morphometry and mRNA profiling in a cohort of Alzheimer’s and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer’s disease, we found significantly....../IV and onwards, i.e., a process preceding advanced Alzheimer’s pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 −/− mice and...

Diagnostic value of somatostatin receptor scintigraphy in patients with intracranial tumours

International Nuclear Information System (INIS)

Luyken, C.; Hildebrandt, G.; Scheidhauer, K.; Kirsch, B.

1993-01-01

The aim of the study was to detect the SR binding sites in intracranial tumours and to evaluate the benefit of SRS in pre- and postoperative diagnostics. 86 patients with 94 intracranial tumours (39 meningiomas, 18 pituitary adenomas, 11 gliomas grade 3 or 4, 8 gliomas grade 2, 5 neurinomas, 5 intracranial metastases, 4 tumours of the orbit, 2 neurofibromas, 1 brain abscess and 1 cystic lesion) were examined. 111 In-octreotide was injected i.v. as 10 μg or 20 μg bolus, corresponding to 110 or 220 MBq (3 or 6 mCi). Gamma-camera images and SPECT were obtained 3-6 h and 24 h post injection. The scintigraphic evaluation was performed without knowledge of CT and MRI results. The histological classification corresponded to the WHO grading system. Somatostatin binding sites were detected in vito using somatostatin-gold conjugates. All patients with meningiomas showed a high focal tracer uptake corresponding to SR binding sites in vitro, whereas only in 50% of the pituitary adenomas SRS was positive. Neurinomas did not show any tracer uptake. In patients with gliomas with disturbed blood-brain-barrier positive tracer uptake was detected, while none of the gliomas with intact blood-brain-barrier could be visualized by SRS but showed somatostatin binding sites in vitro. In intracranial metastases a local tracer uptake was detected in vivo. In vitro 3 of 4 cases showed somatostatin binding sites. In 2 cases extracranial tracer uptake showed the primary tumour and metastases of the lymphnodes. Somatostatin receptor scintigraphy can help to detect or to exclude meningiomas especially in the cerebellopontine angle or in the orbit. In intracranial metastases SRS may point to the primary tumour or other metastases. In all other intracranial tumours receptor scintigraphy provides no clinical relevant information. (orig./MG) [de

Somatostatin receptor scintigraphy on thyroid carcinoma

International Nuclear Information System (INIS)

Pan Weimin; Tan Tianzhi

2004-01-01

Purpose: To study the diagnostic value and clinical method of somatostatin receptor scintigraphy on thyroid carcinoma using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent; Methods: Somatostatin receptor scintigraphy (SRS) were performed on 25 patients with thyroid carcinoma, using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent, controlling with 131 I- whole- body- imaging(1312 -WBI). Results: Of 4 patients with MTC (medullary thyroid carcinoma), positive metastasis and primary tumour were detected on 3 patients by SRS, negative results were obtained by 131 I-WBI, the positive detective rate by SRS is 3/4; of 12 patients with PTC (papillary thyroid carcinoma), positive metastasis and primary tumour were detected on 2 patients by SRS or 131 I-WBI,1 of which only by SRS, while negative results were obtained by 131 I- WBI, the positive detective rate by SRS is 3/12; of 8 patients with FTC(follicular thyroid carcinoma), positive metastasis and primary tumour were detected on 1 patients by SRS or 131 I-WBI, and 2 positive results were obtained only by SRS, while negative by 131 I-WBI, the positive detective rate by SRS is 3/8; of 1 patients with HCC (hurthle cell carcinoma ), positive metastasis and primary tumour were detected by SRS, while negative by 131 I-WBI; Conclusions: SRS using 99 Tc m -RC-160 labeled with direct method as scintigraphy reagent has high diagnostic value on thyroid carcinoma, especially on MTC and HCC. (authors)

IMMUNOHISTOCHEMICAL DETERMINATION OF EXPRESSION OF SOMATOSTATIN RECEPTORS TYPES 1, 2A, 3 AND 5 IN NEUROENDOCRINE TUMORS OF VARIOUS LOCALIZATION AND GRADE

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L. E. Gurevich

2016-01-01

Full Text Available Background: Prediction of clinical benefits of somatostatin analogues in patients with neuroendocrine tumors (NET is very important prior to their administration. Data on immunohistochemical assessment of the expression of somatostatin receptors (SSR of various types, obtained from large samples of NET with various localization, functional activity and degree of malignancy, are scarce; therefore, the study was aimed at assessment of the latter.Materials and methods: We performed an immunohistochemical study with antibodies to SSR1, 2A, 3 and 5  types on tissue samples obtained during diagnostic and intra-operative biopsies from 399 NETs: 168 from pancreas, 120 from gastrointestinal tract (stomach, 48, from small intestine, 39, 14 of which being from duodenum; appendix, 6, colon and the rectum, 15 and 12, respectively, 84 from lung, 6 from thymus/mediastinum, and 21 from NET metastases of unknown primary localization.Results: Very high levels expression of receptors SSR2A preferentially binding to somatostatin analogues, which are currently used in clinical practice, were detected in the small intestine NETs (22/25, 88%, appendix (5/6, 83.3%, colon (10/15, 66.7%, thymus (4/6, 66.7%, atypical carcinoids of the lung (10/15, 66.7%, stomach (27/41, 65.8% and pancreas (105/165, 63.6%. The lowest expression was found in rectal NETs (5/12, 41.7% and small and large cell neuroendocrine lung carcinomas (20, 11.1%. Among functioning NETs, the highest level of SSR2A was found in gastrinomas (18/19, 94.7%, glucagonomas (15/16, 93.8%, small intestine carcinoids (31/35, 88.6%, and somatostatinomas (2/3, 66.7%. The lowest expression was detected in ACTH secreting tumors with Cushing's syndrome (11/12, 50%, and in insulinomas (34/69, 49.3%. SSR2A expression in functionally inactive pancreatic NETs was significantly higher than in insulinomas (57/82, 34/69 vs 69.5 and 49.3%, respectively. SSR2A expression was associated with the degree of malignancy and is

Ga-68 Somatostatin Receptor PET/CT in von Hippel-Lindau Disease

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Oh, Jong-Ryool; Min, Jung-Joon [Chonnam National Univ. Hwasun Hospital, Hwasun (Korea, Republic of); Kulkarui, Harshad; Carreras, Cecilia; Schalch, Georg; Baum, Richard P. [Nuclear Medicine and Center for PET/CT, Zentralk Bad Berka, Bad Verka (Germany)

2012-06-15

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renalcysts and tumors, pancreatic cysts and tumors, pheochromo-cytomas, and epididymal cystadenomas. Cross-sectional mo-dalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease.

Ga-68 Somatostatin Receptor PET/CT in von Hippel-Lindau Disease

International Nuclear Information System (INIS)

Oh, Jong-Ryool; Min, Jung-Joon; Kulkarui, Harshad; Carreras, Cecilia; Schalch, Georg; Baum, Richard P.

2012-01-01

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renalcysts and tumors, pancreatic cysts and tumors, pheochromo-cytomas, and epididymal cystadenomas. Cross-sectional mo-dalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease

Physiologic basics and clinical experience with somatostatin-receptor-scintigraphy

International Nuclear Information System (INIS)

Henze, E.; Eberhardt, J.U.; Bohuslavizki, K.H.

1994-01-01

The introduction of radiolabelled octreotide, an analogon to the receptor binding hormone Somatostatin, has markedly increased the ability to detect structures and tumours carrying somatostatin receptors by nuclear medicine imaging with high sensitivity and specificity. It has been shown that in vitro receptor density and in vivo scintigraphic results correlate well in particular in tumours of neuroendocrine origin of the GI tract such as insulinomas, gastrinomas, glucagonomas, carcionoids, but also in paragangliomas, small cell lung cancer and meningiomas. As receptors were also shown to be present on so called activated leucocytes granulomas, lymphomas and autoimmune disease have been imaged with octreotide successfully. The specific tracer (In-111-DTPA-D-PHE-Octreotide, Octreoscan R ) is rapidly cleared from the blood pool by the kidneys and, partially, via the liver providing a high target to background ratio. Physiologic uptake is usually observed in the pituitary and thyroid glands, in spleen and liver. Optimum tracer accumulation for tumour scintigraphy is seen on the 24-h-images with the best target to background ratios. Additional SPECT-imaging is recommended in particular in the abdominal regions. The sensitivity in imaging the above named tumours ranges from 70 up to 100%. In-111 octreotide imaging is of diagnostic impact both for the primary diagnostic evaluation as well as for detecting or excluding secondary manifestations in known tumour sites. Of specific value is the information on relative receptor density in the tumour to be treated as may be obtained by quantitative In-111 octreotide imaging for decision making whether or not to use cold octreotide (Sandostatin R ) as a receptor blocking drug for therapy as well as for treatment follow-up studies. (author)

Studies on mRNA expression of the somatostatin receptor family in lung cancer

International Nuclear Information System (INIS)

Wang Jing; Deng Jinglan; Wu Shengxi; Qiao Hongqing

2000-01-01

Objective: To investigate the characteristics of expression and distribution of 5 subtypes of somatostatin receptors (SSTR1∼5) in lung cancer. Methods: With [α- 35 S]dATP labelled oligonucleotides of the 5 SSTR subtypes as probes, using in situ hybridization, patterns of mRNA expression were detected in lung cancer tissue sections of 21 cases which fell in varied pathologic types. Additionally, Leica Q-500 image analyzing device was employed to semi-quantitatively analyze density of the expression. Results: Patterns of SSTR1∼5 expression in lung cancer were as follows: SSTR2 expression was dominant in small cell lung cancer (SCLC) while in non-small cell lung cancer (NSCLC) such as adenous and squamous, SSTR1 expression was stronger than that of the other 4 subtypes, In density of SSTR1∼5 expression in lung cancer, NSCLC was higher than SCLC (P<0.01). Conclusions: even though patterns and density of expression of SSTR subtypes in the lung cancer showed heterogeneity in different histopathologic types, as in SCLC and in NSCLC. Therefore, it has positive prospects for somatostatin analog-oriented agents to be used in treatment of both types of the lung cancers

Somatostatin receptor subtype expression in human thyroid tumours.

Science.gov (United States)

Klagge, A; Krause, K; Schierle, K; Steinert, F; Dralle, H; Fuhrer, D

2010-04-01

Somatostatin receptors (SSTR) are expressed in various endocrine tumours. The expression of SSTR at the tumour cell surface confers the possibility for diagnostic imaging and therapy of tumours using radiolabeled somatostatin analogues. The majority of currently available somatostatin analogues show a higher binding affinity for the SSTR2 subtype. To date, the precise expression pattern of the SSTR subtypes 1-5 in thyroid epithelial tumours remains to be determined. We investigated the mRNA expression of SSTR1-5 in benign and malignant epithelial thyroid tumours [20 cold thyroid nodules (CTNs), 20 toxic thyroid nodules (TTNs), 20 papillary, 20 follicular, and 5 anaplastic carcinomas (PTCs, FTCs, ATCs, respectively)] and compared them to normal surrounding thyroid tissues. Four out of five SSTR subtypes were detected in malignant thyroid tumours, benign neoplasia, and normal surrounding tissue with a predominant expression of SSTR2 and SSTR5, and a weak expression of SSTR1 and SSTR3. Weak SSTR4 mRNA expression was detected in some PTCs. Compared to normal thyroid tissue, SSTR2 was significantly upregulated in PTC and ATC. In addition significant upregulation of SSTR3 was found in PTC. SSTR5 mRNA expression was increased in PTC and FTC and significantly decreased in CTN and TTN compared to normal thyroid tissue. SSTR2 is the predominant subtype in thyroid epithelial tumours with a high expression pattern, in particular, in PTC . Perspectively, the expression of distinct SSTR in thyroid epithelial tumours might represent a promising avenue for diagnostics and therapy of advanced thyroid cancer with somatostatin analogues. Georg Thieme Verlag KG Stuttgart New York.

Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum.

Science.gov (United States)

Allen, Jeremy P; Hathway, Gareth J; Clarke, Neil J; Jowett, Mike I; Topps, Stephanie; Kendrick, Keith M; Humphrey, Patrick P A; Wilkinson, Lawrence S; Emson, Piers C

2003-05-01

The peptide somatostatin can modulate the functional output of the basal ganglia. The exact sites and mechanisms of this action, however, are poorly understood, and the physiological context in which somatostatin acts is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional in the striatum. We have investigated the role of SSTR2 in basal ganglia function using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry demonstrated a widespread pattern of expression. By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2. In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons. Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks. However, in beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired. Together these data implicate an important neuromodulatory role for SSTR2 in the striatum.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

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Zhang, Libo; Vines, Douglass C.; Scollard, Deborah A.; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imagin...

Development and preclinical evaluation of radiolabelled somatostatin receptor agonists and αvβ3-integrin antagonists

International Nuclear Information System (INIS)

Stoecklin, G.; Wester, H.J.; Haubner, R.; Schottelius, M.

2002-01-01

Tumours express specific receptors for peptide ligands. This can be exploited for tumour targeting. New bioactive peptides are available, in particular new somatostatin analogs and RGD-Peptides for targeting the α V β 3 -integrin. The design and optimization of radiolabelled peptides with respect to their receptor affinity, tumour uptake, biodistribution, pharmacokinetics and stability may provide better tracers for tumour imaging and therapy. Based on two basic structures, new radioiodinated and carbohydrated somatostatin analogs and cyclic RGD-peptides were developed and evaluated. (author)

Experimental peptide receptor radionuclide therapy in radioiodine negative somatostatin receptor positive thyroid cancer

International Nuclear Information System (INIS)

Nilica, B.; Kroiss, A.; Putzer, D.; Uprimmy, C.; Warwitz, B.; Kendler, D.; Waitz, D.; Virgolini, I.

2015-01-01

Full text of publication follows. Purpose: This retrospective analysis evaluated the time to progression (TTP), progression free survival (PFS) and overall survival (OS) in patients with radioiodine negative thyroid cancer who had undergone peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTA-TATE, 177 Lu-DOTA-LAN, 90 Y-DOTA-TOC or 90 Y-DOTA-LAN after tumor progression. Methods: Data derived from twenty patients with either differentiated (n=15), anaplastic (n=1) or medullary (n=4) somatostatin receptor positive thyroid cancer who had received treatment with PRRT after tumor progression. TTP, PFS and OS were defined according to the clinical trial endpoints suggested by the FDA (Food and Drug Administration). Progressive disease was defined by sonography, FDG-PET, Ga-DOTA-TOC-PET, or CT (RECIST Criteria). Results: In 17 patients the median overall survival time after the first PRRT was 17.3 (range: 0.1 - 109.7) months. Three patients still alive are actually showing stable disease. The median of PFS in 20 Patients (6 with more than one PRRT-cycle or PRRT-substance) has been 10.9 (range: 0.1 - 44.0) months. The median TTP was 15.6 (range 4.4 to 29.2) months. Conclusion: PRRT appears to be useful in patients with somatostatin receptor positive but radioiodine negative thyroid cancer as a complementary palliative cytotoxic therapy. (authors)

Somatostatin: a metabolic regulator

International Nuclear Information System (INIS)

Dileepan, K.N.; Wagle, S.R.

1985-01-01

Somatostatin, the hypothalamic release-inhibiting factor, has been found to stimulate gluconeogenesis in rat kidney cortical slices. Stimulation by somatostatin was linear and dose-dependent. Other bioactive peptides such as cholecystokinin, gastro-intestinal peptide, secretin, neurotensin, vasoactive intestinal peptide, pancreatic polypeptide, beta endorphin and substance P did not affect the renal gluconeogenic activity. Somatostatin-induced gluconeogenesis was blocked by phentolamine (alpha adrenergic antagonist) and prazosin (alpha 1 adrenergic antagonist) but not by propranolol (beta adrenergic antagonist) and yohimbine (alpha 2 adrenergic antagonist) suggesting that the effect is via alpha 1 adrenergic stimuli. Studies on the involvement of Ca 2+ revealed that tissue depletion and omission of Ca 2+ from the reaction mixture would abolish the stimulatory effect of somatostatin. Furthermore, somatostatin enhanced the uptake of 45 calcium in renal cortical slices which could be blocked by lanthanum, an inhibitor of Ca 2+ influx. It is proposed that the stimulatory effect of somatostatin on renal gluconeogenesis is mediated by alpha 1 adrenergic receptors, or those which functionally resemble the alpha 1 receptors and that the increased influx of Ca 2+ may be the causative factor for carrying out the stimulus. 88 references

Diagnostic value of somatostatin receptor scintigraphy in patients with intracranial tumours. Diagnostische Wertigkeit der Somatostatin-Rezeptor-Szintigraphie bei Patienten mit intrakraniellen Raumforderungen

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Luyken, C. (Klinik fuer Neurochirurgie, Koeln Univ. (Germany)); Hildebrandt, G. (Klinik fuer Neurochirurgie, Koeln Univ. (Germany)); Scheidhauer, K. (Klinik fuer Nuklearmedizin, Koeln Univ. (Germany)); Kirsch, B. (Anatomisches Inst., Kiel Univ. (Germany))

1993-12-01

The aim of the study was to detect the SR binding sites in intracranial tumours and to evaluate the benefit of SRS in pre- and postoperative diagnostics. 86 patients with 94 intracranial tumours (39 meningiomas, 18 pituitary adenomas, 11 gliomas grade 3 or 4, 8 gliomas grade 2, 5 neurinomas, 5 intracranial metastases, 4 tumours of the orbit, 2 neurofibromas, 1 brain abscess and 1 cystic lesion) were examined. [sup 111]In-octreotide was injected i.v. as 10 [mu]g or 20 [mu]g bolus, corresponding to 110 or 220 MBq (3 or 6 mCi). Gamma-camera images and SPECT were obtained 3-6 h and 24 h post injection. The scintigraphic evaluation was performed without knowledge of CT and MRI results. The histological classification corresponded to the WHO grading system. Somatostatin binding sites were detected in vito using somatostatin-gold conjugates. All patients with meningiomas showed a high focal tracer uptake corresponding to SR binding sites in vitro, whereas only in 50% of the pituitary adenomas SRS was positive. Neurinomas did not show any tracer uptake. In patients with gliomas with disturbed blood-brain-barrier positive tracer uptake was detected, while none of the gliomas with intact blood-brain-barrier could be visualized by SRS but showed somatostatin binding sites in vitro. In intracranial metastases a local tracer uptake was detected in vivo. In vitro 3 of 4 cases showed somatostatin binding sites. In 2 cases extracranial tracer uptake showed the primary tumour and metastases of the lymphnodes. Somatostatin receptor scintigraphy can help to detect or to exclude meningiomas especially in the cerebellopontine angle or in the orbit. In intracranial metastases SRS may point to the primary tumour or other metastases. In all other intracranial tumours receptor scintigraphy provides no clinical relevant information. (orig./MG)

Somatostatin receptors

DEFF Research Database (Denmark)

Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

2003-01-01

functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

Radioautographic localization of somatostatin-14 and somatostatin-28 binding sites in the rat brain

International Nuclear Information System (INIS)

Leroux, P.; Pelletier, G.

1984-01-01

Somatostatin-14 (S14) and its precursor, somatostatin-28 (S28), are widely distributed throughout the rat brain, suggesting that they could act as neurotransmitter or neuromodulator in the central nervous system. The present study was undertaken to study the localization of S14 and S28 receptors in the rat brain determined by ''in vitro'' radioautography. The study performed on slide mounted frozen brain section with iodinated S14 and S28 analogs revealed an identical distribution of binding sites for the two forms of somatostatin. A good correlation could be observed between receptor distribution and immunohistologically localized neuropeptides except for striatum and hypothalamus. However, receptors were not detectable in the hypothalamus and were found in low concentration in the caudate-putamen nucleus, two regions containing high amounts of S28 and S14, suggesting a high occupancy of receptors in these areas by endogenous peptides or an inverse correlation between receptor and peptide concentrations

Somatostatin: a metabolic regulator

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Dileepan, K.N.; Wagle, S.R.

1985-12-23

Somatostatin, the hypothalamic release-inhibiting factor, has been found to stimulate gluconeogenesis in rat kidney cortical slices. Stimulation by somatostatin was linear and dose-dependent. Other bioactive peptides such as cholecystokinin, gastro-intestinal peptide, secretin, neurotensin, vasoactive intestinal peptide, pancreatic polypeptide, beta endorphin and substance P did not affect the renal gluconeogenic activity. Somatostatin-induced gluconeogenesis was blocked by phentolamine (alpha adrenergic antagonist) and prazosin (alpha/sub 1/ adrenergic antagonist) but not by propranolol (beta adrenergic antagonist) and yohimbine (alpha/sub 2/ adrenergic antagonist) suggesting that the effect is via alpha/sub 1/ adrenergic stimuli. Studies on the involvement of Ca/sup 2 +/ revealed that tissue depletion and omission of Ca/sup 2 +/ from the reaction mixture would abolish the stimulatory effect of somatostatin. Furthermore, somatostatin enhanced the uptake of /sup 45/calcium in renal cortical slices which could be blocked by lanthanum, an inhibitor of Ca/sup 2 +/ influx. It is proposed that the stimulatory effect of somatostatin on renal gluconeogenesis is mediated by alpha/sub 1/ adrenergic receptors, or those which functionally resemble the alpha/sub 1/ receptors and that the increased influx of Ca/sup 2 +/ may be the causative factor for carrying out the stimulus. 88 references.

Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

Science.gov (United States)

Oh, Sowon; Prasad, Vikas; Lee, Dong Soo; Baum, R. P.

2011-01-01

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression. PMID:22121482

Molecular imaging of neuroendocrine tumors using 68Ga-labeled peptides (Somatostatin receptor PET/CT)

International Nuclear Information System (INIS)

Baum, R.P.; Prasad, V.; Hoersch, D.

2009-01-01

Receptor PET/CT using 68 Ga-labeled somatostatin analogues (DOTA-NOC, DOTA-TOC or DOTA-TATE) enables the highly sensitive molecular imaging of neuroendocrine tumors (NETs) based on the expression of somatostatin receptors and even the detection of receptor subtypes. Our experience after more than 3000 studies shows that receptor PET/CT has a significantly higher tumor detection rate than conventional scintigraphy (even in SPECT/CT technique), and that tumor lesions can be very accurately localized. By calculating standardized uptake values (SUV) - which are reproducible and investigator-independent - patients can be selected for peptide receptor radiotherapy and also the course after therapy can be controlled. Receptor-PET/CT is the most sensitive imaging modality for the detection of unknown primary tumors (CUP syndrome), which is especially true for the detection of neuroendocrine tumors of the pancreas and small bowel; whole-body staging (''one stop shop'') as well as restaging and selection of patients for peptide receptor radiotherapy can be performed using a patient-friendly procedure (examination finished within one hour) exposing the patient to less radiation than whole-body CT scanning. The 68 Ge/ 68 Ga generator has proved very reliable over the years - even in a hospital environment. The effective costs for 68 Ga labeled somatostatin analogues might be less than for scintigraphic agents, provided a certain number of studies per year are performed. The development of new tumor-specific peptides as well as of other DOTA- or NOTA-coupled radiopharmaceuticals opens a new avenue into the future: finally, the 68 Ga generator could play a similar important role for PET/CT as did the 99m Tc-Generator for conventional gamma camera imaging over the last decades. (orig.)

Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

Directory of Open Access Journals (Sweden)

Andreas eStengel

2013-01-01

Full Text Available Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G-protein coupled somatostatin receptor subtypes (sst1-5 that are widely expressed in the brain and peripheral organs. The characterization of somatostatin’s effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points towards a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin in rats. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin in rats. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D-cell derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

Receptor binding of somatostatin-14 and somatostatin-28 in rat brain: differential modulation by nucleotides and ions.

Science.gov (United States)

Srikant, C B; Dahan, A; Craig, C

1990-02-04

The tissue-selective binding of the two principal bioactive forms of somatostatin, somatostatin-14 (SS-14) and somatostatin-28 (SS-28), their ability to modulate cAMP-dependent and -independent regulation of post-receptor events to different degrees and the documentation of specific labelling of SS receptor subtypes with SS-28 but not SS-14 in discrete regions of rat brain suggest the existence of distinct SS-14 and SS-28 binding sites. Receptor binding of SS-14 ligands has been shown to be modulated by nucleotides and ions, but the effect of these agents on SS-28 binding has not been studied. In the present study we investigated the effects of adenine and guanine nucleotides as well as monovalent and divalent cations on rat brain SS receptors quantitated with radioiodinated analogs of SS-14 ([125I-Tyr11]SS14, referred to in this paper as SS-14) and SS-28 ([Leu8, D-Trp22, 125I-Tyr25] SS-28, referred to as LTT* SS-28) in order to determine if distinct receptor sites for SS-14 and SS-28 could be distinguished on the basis of their modulation by nucleotides and ions. GTP as well as ATP exerted a dose-dependent inhibition (over a concentration range of 10(-7)-10(-3) M) of the binding of the two radioligands. The nucleotide inhibition of binding resulted in a decrease the Bmax of the SS receptors, the binding affinity remaining unaltered. GTP (10(-4) M) decreased the Bmax of LTT* SS-28 binding sites to a greater extent than ATP (145 +/- 10 and 228 +/- 16 respectively, compared to control value of 320 +/- 20 pmol mg-1). Under identical conditions GTP was less effective than ATP in reducing the number of T* SS-14 binding sites (Bmax = 227 +/- 8 and 182 +/- 15, respectively, compared to 340 +/- 15 pmol mg-1 in the absence of nucleotides). Monovalent cations inhibited the binding of both radioligands, Li+ and Na+ inhibited the binding of T* SS-14 to a greater extent than K+. The effect of divalent cations on the other hand was varied. At low concentration (2 mM) Mg2+, Ba2

Somatostatin receptors in rat hippocampus: localization to intrinsic neurons

International Nuclear Information System (INIS)

Palacios, J.M.; Reubi, J.C.; Maurer, R.

1986-01-01

The effect of neurotoxic chemical and electrolytical lesions on somatostatin (SS) receptor binding in the septo-hippocampal afferents, pyramidal and granule cells of the rat hippocampus was examined by autoradiography using the stable SS analogue 125 I-204-090 as radioligand. Electrolytical lesions of the septum did not result in modification of SS binding in the hippocampus. In contrast, both granule cell lesion with colchicine and pyramidal or pyramidal and granule cell lesions with increasing kainic acid doses did result in a specific decrease of binding in the dentate gyrus and hippocampus (CA 1 and CA 3 ). These results suggest that SS receptors in the hippocampus are probably associated with elements from intrinsic neurons. (Author)

Somatostatin receptor scintigraphy - a case report and review of the literature

International Nuclear Information System (INIS)

Yamaga, Lilian Yuri Itaya; Belfer, Aron J.; Segal, Amisa

1997-01-01

The authors report a case of carcinoid tumor, diagnosed in a 75-year-old male patient, confirmed by laparotomy and anatomo-pathological study. The patient was examined by somatostatin receptor scintigraphy with In-pentetreotide, and correlation was performed with I-MIBG and CT scan. A review of current literature about this new tracer for detection of carcinoid tumor is presented. (author)

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

International Nuclear Information System (INIS)

Kaemmerer, Daniel; Haugvik, Sven-Petter; Hommann, Merten; Peter, Luisa; Lupp, Amelie; Schulz, Stefan; Saenger, Joerg; Prasad, Vikas; Kulkarni, Harshad; Baum, Richard Paul

2011-01-01

Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative 68 Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV max and SUV mean ) were used for PET/CT. The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV max on the PET/CT (p mean (p max on the 68 Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of 68 Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using 68 Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy. (orig.)

Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases.

NARCIS (Netherlands)

A. Mearadji (Amir); W.A.P. Breeman (Wouter); L.J. Hofland (Leo); R.L. Marquet (Richard); J. Jeekel (Hans); E.P. Krenning (Eric); C.H.J. van Eijck (Casper); P.M. van Koetsveld (Peter)

2002-01-01

textabstractOBJECTIVE: To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.SUMMARY BACKGROUND DATA: Previously the authors have shown highly effective therapy with

δ-opioid receptor and somatostatin receptor-4 heterodimerization: possible implications in modulation of pain associated signaling.

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Rishi K Somvanshi

Full Text Available Pain relief is the principal action of opioids. Somatostatin (SST, a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4. In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

Evolutionary history of the somatostatin and somatostatin receptors

Indian Academy of Sciences (India)

Table 1. The identified somatostations. Somatostatin (SST1). Name. Scientific name. Length. High ID (to). Low ID (to) Chromosome. GS. Drs. Danio rerio. 324. 48.1 mms ...... ancestral source. References. Baranowska B., Chmielowska M., Wolinska-Witort E., Bik W.,. Baranowska-Bik A. and Martynska L. 2006 Direct effect of.

99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy in daily clinical practice.

Science.gov (United States)

Chrapko, Beata Ewa; Nocuń, Anna; Gołebiewska, Renata; Stefaniak, Bogusław; Korobowicz, Elzbieta; Czekajska-Chehab, Elzbieta; Sawicki, Marek; Polkowski, Wojciech Piotr

2010-04-01

This study aimed to assess the impact of 99mTc-EDDA/HYNIC-TOC (99mTc-TOC) somatostatin receptor scintigraphy (SRS) in clinical practice. One hundred seventeen patients were divided into 6 groups: 1, initial detection and localization of suspected neuroendocrine tumor (NET); 2, tumor staging before therapy; 3, staging of NET of unknown origin, 4, restaging after surgery of primary tumor; 5, diagnosis of solitary pulmonary nodules (SPNs), and 6, follow-up after "cold" somatostatin analogues treatment. In group 1, clinical suspicions were not confirmed in any of the patients; in group 2, most of the primary lesions showed overexpression of somatostatin receptors (SSRT); in group 3, the primary tumor was not identified in any of the patients; in group 4, recurrences were depicted in 7 out of 47 patients; in group 5, only 1 malignant SPN was detected, and in group 6, regression of primary mass and metastases were seen on follow-up SRS in 1 patient. 99mTc-TOC SRS is useful in staging of SSRT-overexpressing tumors of known and unknown primary origin, as well as in restaging after primary tumor surgery. This method is less effective in detecting suspected NET and assessing SPNs. Further investigation is necessary to evaluate the usefulness of SRS in monitoring patients after biological treatment.

“In-house” preparation of 99mTc-EDDA/HYNIC-TOC, a specific targeting agent for somatostatin receptor scintigraphy

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Sonja Kuzmanovska

2012-01-01

Full Text Available The use of radiolabeled peptide ligands as diagnostics and therapeutics in nuclear oncology has increased recently. One of the most frequently used radiopharmaceutical is 99mTc-EDDA/HYNIC-TOC, a somatostatin analog with affinity for certain types of somatostatin receptors, overexpressed in tumors of neuroendocrine origin. The radiopharmaceutical is not readily available; therefore we introduced its “in house” preparation within project activities supported by the International Atomic Energy Agency (IAEA. We optimized the radiolabeling protocol, prepared a small batch of frozen kits, performed ITLC quality control and animal biodistribution during the preclinical evaluation procedures. The co-ligand exchange labeling procedure was carried out at 100°C during 10 min, resulting in radiochemical purity >90%. The biodistribution scintigrams in normal Wistar rats showed rapid blood clearance after 15 min and predominant kidney accumulation after 4 h, in accordance with the data reported by other authors. Storage stability of the formulated small batch frozen kit (-20°C was evaluated within 6 months, with radiolabeling yield ranging between 94,3% and 96,9%. We conclude that frozen kit can be a safe alternative to the freeze-dried for small batch in house production, and after the satisfactory preclinical evaluation, the “in house” prepared 99mTc-EDDA/ HYNIC-TOC can be introduced in clinical practice as specific targeting agent for somatostatin receptor scintigraphy.

Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells

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Allouche Stéphane

2009-06-01

Full Text Available Abstract Background opioid and somatostatin receptors (SSTRs that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. Materials and methods: SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI staining and apoptosis by annexin V-PI labelling. Results almost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also μ-opioid receptors (MOP-R. XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments. Conclusion these data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.

Somatostatin receptor scintigraphy in sarcoidosis: relation to selected clinical and laboratory markers.

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Piotrowski, Wojciech J; Bieńkiewicz, Małgorzata; Frieske, Izabella; Marczak, Jerzy; Antczak, Adam; Górski, Paweł; Kuśmierek, Jacek; Płachcińska, Anna

2012-01-01

Discriminating between active and inactive sarcoidosis may be problematic in everyday clinical practice. There are numerous biochemical markers used in the diagnosis and monitoring of sarcoidosis. Somatostatin receptor (SR) scintigraphy with the use of 99mTc-octreotide may be used to estimate disease activity. The aim of the paper was to assess the value of traditional biomarkers (serum angiotensin-converting enzyme [SACE], C-reactive protein, markers of calcium metabolism, bronchoalveolar lavage fluid [BALF] lymphocytes) and a novel biomarker, 8-isoprostane (8-IP) in exhaled breath condensate (EBC), in the assessment of sarcoidosis activity in relation to somatostatin receptor scintigraphy. The study included 32 patients with sarcoidosis. Scintigraphy was performed using somatostatin analogue, 99mTc-HYNIC-TOC; planar and SPECT/CT images were recorded. The study group was divided into a subgroup with positive radiotracer uptake (n = 20) and without a visible uptake (n = 12). 8-IP levels were measured in EBC by an immunoenzymatic assay. RESULTS We observed a significantly higher EBC 8-IP levels in the subgroup with positive uptake compared with those with negative uptake (19.1 ± 19.8 vs. 5.4 ± 3.5 pg/ml, P = 0.02). The levels of SACE and the percentage of BALF lymphocytes were also nonsignificantly elevated. In the group of patients with positive scintigraphy results, a positive correlation was observed between the uptake ratio and SACE (r = 0.44, P = 0.041). The results indicate low value of biochemical markers in the assessment of disease activity. SR scintigraphy may have practical usefulness in the monitoring of sarcoidosis.

Therapy with radiolabelled somatostatin analogs in neuroendocrine tumors

International Nuclear Information System (INIS)

Kunikowska, J.; Krolicki, L.

2007-01-01

In the 80's the discovery of somatostatin receptors expression on NET cells enabled the application of somatostatin analogues in diagnosis and therapy. Initially, 'cold' somatostatin analogs were used for therapeutical purpose, with overall good clinical response, but with minimal anti-proliferation effect. Furthermore, radiolabelled receptor-binding peptides have been shown to be an important class of radiopharmaceuticals for tumor diagnosis and therapy with minimal side-effects. Specific binding between receptor on tumor cell and peptide with beta emitting radionuclide act not only on tumor related symptoms but also on tumor cell via radiotoxic effect of beta radiation. Discoveries of next receptor combinations, allow the work over synthesis and applications of next receptors' analogs both in diagnosis and in therapy. Due to complex characteristics of NET's, the use therapeutic 'cocktail' containing the variety analogs may be of great importance. (author)

Development of antibodies against the rat brain somatostatin receptor.

Science.gov (United States)

Theveniau, M; Rens-Domiano, S; Law, S F; Rougon, G; Reisine, T

1992-05-15

Somatostatin (SRIF) is a neurotransmitter in the brain involved in the regulation of motor activity and cognition. It induces its physiological actions by interacting with receptors. We have developed antibodies against the receptor to investigate its structural properties. Rabbit polyclonal antibodies were generated against the rat brain SRIF receptor. These antibodies (F4) were able to immunoprecipitate solubilized SRIF receptors from rat brain and the cell line AtT-20. The specificity of the interaction of these antibodies with SRIF receptors was further demonstrated by immunoblotting. F4 detected SRIF receptors of 60 kDa from rat brain and adrenal cortex and the cell lines AtT-20, GH3, and NG-108, which express high densities of SRIF receptors. They did not detect immunoreactive material from rat liver or COS-1, HEPG, or CRL cells, which do not express functional SRIF receptors. In rat brain, 60-kDa immunoreactivity was detected by F4 in the hippocampus, cerebral cortex, and striatum, which have high densities of SRIF receptors. However, F4 did not interact with proteins from cerebellum and brain stem, which express few SRIF receptors. Immunoreactive material cannot be detected in rat pancreas or pituitary, which have been reported to express a 90-kDa SRIF receptor subtype. The selective detection of 60-kDa SRIF receptors by F4 indicates that the 60- and 90-kDa SRIF receptor subtypes are immunologically distinct. The availability of antibodies that selectively detect native and denatured brain SRIF receptors provides us with a feasible approach to clone the brain SRIF receptor gene(s).

Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

International Nuclear Information System (INIS)

Ugur, Oemer; Kothari, Paresh J.; Finn, Ronald D.; Zanzonico, Pat; Ruan, Shutian; Guenther, Ilonka; Maecke, Helmut R.; Larson, Steven M.

2002-01-01

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe 1 -Tyr 3 -octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T 1/2 =9.5 hr; β + =56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66 Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67 Ga- and 68 Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was >95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET TM images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0±0.7, 13.2±2.1 and 9.8±1.5 for 66 Ga-, 67 Ga-, and 68 Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66 Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively. We conclude that 66 Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66 Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio 1.64), and high kidney uptake must

Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues.

Science.gov (United States)

Erchegyi, Judit; Cescato, Renzo; Grace, Christy Rani R; Waser, Beatrice; Piccand, Véronique; Hoyer, Daniel; Riek, Roland; Rivier, Jean E; Reubi, Jean Claude

2009-05-14

The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst(1)) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA(1,4-6,10,12,13)-[DTyr(2),DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (25) was radio-iodinated ((125)I-25) and specifically labeled sst(1)-expressing cells and tissues. 3D NMR structures were calculated for des-AA(1,4-6,10,12,13)-[DPhe(2),DTrp(8),IAmp(9)]-SRIF-Thr-NH(2) (16), des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (23), and des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9),Tyr(11)]-SRIF-NH(2) (27) in DMSO. Though the analogues have the sst(1) pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst(1) binding of these novel, less constrained sst(1)-selective family members.

The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

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Li Li

2014-01-01

Full Text Available The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG evoked by bee venom (BV. The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Characterization of somatostatin receptors and associated signaling pathways in pancreas of R6/2 transgenic mice.

Science.gov (United States)

Somvanshi, Rishi K; Jhajj, Amrit; Heer, Michael; Kumar, Ujendra

2018-02-01

The present study describes the status of somatostatin receptors (SSTRs) and their colocalization with insulin (β), glucagon (α) and somatostatin (δ) producing cells in the pancreatic islets of 11weeks old R6/2 Huntington's Disease transgenic (HD tg) and age-matched wild type (wt) mice. We also determined expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and presynaptic marker synaptophysin (SYP) in addition to signal transduction pathways associated with diabetes. In R6/2 mice, islets are relatively smaller in size, exhibit enhanced expression and nuclear inclusion of mHtt along with the loss of insulin, glucagon and somatostatin expression. In comparison to wt, R6/2 mice display enhanced mRNA for all SSTRs except SSTR2. In the pancreatic lysate, SSTR1, 4 and 5 immunoreactivity decreases whereas SSTR3 immunoreactivity increases with no discernible changes in SSTR2 immunoreactivity. Furthermore, at the cellular level, R6/2 mice exhibit a receptor specific distributional pattern of SSTRs like immunoreactivity and colocalization with β, α and δ cells. While GAD expression is increased, TH and SYP immunoreactivity was decreased in R6/2 mice, anticipating a cross-talk between the CNS and pancreas in diabetes pathophysiology. We also dissected out the changes in signaling pathway and found decreased activation and expression of PKA, AKT, ERK1/2 and STAT3 in R6/2 mice pancreas. These findings suggest that the impaired organization of SSTRs within islets may lead to perturbed hormonal regulation and signaling. These interconnected complex events might shed new light on the pathogenesis of diabetes in neurodegenerative diseases and the role of SSTRs in potential therapeutic intervention. Copyright © 2017 Elsevier B.V. All rights reserved.

Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC

International Nuclear Information System (INIS)

Freudenberg, L.S.; Goerges, R.; Stergar, H.; Bockisch, A.; Gauler, T.; Bauer, S.; Antoch, G.; Schuette, J.

2008-01-01

Aims: objective of this prospective study was to evaluate the role of somatostatin receptor scintigraphy (SRS) in advanced renal cell carcinoma (RCC) with respect to potential therapy with somatostatin analogue (SST-A) and to assess the response rate under therapy with SST-A. Patients, methods: 16 patients with documented progression of histologically confirmed advanced RCC were included. Planar whole-body SRS was performed 4, 24 and 48h post i.v. injection of 175-200 MBq 111 In-pentetreoide. 5 and 25 h p.i. SPECT of thorax and abdomen were performed. Documentation of somatostatin receptor expression via SRS in > 50% of known tumour lesions was the criteria for treatment start with SST-A (Sandostatin LAR registered -Depot 30mg i.m. every four weeks). Results: in 9/16 of the patients SRS showed at least one metastasis with moderate (n = 5) or intense (n = 4) tracer uptake. Lesion-based SRS evaluation showed only 12.1% (20/165) of all metastases. Most false-negative lesions were located in the lungs. In too patients, the majority of the known metastases was SRS positive and these patients received SST-A therapy. The first radiographic evaluation after a two-month interval showed progressive disease in both patients. Conclusions: we conclude that SRS is of limited value in staging of advanced RCC. In our patients SST-A did not result in a growth control of RCC. Consequently, the use of SST-A in advanced RCC seems to be no relevant therapeutic option. (orig.)

DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

International Nuclear Information System (INIS)

Wild, Damian; Schmitt, Joerg S.; Ginj, Mihaela; Maecke, Helmut R.; Bernard, Bert F.; Krenning, Eric; Jong, Marion de; Wenger, Sandra; Reubi, Jean-Claude

2003-01-01

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [ 111 In, 90 Y-DOTA]-1-Nal 3 -octreotide ( 111 In, 90 Y-DOTA-NOC), was isolated which showed an improved profile. In III -DOTA-NOC exhibited the following IC 50 values (nM) when studied in competition with [ 125 I][Leu 8 , d-Trp 22 , Tyr 25 ]somatostatin-28 (values for Y III -DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. In III -DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than In III ,Y III -DOTA-Tyr 3 -octreotide (In III ,Y III -DOTA-TOC). In addition, [ 111 In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [ 111 In]DOTA-TOC and three times higher than that of [ 111 In]DOTA-octreotide ([ 111 In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steady

Molecular imaging with {sup 68}Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Kaemmerer, Daniel; Haugvik, Sven-Petter; Hommann, Merten [Zentralklinik Bad Berka GmbH, Department of General and Visceral Surgery, Bad Berka (Germany); Peter, Luisa; Lupp, Amelie; Schulz, Stefan [University of Jena, Department of Pharmacology and Toxicology, Jena (Germany); Saenger, Joerg [Laboratory of Pathology and Cytology, Bad Berka (Germany); Prasad, Vikas; Kulkarni, Harshad; Baum, Richard Paul [Zentralklinik Bad Berka, Department of Nuclear Medicine and Center for PET, Bad Berka (Germany)

2011-09-15

Somatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3-5. Overall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative {sup 68}Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUV{sub max} and SUV{sub mean}) were used for PET/CT. The IRS for SSTR2A and SSTR5 correlated highly significant with the SUV{sub max} on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUV{sub mean} (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading. The highly significant correlation between SSTR2A and SSTR5 and the SUV{sub max} on the {sup 68}Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of {sup 68}Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using {sup 68}Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy. (orig.)

Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.

Directory of Open Access Journals (Sweden)

Padmesh S Rajput

Full Text Available Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD. However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5.To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2. Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32 and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/- and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.

Somatostatin Receptor SPECT/CT using 99mTc Labeled HYNIC-TOC Aids in Diagnosis of Primary Optic Nerve Sheath Meningioma.

Science.gov (United States)

Chandra, Piyush; Purandare, Nilendu; Shah, Sneha; Agrawal, Archi; Rangarajan, Venkatesh

2017-01-01

Primary optic nerve sheath meningiomas (ONSM) are rare, benign and slow growing tumor involving the intra-orbital/intra-canalicular segment of the optic nerve. Untreated, they can potentially lead to visual deterioration. Magnetic resonance (MR) is the gold standard imaging modality for diagnosing the entity. Often, a clinical dilemma exists to narrow the differential diagnosis of an enhancing intra-orbital mass on MR. Molecular imaging provides a high degree of precision in diagnosing meningioma in view of relatively high levels of somatostatin receptor expression by these tumors. The following case demonstrates the potential clinical utility of somatostatin receptor SPECT using 99m Tc- labeled HYNIC-TOC in clinical diagnosis of ONSM.

Scintigraphy with labelled analogues of the somatostatin

International Nuclear Information System (INIS)

Duet, M.; Ajzenberg, C.; Warnet, A.; Mundler, O.

1998-01-01

The receptors of the somatostatin have been localized in a big number of tumors, whom a great number are neuro-endocrine tumors. However, some tumors that have not this differentiation (breast cancer, lymphomas, cerebral tumors) possess them as well. Analogues of somatostatin, labelled with isotopes having a gamma emission, allow from now their detection in vivo. (N.C.)

Technetium-99m labeled somatostatin and analogs: synthesis, characterization and in vivo evaluation

International Nuclear Information System (INIS)

Amartey, J.K.

1993-01-01

Technetium-99m complexes of somatostatin and analogs were synthesized following the introduction of sulfhydryl groups with 2-iminothiolane (Traut's Reagent). In rats the complex was taken up by the liver, kidneys, adrenals, lungs and the pancreas. Analysis of urine samples of treated rats showed that the radiochemicals have reasonably good in vivo stability. This implies that the complexes may be potentially useful for biochemical characterization of somatostatin receptors and also in scintigraphic detection of somatostatin receptor positive tumors, especially for metastatic deposits in patients on somatostatin therapy. (Author)

Preliminary clinical evaluation of Somatostatin Receptor Scintigraphy (SRS) with 99mTc-EDDA/HYNIC-TATE in comparison to 111In-Octreoscan and 131 I MIBG scans

International Nuclear Information System (INIS)

Hubalewska, A.; Fross, K.; Staszczak, A.; Huszno, B.; Mikolajczak, R.; Gorska, A.

2004-01-01

Full text: Over expression of somatostatin receptors in various neuroendocrine tumours prompted development of somatostatin analogues, which after radioactive labelling, could be used in oncological diagnostics. Somatostatin Receptor Positive Tumour (Spt) imaging with 111In-DTPA-DPhe1- octreotide (111In-Octreoscan) has become a widely used diagnostic procedure in clinical nuclear medicine. However 111In as a radiolabel has several drawbacks, including limited availability, sub optimal gamma energy and high radiation burden to the patient. Technetium (99mTc) labelling of somatostatin analogues is especially attractive due to the ready availability of 99mTc from generators and its well recognised favourable imaging characteristics. HYNIC conjugated Tyr 3 -Octreotate (HYNIC-TATE) prepared in our laboratory in a dry kit form was labelled with technetium-99mTc, with tricine and EDDA used as coligands. Tyr3-octreotate differs from octreotide (OC) by more hydrophilic tyrosine in the third position and the terminal threonine, which replaced threoninol present in OC. In vitro studies using cell lines transfected with somatostatin receptors (SSTR) revealed that octreotate shows 14- 17 times better binding affinity for SSTR type 2 than does OC. It is expected to clear more rapidly from non-target tissues as a result of the carboxylic group at the C-terminal of the peptide. HYNIC has been used as bifunctional chelator in 99mTc-HYNIC-Tyr3-octreotide (TOC) by Maecke and Behe, who reported on its favourable preclinical characteristics when EDDA was used as a co-ligand. These pre-clinical data were confirmed by Decristoforo and Mather and their early clinical studies appeared recently. The new radiopharmaceutical - 99mTc-DDA/HYNICTATE was evaluated in-vitro and in-vivo in an animal model and its potential for SSTR scintigraphy was documented. In the current patient study the diagnostic usefulness of the new radiopharmaceutical was tested for detection of tumours expressing SSTR

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

DEFF Research Database (Denmark)

Lauritsen, Marlene B; Nyegaard, Mette; Betancur, Catalina

2003-01-01

growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine......Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports...... of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased...

Novel Somatostatin Receptor Ligands Therapies for Acromegaly

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Rosa Maria Paragliola

2018-03-01

Full Text Available Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs octreotide (OCT, lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients’ compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029, delivered via prefilled syringes and oral OCT that uses a “transient permeability enhancer” technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003, which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.

Ga-66 labeled somatostatin analogue DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

Energy Technology Data Exchange (ETDEWEB)

Ugur, Oemer E-mail: ougur@hacettepe.edu.tr; Kothari, Paresh J.; Finn, Ronald D.; Zanzonico, Pat; Ruan, Shutian; Guenther, Ilonka; Maecke, Helmut R.; Larson, Steven M

2002-02-01

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T{sub 1/2} =9.5 hr; {beta}{sup +}=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of {sup 66}Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with {sup 67}Ga- and {sup 68}Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was >95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET{sup TM} images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0{+-}0.7, 13.2{+-}2.1 and 9.8{+-}1.5 for {sup 66}Ga-, {sup 67}Ga-, and {sup 68}Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for {sup 66}Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively. We conclude that {sup 66}Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. {sup 66}Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the

Preparation, formulation and quality control of one step kit 99m Tc - EDDA/HYNIC-Tyr3-Octreotide as a peptide radiopharmaceutical for imaging somatostatin receptor positive tumors

International Nuclear Information System (INIS)

Gandomkar, M.; Najafi, R.; Sadat-Ebrahimi, E.; Babaei, M.H.

2004-01-01

The high expression of somatostatin receptors in many tumours, have made receptor scintigraphy with 11I n-DTPA-Octreotide a widely used procedure in nuclear medicine. Despite its clinical success, some limitation and drawbacks of radiolabelling with 11I n remain, especially those concerned with the cost, availability and physical decay properties of this radionuclide. 99m Tc - EDDA/HYNIC-Tyr 3 -Octreotide was studied as a new agent with the potential to replace octreoscan in somatostatin receptor scintigraphy. This hydrazino nicotinic acid derivatized somatostatin complex contains ethylenediamine N, N diacetic acid as a co-ligand resulting in a high in vitro and in vivo stability. High labeling yields (>90%) were achieved at high specific activities. Characterization via HPLC, biodistribution and receptor binding of the resulting complex are described. The formulation developed enables rapid and simple labeling of 99m Tc - EDDA/HYNIC-TOC in a manner suitable for clinical setting

Tumor-associated macrophages in glioblastoma multiforme-a suitable target for somatostatin receptor-based imaging and therapy?

Directory of Open Access Journals (Sweden)

Constantin Lapa

Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN',N″,N'″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM.15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68, proliferative activity (Ki67 as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET imaging using 68Ga-DOTATATE was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry.The amount of microglia/macrophages ranged from 50% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns.SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.

Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

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Rishi K. Somvanshi

2012-04-01

Full Text Available G-protein coupled receptors (GPCRs are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs in pathophysiology of diseases and as the potential candidate for drug discovery.

Synthesis of a Fluorescently Labeled 68Ga-DOTA-TOC Analog for Somatostatin Receptor Targeting.

Science.gov (United States)

Ghosh, Sukhen C; Hernandez Vargas, Servando; Rodriguez, Melissa; Kossatz, Susanne; Voss, Julie; Carmon, Kendra S; Reiner, Thomas; Schonbrunn, Agnes; Azhdarinia, Ali

2017-07-13

Fluorescently labeled imaging agents can identify surgical margins in real-time to help achieve complete resections and minimize the likelihood of local recurrence. However, photon attenuation limits fluorescence-based imaging to superficial lesions or lesions that are a few millimeters beneath the tissue surface. Contrast agents that are dual-labeled with a radionuclide and fluorescent dye can overcome this limitation and combine quantitative, whole-body nuclear imaging with intraoperative fluorescence imaging. Using a multimodality chelation (MMC) scaffold, IRDye 800CW was conjugated to the clinically used somatostatin analog, 68 Ga-DOTA-TOC, to produce the dual-labeled analog, 68 Ga-MMC(IRDye 800CW)-TOC, with high yield and specific activity. In vitro pharmacological assays demonstrated retention of receptor-targeting properties for the dual-labeled compound with robust internalization that was somatostatin receptor (SSTR) 2-mediated. Biodistribution studies in mice identified the kidneys as the primary excretion route for 68 Ga-MMC(IRDye 800CW)-TOC, along with clearance via the reticuloendothelial system. Higher uptake was observed in most tissues compared to 68 Ga-DOTA-TOC but decreased as a function of time. The combination of excellent specificity for SSTR2-expressing cells and suitable biodistribution indicate potential application of 68 Ga-MMC(IRDye 800CW)-TOC for intraoperative detection of SSTR2-expressing tumors.

The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-dPhe1,Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours

International Nuclear Information System (INIS)

Stolz, B.; Weckbecker, G.; Smith-Jones, P.M.; Albert, R.; Raulf, F.; Bruns, C.

1998-01-01

Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe 1 , Tyr 3 ]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst 2 ) (human sst 2 IC 50 =0.9 nM, rat sst 2 IC 50 =0.5 nM). In vivo, 90 Y-SMT 487 distributed rapidly to the sst 2 expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg 90 Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 μg/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of 90 Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997. (orig.)

Preparation and biological evaluation of [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide for somatostatin receptor-positive tumor imaging.

Science.gov (United States)

Erfani, Mostafa; Shafiei, Mohammad; Mazidi, Mohammad; Goudarzi, Mostafa

2013-04-01

Somatostatin-derived analogues play an important role in the diagnosis and treatment of neuroendocrine tumors. The aim of this study was to evaluate a new somatostatin analogue designed for labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), β-(3-benzothienyl)-Ala (BzThi(3))]-octreotide ([HYNIC]-BOC), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was performed on a solid phase using a standard Fmoc strategy. The HYNIC-peptide conjugate was radiolabeled with (99m)Tc and characterized by ITLC and high-performance liquid chromatography (HPLC). In vitro studies were carried out in sstr2 expressing AR4-2J cell lines. In vivo distribution studies were performed in rats bearing the AR4-2J tumor. The radiolabeled complex could be prepared at high-specific activities and >95% radiochemical yield as determined by HPLC. The peptide conjugate showed high-affinity binding for sstr2. The radioligand showed high and specific internalization into AR4-2J cells (18.19%±0.21% at 4 hours). In vivo distribution studies in rats bearing tumor have shown a receptor-specific uptake of radioactivity in somatostatin receptor-positive organs. After 4 hours, uptake in the AR4-2J tumor was 1.71%±0.36% injected dose per gram tissue (%ID/g). These data show that [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies.

Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

International Nuclear Information System (INIS)

Kwekkeboom, D.J.; Krenning, E.P.

1997-01-01

[ 111 In-DTPA-D-Phe 1 [-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established. (orig.). With 4 figs., 1 tab

NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia

Directory of Open Access Journals (Sweden)

Fatemah Alherz

2017-06-01

Full Text Available This review investigates the association between N-methyl-d-Aspartate receptor (NMDAR hypofunction and somatostatin-expressing GABAergic interneurons (SST+ and how it contributes to the cognitive deficits observed in schizophrenia (SZ. This is based on evidence that NMDAR antagonists caused symptoms resembling SZ in healthy individuals. NMDAR hypofunction in GABAergic interneurons results in the modulation of the cortical network oscillation, particularly in the gamma range (30–80 Hz. These gamma-band oscillation (GBO abnormalities were found to lead to the cognitive deficits observed in the disorder. Postmortem mRNA studies have shown that SST decreased more significantly than any other biomarker in schizophrenic subjects. The functional role of Somatostatin (SST in the aetiology of SZ can be studied through its receptors. Genetic knockout studies in animal models in Huntington's disease (HD have shown that a specific SST receptor, SSTR2, is increased along with the increased NMDAR activity, with opposing patterns observed in SZ. A direct correlation between SSTR and NMDAR is hence inferred in this review with the hope of finding a potential new therapeutic target for the treatment of SZ and related neurological conditions.

Detecting somatostatin receptor in breast tumor tissue and its clinical significance

International Nuclear Information System (INIS)

Zhang Yongjian; Yu Xian; Lin Wei; Ding Xuan; Huang Shizhang; Lu Guangming

2002-01-01

The authors observe the difference of somatostatin receptor (SSR) between benign and malignant breast tumor and the relation between SSR and estrogen receptor (ER) or progesterone receptor (PR) in breast tumor tissue, and to predict the clinical value of detecting breast tumor by SSR receptor imaging. These tissues excised from operation in breast tumor were divided into 4 groups: breast malignant tumor group (BMTG) and its control group (C1G), breast benign tumor group (BBTG) and its control group (C2G). SSR was detected by radioligand binding assay (RBA) and ER, PR by LsAB method in these groups. Results is: (1) The SSR express quantity is 108.6 +- 67.3 fmol/mg pr, 37.2 +- 9.6 fmol/mg pr, 43.4 +- 12.6 fmol/mg pr 33.9 +- 10.2 fmol/mg pr respectively in BMTG, C1G, BBTG, C2G. The SSR of BMTG is the most among these groups, the difference is obvious, P 0.05); (2) The correlation coefficient of SSR and ER is 0.859, SSR and PR is 0.750. Most breast tumor tissues express high density SSR, the authors suppose that malignant tumor can been distinguished from benign tumor preliminarily by SSR receptor imaging. There is a good correlation between SSR and ER, PR, detecting SSR may predict the quality of tumor and the prognosis of the patient

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors.

Science.gov (United States)

Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-08-01

Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), 1-Nal(3), Thr(8)]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with (99m)Tc was performed at 100 degrees C for 10 min using SnCl(2) as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr(2)-expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr(2). The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13+/-0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33+/-0.23%ID/g (percentage of injected dose per gram of tissue). These data show that [(99m)Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies.

Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors

International Nuclear Information System (INIS)

Gandomkar, Mostafa; Najafi, Reza; Shafiei, Mohammad; Mazidi, Mohammad; Ebrahimi, Sayed Esmaeil Sadat

2007-01-01

Purpose: Radiolabeled somatostatin analogues are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin-receptor-positive tumors. The aim of this study was to evaluate a new somatostatin analogue designed for the labeling with 99m Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC 0 ), 1-Nal 3 , Thr 8 ]-octreotide ([HYNIC]-NATE), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Methods: Synthesis was preformed on a solid phase using a standard Fmoc strategy. Labeling with 99m Tc was performed at 100 o C for 10 min using SnCl 2 as a reductant. Radiochemical analysis involved ITLC and high-performance liquid chromatography methods. Peptide conjugate affinity was determined in AR4-2J cell membranes. The internalization and externalization rates were studied in sstr 2 -expressing AR4-2J cells. Biodistribution of radiopeptide was studied in rats bearing the AR4-2J tumor. Results: Radiolabeling was performed at high specific activities, and radiochemical purity was >95%. Peptide conjugate showed high affinity binding for sstr 2 . The radioligand showed a moderate and specific internalization into AR4-2J cells (14.13±0.61% at 4 h). In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in somatostatin-receptor-positive organs. After 4 h, uptake in the AR4-2J tumor was 1.33±0.23%ID/g (percentage of injected dose per gram of tissue). Conclusion: These data show that [ 99m Tc/EDDA/tricine/HYNIC]-NATE is a specific radioligand for the somatostatin-receptor-positive tumors and is a suitable candidate for clinical studies

99mTc-EDDA/HYNIC-TOC in management of patients with head and neck somatostatin receptor positive tumors.

Science.gov (United States)

Trogrlic, Mate; Tezak, Stanko

2016-01-01

Aim of this study was to determine the value of technetium-99m-hydrazinonicotinyl-Tyr3-octreotide (99mTc-ED-DA/HYNIC-TOC) in patients with somatostatin receptor (SSR) positive tumors of head and neck region. A total number of 16 patients were enrolled in this study. Planar whole body (WB) and single photon emission computed tomography (SPECT) images were acquired at 2 and 4 hours after the injection of approximately 670 MBq of 99mTc-EDDA/HYNIC-TOC. Additional single photon emission computed tomography/computed tomography (SPECT/CT) images of the head and neck region were acquired at 4h post tracer injection. Clinical and imaging follow up were taken as the reference standard. There were 10 female and 6 male patients of age 57.7 ± 12.9 years (58.5; 32-78) years. 99mTc-EDDA/HYNIC-TOC somatostatin receptor scintigraphy (SRS) was TP in 13 patients, TN in two and FP in one. Follow up period for SRS was 31.1 ± 19.4 (29; 2-63) months. 99mTc-EDDA/HYNIC-TOC scintigraphy provided additional information in 50% of patients, with impact on patient management in the same percentage of patients. Distant metastases were found in nine out of 16 patients (56%). 99mTc-EDDA/HYNIC-TOC SRS had sensitivity of 100% (75.3-100%), specificity of 66.7% (9.4-99.2%), accuracy of 93.7%, positive predictive value of 92.9% (66.1-99.8%), and negative predictive value of 100% (15.8-100%). Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC is very useful imaging method in the evalu-ation of patients with SSR positive tumors of head and neck region.

Tissue-type plasminogen activator in somatostatin cells of rat pancreas and hypothalamus

DEFF Research Database (Denmark)

Kristensen, P; Larsson, L I; Danø, K

1987-01-01

-PA, and immunoblotting analysis demonstrated one band with a similar electrophoretic mobility. No urokinase-type PA immunoreactivity was found in the rat endocrine pancreas. A granular t-PA immunoreactivity resembling that found in adjacent sections with somatostatin antiserum was found in the median eminence...

The somatostatin receptor-targeted radiotherapeutic [{sup 90}Y-DOTA-dPhe{sup 1},Tyr{sup 3}]octreotide ({sup 90}Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours

Energy Technology Data Exchange (ETDEWEB)

Stolz, B.; Weckbecker, G.; Smith-Jones, P.M.; Albert, R.; Raulf, F.; Bruns, C. [Novartis Pharma AG, Basel (Switzerland)

1998-07-01

Somatostatin receptor-expressing tumours are potential targets for therapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-dPhe{sup 1}, Tyr{sup 3}]octreotide (SMT 487) as the most promising candidate molecule because of its advantageous properties in cellular and in vivo tumour models. In the current paper we describe the radiotherapeutic effect of yttrium-90 labelled SMT 487 in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomolar affinity to both the human and the rat somatostatin receptor subtype 2 (sst{sub 2}) (human sst{sub 2} IC{sub 50}=0.9 nM, rat sst{sub 2} IC{sub 50}=0.5 nM). In vivo, {sup 90}Y-SMT 487 distributed rapidly to the sst{sub 2} expressing CA 20948 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg {sup 90}Y-SMT 487 resulted in a complete remission of the tumours in five out of seven CA 20948 tumour-bearing Lewis rats. No regrowth of the tumours occurred 8 months post injection. Control animals that were treated with 30 {mu}g/kg of unlabelled SMT 487 had to be sacrificed 10 days post injection due to excessive growth or necrotic areas on the tumour surface. Upon re-inoculation of tumour cells into those rats that had shown complete remission, the tumours disappeared after 3-4 weeks of moderate growth without any further treatment. The present study shows for the first time the curative potential of {sup 90}Y-SMT 487-based radiotherapy for somatostatin receptor-expressing tumours. Clinical phase I studies with yttrium-labelled SMT 487 have started in September 1997. (orig.) With 4 figs., 2 tabs., 29 refs.

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response

OpenAIRE

Andreas Stengel; Yvette F. Taché; Yvette F. Taché

2017-01-01

Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates—in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis—other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a br...

Examination of the somatostatin receptor status in non-medullary thyroid cancer; Untersuchungen zum Somatostatinrezeptor-Status bei nicht-medullaeren Schilddruesenkarzinomen

Energy Technology Data Exchange (ETDEWEB)

Goerges, R.; Brandt-Mainz, K.; Bockisch, A. [Essen Univ. (Gesamthochschule) (Germany). Klinik und Poliklinik fuer Nuklearmedizin; Kahaly, G. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Medizin - Endokrinologie und Stoffwechselerkrankungen; Mueller-Brand, J.; Maecke, H. [Kantonsspital Basel (Switzerland). Inst. fuer Nuklearmedizin; Walgenbach, S. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Allgemein- und Abdominalchirurgie; Bruns, C. [Praeklinische Forschung Novartis, Basel (Switzerland); Andreas, J. [Universitaetsklinik Mainz (Germany). Klinik und Poliklinik fuer Nuklearmedizin

1999-06-01

Aim: Recent in-vitro and in-vivo studies demonstrated a somatostatin receptor expression in some non-medullary thyroid carcinomas. In this study we investigated the somatostatin receptor status for this particular tumor entity in a larger patient group. Subject and methods: We compared 131-iodine with 111-In-pentetreotide scans in 24 patients with metastasizing, non-medullary thyroid cancer. The findings were correlated with other imaging modalities. Additionally, we performed receptor autoradiography in one patient, octreotide therapy in another patient and administration of 90-Y- and 111-In-DOTATOC in 2 consecutive patients. Results: In the 15 patients with papillary or follicular carcinoma, 111-In-pentetreotide was inferior to 131-I in 8/15, equal in 1/15, and superior in 6/15 patients. In 8/9 of the patients with Huerthle cell cacinoma, metastases showed a 111-In-pentetreotide accumulation of various intensity, while 131-iodine scans were negative except for one patient. 111-In-pentetreotide was equal or superior compared to 201-Tl or 99m-Tc-sestamibi, but for the most part inferior in comparison with 18-F-FDG-PET. The findings of 111-In-pentetreotide scintigraphy correlated well with the receptor autoradiography and the accumulation of DOTATOC, but not with the therapeutic effect of `cold` octreotide on the thyroid cancer metastases. Conclusions: Several metastases of papillary and follicular carcinoma, and the majority of Huerthle cell cancer metastases can express somatostatin receptors. 111-In-pentetreotide scintigraphy is a promising tool for localization of metastases especially in Huerthle cell cancer or if PET is not available, and may be useful for selection of possible candidates, if therapeutic effective {beta}-emitting somatostatin analogues will be available for routine application. (orig.) [Deutsch] Ziel: in aktuellen In-vitro und In-vivo-Untersuchungen wurde eine Somatostatinrezeptor-Expression bei einigen nicht

Synthesis and evaluation of ligand targeting the somatostatin receptor for drug delivery to tumor cell

Energy Technology Data Exchange (ETDEWEB)

Lee, So Young; Hong, Young Don; Jung, Sung Hee; Choi, Sun Ju [Radioisotope Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2015-12-15

Most of targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells to produce its cytotoxic effect. Either small molecule drugs or monoclonal antibodies are mostly used in targeted therapies. Unfortunately, targeted therapy has a certain degree of unwanted side effect like other cytotoxicity inducing chemotherapies. To overcome and to reduce unwanted side effects during a cancer therapy, recently radiopeptide therapies has got the worlds' attraction for the tumor targeting modalities due to its beneficial effect on less side effect compared to cytotoxic chemotherapies. Among radiopeptide therapies, {sup 177}Lu-DOTATATE is a major modality as an effective one invented so far in treating neuroendocrine tumor (NET) and it has been in clinical trials at least one decade. Although it does have rather effective therapeutic effect on NET, it has less effective in rather large solid tumor. There are many ways to improve or increase therapeutic effect of radiopeptide are a finding the potent small molecules to target the tumor site selectively, or a labeling with radioisotope of emitting high energy, or an improving its biological half-life by introducing different moieties to increase lipophilicity. Present study was focus to increase a biological halflife of radio somatostatin which will target the somatostatin receptor by altering the bifunctional chelator (BFCA) by introducing lipophilic moiety to the somatostatin, which would make the labeled peptide stay longer in the tumor site and thus it can intensify the therapeutic effect on tumor cell itself and around tissues.

Induction of Human Somatostatin Receptor Subtype 2 on Breast Tumors with an Adenoviral Vector for Their Treatment and Detection with a Radiolabeled Peptide

National Research Council Canada - National Science Library

Rogers, Buck

2002-01-01

.... An adenoviral vector encoding the human somatostatin receptor subtype 2 (AdSSTr2) has been produced. The MDA- MB-468 and BT-474 human breast cancer cells were infected with AdSSTr2 and harvested 48 h later for membrane preparations...

Sensitive radioimmunoassay for somatostatin using N-(/sup 125/I)-tyr-somatostatin as labelled antigen

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Dupont, A [CHUL, Quebec (Canada). Lab. of Molecular Endocrinology and Service of Gastro-Enterology; Coy, D H; Alvarado-Urbina, G; Cote, J; Meyers, C A; McManus, J; Barden, N; De Lean, A; Labrie, F

1979-01-01

A sensitive radioimmunoassay for somatostatin using N-(/sup 125/I)-Tyr-somatostatin is described and compared with using (/sup 125/I)-Tyr/sup 1/-somatostatin. The minimum detectable amount of somatostatin using N-(/sup 125/I)-Tyr-somatostatin as tracer was 0.1 to 0.5 pg, which is approximately 10-fold lower detection limit of the RIA using (/sup 125/I)-Tyr/sup 1/-somatostatin. Moreover, it was found that the shelf-life of N-(/sup 125/I)-Tyr-somatostatin was prolonged in comparison with labelled Tyr/sup 1/-somatostatin. Human pancreatic and gastric extracts displayed immunological similarity to synthetic somatostatin tetradecapeptide.

Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

International Nuclear Information System (INIS)

Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

2010-01-01

Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

Normal uptake of 68Ga-DOTA-TOC by the pancreas uncinate process mimicking malignancy at somatostatin receptor PET.

Science.gov (United States)

Jacobsson, Hans; Larsson, Patricia; Jonsson, Cathrine; Jussing, Emma; Grybäck, Per

2012-04-01

To characterize a commonly occurring increased uptake by the uncinate process of the pancreas at PET/CT using 68Ga-DOTA-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC). This tracer has replaced In pentetreotide (OctreoScan®) for somatostatin receptor scintigraphy at our laboratory. Fifty of our first 74 PET/CT examinations with 68Ga-DOTA-TOC could be evaluated in retrospect. None of these patients had surgery or showed any pathology in the pancreas head at the concomitant CT. Thirty-five of the 50 examinations (70%) showed an uptake by the uncinate process sufficiently intense to be interpreted as pathologic and simulating a tumor. Mean SUVmax was 9.2. Mean SUVmean using an isoactivity cut-off of >75% and >50% was 7.8 and 6.0, respectively. Volume calculations of the uncinate process activity using these definitions gave 0.9 mL and 4.2 mL, respectively. There is a frequent physiological uptake of 68Ga-DOTA-TOC by the pancreas uncinate process. This may be caused by an accumulation of pancreatic polypeptide-containing cells expressing somatostatin receptors. If there is a normal finding at concomitant diagnostic CT, this uptake should be regarded as physiological.

Immunohistochemical Detection and Localization of Somatostatin Receptor Subtypes in Prostate Tissue from Patients with Bladder Outlet Obstruction

Directory of Open Access Journals (Sweden)

Rodolfo Montironi

2008-01-01

Full Text Available Background and Aim of the Study: Scant information on the cellular distribution of the five somatostatin receptor (SSTR subtypes in the normal prostate and in neoplasms of the prostate has been reported in very few studies in which techniques, such as in situ hybridization histochemistry, autoradiography, and more recently immunohistochemistry, have been applied. The aim of the study was to examine immunohistochemically the distribution and localization of these 5 subtypes in the various tissue components in normal prostate.

Molecular imaging of neuroendocrine tumors using {sup 68}Ga-labeled peptides (Somatostatin receptor PET/CT); Molekulare Bildgebung neuroendokriner Tumoren mit {sup 68}Ga-markierten Peptiden (Somatostatinrezeptor-PET/CT)

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Baum, R.P.; Prasad, V. [Zentralklinik Bad Berka GmbH (Germany). Klinik fuer Nuklearmedizin/PET-Zentrum; Hoersch, D. [Zentralklinik Bad Berka GmbH (Germany). Klinik fuer Innere Medizin, Gastroenterologie, Onkologie, Endokrionologie

2009-06-15

Receptor PET/CT using {sup 68}Ga-labeled somatostatin analogues (DOTA-NOC, DOTA-TOC or DOTA-TATE) enables the highly sensitive molecular imaging of neuroendocrine tumors (NETs) based on the expression of somatostatin receptors and even the detection of receptor subtypes. Our experience after more than 3000 studies shows that receptor PET/CT has a significantly higher tumor detection rate than conventional scintigraphy (even in SPECT/CT technique), and that tumor lesions can be very accurately localized. By calculating standardized uptake values (SUV) - which are reproducible and investigator-independent - patients can be selected for peptide receptor radiotherapy and also the course after therapy can be controlled. Receptor-PET/CT is the most sensitive imaging modality for the detection of unknown primary tumors (CUP syndrome), which is especially true for the detection of neuroendocrine tumors of the pancreas and small bowel; whole-body staging (''one stop shop'') as well as restaging and selection of patients for peptide receptor radiotherapy can be performed using a patient-friendly procedure (examination finished within one hour) exposing the patient to less radiation than whole-body CT scanning. The {sup 68}Ge/{sup 68}Ga generator has proved very reliable over the years - even in a hospital environment. The effective costs for {sup 68}Ga labeled somatostatin analogues might be less than for scintigraphic agents, provided a certain number of studies per year are performed. The development of new tumor-specific peptides as well as of other DOTA- or NOTA-coupled radiopharmaceuticals opens a new avenue into the future: finally, the {sup 68}Ga generator could play a similar important role for PET/CT as did the {sup 99m}Tc-Generator for conventional gamma camera imaging over the last decades. (orig.)

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

Science.gov (United States)

Zhang, Libo; Vines, Douglass C; Scollard, Deborah A; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68 Ga-DOTA-TATE uptake and 177 Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68 Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68 Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177 Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro , NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131 I-MIBG therapy, low 123 I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68 Ga-DOTA-TATE uptake and antitumor efficacy of 177 Lu-DOTA-TATE. 68 Ga-DOTA-TATE PET is superior to 123 I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177 Lu-DOTA-TATE therapy.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

Directory of Open Access Journals (Sweden)

Libo Zhang

2017-01-01

Full Text Available Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2 expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15 compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2. Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal, tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET, a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

Impact of the scintigraphy of somatostatin receptors upon the therapeutic strategy in patients bearing digestive endocrine tumors

International Nuclear Information System (INIS)

Lebtahi, R.; Cadiot, G.; Genin, R.; Delahaye, N.; Faraggi, M.; Daou, D.; Peker, C.; Migon, M.; Le Guludec, D.

1997-01-01

The scintigraphy of somatostatin receptors (SSR) is a sensible method for detecting the gastroenteric-pancreatic endocrine tumors and their metastases. The aim of this study is to evaluate the clinical impact of the results of SSR in taking patients in therapeutic charge. A hundred and sixty patients bearing biologically and/or histologically proved digestive endocrine tumors were prospectively studied. The patients were classified in 3 groups: group I - 90 patients with no known metastases; group II - 59 patients with liver metastases and group III - 11 patients with known extra-hepatic metastases. The results of the scintigraphy were compared with those of conventional imaging. The following results were obtained: in group 1 (90 patients) the conventional imaging has allowed detecting 53 primitive tumors in 44 patients. The SSR visualized 68% of these sites and has detected 26 supplementary primitive sites in 20 patients and 29 metastatic sites in 25 patients. In group II the scintigraphy has detected 95% of hepatic metastases and revealed 23 new metastasis sites and 18/59 patients. In group III the scintigraphy has detected 11 new sites in 7 patients. The results of scintigraphy modified the patient's classification in 38 cases (24%). The therapeutic strategy was modified for 40 patients (25%). In conclusion, the scintigraphy of somatostatin receptors is able to detect a significant number of digestive endocrine tumors what has important implications for therapeutical planning of the treatment of patients. It must be carried out during pre-therapeutic extension examination of these tumors

Somatostatin-IRES-Cre Mice: Between Knockout and Wild-Type?

Science.gov (United States)

Viollet, Cécile; Simon, Axelle; Tolle, Virginie; Labarthe, Alexandra; Grouselle, Dominique; Loe-Mie, Yann; Simonneau, Michel; Martel, Guillaume; Epelbaum, Jacques

2017-01-01

The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre (SOM-cre) mouse strains are increasingly used to unravel the physiology of SOM-containing neurons. However, while knock-in targeting strategy greatly improves Cre-Lox system accuracy, recent reports have shown that genomic insertion of Cre construct per se can markedly affect physiological function. We show that Cre transgene insertion into the 3'UTR of the somatostatin gene leads to the selective and massive depletion of endogenous SOM in all tested brain regions. It also strongly impacts SOM-related neuroendocrine responses in a similar manner to what has been reported for SST KO mice: increased corticosterone levels after 30-min restraint stress, decreased amplitude and regularity of ultradian growth hormone secretory patterns accompanied by changes in sexually dimorphic liver gene expression ( serpina1, Cyp2b9, Cyp2a4, Cyp2d9, and Cyp7b1 ). In addition to demonstrating the need for examination of the consequences of Cre transgenesis, these results also reveal how this SOM-cre strain may be a useful tool in studying the functional consequences of moderate to low SOM levels as reported in neurological and psychiatric disorders.

New octreotide derivatives for in vivo targeting of somatostatin receptor-positive tumors for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET)

International Nuclear Information System (INIS)

Maecke, H.R.; Smith-Jones, P.; Maina, T.; Stolz, B.; Albert, R.; Bruns, C.; Reist, H.

1993-01-01

Two new modifications of the somatostatin analog octreotide, designed to hold the gallium isotopes 67 Ga and 68 Ga (DFO-SMS) and 99m Tc (PnAO-SMS) have been synthesized and evaluated in vitro and in vivo in tumor bearing rats. DFO-SMS can be labeled with 67 Ga 3+ and 68 Ga 3+ with high specific activity within less than 30 minutes in a ''cold kit'' type formulation. The labeled conjugate is stable under physiologgical conditions. Moreover the binding affinity to somatostatin receptors on rat brain cortex membranes was shown to be retained. In vivo fast tumor localization was demonstrated and the pharmacokinetics proved to be favourable as the main excretion route was via the kidneys. First PET studies with [ 68 Ga]-DFO-SMS showed a rapid accumulation in the tumor and a residence half-life at the tumor site of about 6 hours. PnAO-SMS can be labeled with 99m Tc with high radiochemical purity. In vivo the radiotracer accumulates well in the tumor but due to its high lipohilicity, its main excretion route is via the hepatobiliary system. (orig.)

Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjögren's syndrome treated with Infliximab: a pilot study.

Science.gov (United States)

Anzola-Fuentes, L K; Chianelli, M; Galli, F; Glaudemans, A W J M; Martin Martin, L; Todino, V; Migliore, A; Signore, A

2016-12-01

Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue ((99m)Tc-EDDA/tricine-HYNIC-tyr(3)-octreotide ((99m)Tc-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjögren's syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment. Eighteen patients with rheumatoid arthritis and secondary Sjögren's syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-α. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer's test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3-6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of (99m)Tc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively. All patients showed uptake of (99m)Tc-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands. SRS using (99m)Tc-EDDA/HYNIC-TOC may be a useful imaging tool to assess

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

Energy Technology Data Exchange (ETDEWEB)

Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)

2013-12-06

Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma.

Science.gov (United States)

Czepczyński, Rafał; Parisella, Maria Gemma; Kosowicz, Jerzy; Mikołajczak, Renata; Ziemnicka, Katarzyna; Gryczyńska, Maria; Sowiński, Jerzy; Signore, Alberto

2007-10-01

Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue (99m)Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using (99m)Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, (99m)Tc(V)-DMSA, (131)I-MIBG, (99m)Tc-MDP, (111)In-DTPA-octreotide and (18)F-FDG-PET) and compared with (99m)Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using (99m)Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. (99m)Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making.

Somatostatin receptor scintigraphy using 99mTc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

International Nuclear Information System (INIS)

Czepczynski, Rafal; Kosowicz, Jerzy; Ziemnicka, Katarzyna; Gryczynska, Maria; Sowinski, Jerzy; Parisella, Maria G.; Mikolajczak, Renata; Signore, Alberto

2007-01-01

Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue 99m Tc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Forty-five patients with MTC, aged 14-83 years, were investigated. Scintigraphy using 99m Tc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, 99m Tc(V)-DMSA, 131 I-MIBG, 99m Tc-MDP, 111 In-DTPA-octreotide and 18 F-FDG-PET) and compared with 99m Tc-EDDA/HYNIC-TOC. In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using 99m Tc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. 99m Tc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making. (orig.)

Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome

International Nuclear Information System (INIS)

Joshi, Prathamesh; Lele, Vikram

2013-01-01

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20%-50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of 123 I/ 131 I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with 68 Gallium- DOTA-DPhe 1 , Tyr 3 -octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA

Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome.

Science.gov (United States)

Joshi, Prathamesh; Lele, Vikram

2013-04-01

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20%-50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of (123)I/(131)I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with (68)Gallium- DOTA-DPhe(1), Tyr(3)-octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA.

Expression of somatostatin receptors subtype 2 and 5 in extraocular muscle tissue of hypothyroidism animal induced by 131I

International Nuclear Information System (INIS)

Li Fangdu; Chu Qiaomei; Xu Peikang; Yao Xiaohong; Shen Jiangfan

2012-01-01

Objective: To observe the expression and distribution of somatostatin receptors 2 and 5 (SSTR2, 5) in extraocular muscle in hypothyroidism and thyroid associated ophthalmopathy (TAO) Wister rats induced by 131 I. Methods: 20 Wister rats were randomly divided into experimental group and normal group(group D). According to 131 I doses of intraperitoneal injection, the experimental groups were divided into low (group A), middle (group B) and high dose group (group C). After 8 weeks, all rats were sacrificed and orbital tissue sections were applied to HE staining and Immunohistochemistry for the analysis of rat orbital tissue changes and SSTR2 and 5 distribution in extraocular muscle. Results: The serum FT 4 levels in group A (16.98±2.92 pmol / L), group B (1.84±0.44 pmol / L) and group C (1.35 ±0.37 pmol /L) eight weeks after 131 I injection were decreased, and had significant difference compared with group D (P 4 levels in group B and C were significantly lower than that in group A (P 0.05). Orbital tissue in experimental group showed mucoid degeneration and edema, the extent was about 25% in group A, 50% in group B, 70% in group C. The rats in group B and group C appeared obvious proliferation of fibrous and adipose tissue, muscle fibers degeneration fracture, even extraocular muscles in group C have vacuole formation. Immunohistochemical analysis displayed highest SSTR5 distribution and strongest expression was in extraocular muscle of group C, second in A B combination group (A and B groups)and weakest in group D. There were significant differences between A B combination group,group C and group D (P 0.05). Conclusion: This study observed the distribution and expression of SSTR2 and SSTR5 in extraocular muscle on the established hypothyroidism animal model. It is some significance for understanding the mechanism of somatostatin receptors in occurrence and development of TAO, similar to provide a reference for the use of somatostatin analogue orbital imaging

99mTc-N4-[Tyr3]Octreotate Versus 99mTc-EDDA/HYNIC-[Tyr3]Octreotide: an intrapatient comparison of two novel Technetium-99m labeled tracers for somatostatin receptor scintigraphy.

Science.gov (United States)

Gabriel, Michael; Decristoforo, Clemens; Maina, Theodosia; Nock, Berthold; vonGuggenberg, Elisabeth; Cordopatis, Paul; Moncayo, Roy

2004-02-01

Tetraamine-[Tyr3]octreotate (Demotate) is a somatostatin (SST) analogue that can be easily labeled with 99mTc at high specific activities and showed promising preclinical properties for SST receptor scintigraphy. This study reports on the first intra-patient comparison of 99mTc-Demotate and another 99mTc-labeled SST analogue, 99mTc-EDDA/HYNIC-TOC (HYNIC-TOC). Five patients with carcinoid tumors (n = 2) and endocrine pancreatic tumors (n = 3) were investigated with both radiopharmaceuticals. 99mTc-Demotate rapidly visualized somatostatin receptor positive tumors as early as 15 minutes post-injection (p.i.) with maximum tumor uptake and tumor/organ ratios already 1 hour p.i. Organs of predominant physiological uptake were the spleen and the kidneys with no intestinal excretion detectable up to 24 hours. 99mTc-Demotate exhibited faster pharmacokinetic properties compared to HYNIC-TOC. Tumor/organ ratios at equivalent time points were higher or comparable for 99mTc-Demotate in three patients with a matching scan result. Equivocal findings were observed in two patients, i.e. comparable uptake behavior in larger lesions with differences in smaller ones. 99mTc-Demotate is a promising agent for somatostatin receptor scintigraphy providing images of excellent quality as early as 1 hour after injection.

Evaluation of somatostatin receptors in large cell pulmonary neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy.

Science.gov (United States)

Nocuń, Anna; Chrapko, Beata; Gołębiewska, Renata; Stefaniak, Bogusław; Czekajska-Chehab, Elżbieta

2011-06-01

Large cell pulmonary neuroendocrine carcinoma (LCNEC) is a poorly differentiated and high-grade neoplasm. It is positioned between an atypical carcinoid and small cell neuroendocrine carcinoma of the lung in a distinct family of pulmonary neuroendocrine tumors. The aim of our study was to detect somatostatin receptors in this uncommon malignancy and to evaluate the sensitivity of somatostatin receptor scintigraphy (SRS) in LCNEC staging. We analyzed data of 26 patients (mean age: 61.5±7.9 years) with histologically confirmed diagnosis of LCNEC, including 18 cases not treated surgically and eight patients after the resection of the primary tumor. SRS was carried out with technetium-99m ethylene diamine-diacetic acid/hydrazinonicotinyl-Tyr3-octreotide (Tc-TOC). A visual analysis of scintigraphic images was done with reference to conventional imaging modalities (computed tomography and bone sicintigraphy). SRS sensitivity for the detection of primary lesions, supradiaphragmatic metastases, and infradiaphragmatic metastases was 100, 83.3%, and 0%, respectively. Five out of 13 metastases to the liver appeared on SRS as photopenic foci, visible on the background of physiological hepatic activity. Only one of the nine metastases to the skeletal system was found by SRS with sensitivity as low as 11.1%. The overall SRS sensitivity for the detection of secondary lesions and of all lesions was 54.8 and 62.2%, respectively. Within a rather large series of LCNEC, the primary tumor showed an uptake of Tc-TOC in all cases, whereas some metastases did show Tc-TOC uptake and some others did not.

Unicentric Castleman's Disease Revealed by 18F-FDG PET/CT and Somatostatin Receptor Scintigraphy With 99mTc-HYNIC-TOC.

Science.gov (United States)

Luo, Yaping; Wang, Ling; Pan, Qingqing; Ma, Yanru; Li, Fang

2018-07-01

A 51-year-old woman with a history of hypertension and abdominal pain was found with a retroperitoneal mass. The mass had intense enhancement in contrast-enhanced CT, and it showed a moderate degree of increased FDG uptake in PET/CT. The mass was also positive in somatostatin receptor scintigraphy with Tc-HYNIC-TOC, but it was negative in I-MIBG scan. The histopathological result after surgical resection of the mass confirmed the diagnosis of Castleman's disease, the hyaline vascular variant.

Guideline for PET/CT imaging of neuroendocrine neoplasms withGa-DOTA-conjugated somatostatin receptor targeting peptides andF-DOPA

DEFF Research Database (Denmark)

Bozkurt, Murat Fani; Virgolini, Irene; Balogova, Sona

2017-01-01

PURPOSE & METHODS: Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing......, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using68Ga-DOTA-conjugated peptides, as well as18F-DOPA imaging for various neuroendocrine neoplasms. RESULTS & CONCLUSION: The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with68Ga...

Pattern of somatostatin receptors expression in normal and bladder cancer tissue samples.

Science.gov (United States)

Karavitakis, Markos; Msaouel, Pavlos; Michalopoulos, Vassilis; Koutsilieris, Michael

2014-06-01

Known risks factors for bladder cancer progression and recurrence are limited regarding their prognostic ability. Therefore identification of molecular determinants of disease progression could provide with more specific prognostic information and could be translated into new approaches for biomarker development. In the present study we evaluated, the expression patterns of somatostatin receptors 1-5 (SSTRs) in normal and tumor bladder tissues. The expression of SSTR1-5 was characterized in 45 normal and bladder cancer tissue samples using reverse transcriptase-polymerase chain reaction (RT-PCR). SSTR1 was expressed in 24 samples, SSTR2 in 15, SSTR3 in 23, SSTR4 in 16 and SSTR5 in all but one sample. Bladder cancer tissue samples expressed lower levels of SSTR3. Co-expression of SSTRs was associated with superficial disease. Our results demonstrate, for the first time, that there is expression of SSTR in normal and bladder cancer urothelium. Further studies are required to evaluate the prognostic and therapeutic significance of these findings. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study.

Science.gov (United States)

Pivonello, Claudia; Rousaki, Panagoula; Negri, Mariarosaria; Sarnataro, Maddalena; Napolitano, Maria; Marino, Federica Zito; Patalano, Roberta; De Martino, Maria Cristina; Sciammarella, Concetta; Faggiano, Antongiulio; Rocco, Gaetano; Franco, Renato; Kaltsas, Gregory A; Colao, Annamaria; Pivonello, Rosario

2017-06-01

Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors

In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ((123I)SDZ 204-090)

Energy Technology Data Exchange (ETDEWEB)

Faglia, G.; Bazzoni, N.; Spada, A.; Arosio, M.; Ambrosi, B.; Spinelli, F.; Sara, R.; Bonino, C.; Lunghi, F. (Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS (Italy))

1991-10-01

The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of (125I)Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, (123I)Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

Influence of PET/CT 68Ga somatostatin receptor imaging on proceeding with patients, who were previously diagnosed with 99mTc-EDDA/HYNIC-TOC SPECT.

Science.gov (United States)

Madrzak, Dorota; Mikołajczak, Renata; Kamiński, Grzegorz

2016-01-01

The aim of this study was the assessment of utility of somatostatin receptor scintigraphy (SRS) by SPECT imaging using 99mTc-EDDA/HYNIC-Tyr3-octreotide (99mTc-EDDA/HYNIC-TOC) in patients with neuroendocrine neoplasm (NEN) or suspected NEN, referred to Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The selected group of patients was referred also to 68Ga PET/CT. The posed question was the ratio of patients for whom PET/CT with 68Ga would change their management. The distribution of somatostatin receptors was imaged using 99mTc-EDDA/HYNIC-TOC in 61 planar and SPECT studies between 13/05/2010 and 04/02/2013 in Nuclear Medicine Dept. of Voivodship Specialty Center in Rzeszow. The patient age was within a range of 17-80, with the average age of 57.6. The average age of women (65% of patients over-all) was 55.6 and the average age of men (35% of patients overall) was 61.4. In 46 participants (75% of the study group), that underwent SRS, NEN was documented using pathology tests. Selected patients were referred to PET/CT with 68Ga labeled somatostatin analogs, DOTATATE or DOTANOC. This study group consisted of 14 female and 10 male participants with age range of 35-77 and average age of 55.5 years. Patients were classified into 3 groups, as follows: detection - referral due to clinical symptoms and/or biochemical markers (CgA-Chromogranin A, IAA-indoleacetic acid) with the aim of primary diagnosis, staging - referral with the aim of assessment of tumor spread, and follow-up - assessment of the therapy. Out of 61 patients, 24 underwent both 99mTc-EDDA/HYNIC-Tyr3-octreotide SPECT and 68Ga PET/CT. The result of PET/CT was used as a basis for further evaluation. Therefore, the patients were divided into groups; true positive TP (confirmed presence of tissue somatostatin receptors with 68Ga PET/CT) and TN (68Ga PET/CT did not detect any changes and the results were comparable and had the same influence on treatment protocol). In case of SPECT, the results

The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

DEFF Research Database (Denmark)

Ørgaard, Anne; Holst, Jens J

2017-01-01

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion...... on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn...

Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: a potential PET tracer for beta cell mass measurement.

Science.gov (United States)

Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

2013-12-06

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM. Copyright © 2013 Elsevier Inc. All rights reserved.

Synthesis, radiochemistry and biological evaluation of a new somatostatin analogue (SDZ 219-387) labelled with technetium-99m

International Nuclear Information System (INIS)

Maina, T.; Stolz, B.; Albert, R.; Bruns, C.; Koch, P.; Maecke, H.

1994-01-01

A new derivative of octreotide SDZ 219-387 [PnAO-(D)Phe 1 -octreotide] was synthesized, which binds specifically and with high affinity to somatostatin receptors in vitro (pK i =9.79±0.16). This new somatostatin analogue chelates technetium-99m under mild labelling conditions in good yields. The resulting [ 99m Tc]SDZ 219-387 was stable up to 6 h after labelling and could be isolated in a pure radiochemical and chemical form by high-perfomance liquid chromatographic purification. The intravenous administration of purified [ 99m Tc]SDZ 219-387 revealed that the radioligand was rapidly cleared from circulation, and tumour uptake of 0.38% ID/g was observed at 1.5 h post injection. [ 99m Tc]SDZ 219-387 specifically interacted with somatostatin binding sites on the tumour. However, the radioligand is highly lipophilic and excreted mainly through the hepatobiliary system. As a consequence, [ 99m Tc]SDZ 219-387 exhibits increased background activity and therefore is not appropriate for the in vivo visualization of somatostatin receptor-positive tumours and/or their metastases in the abdomen. (orig.)

Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging

International Nuclear Information System (INIS)

Buder, Kristina; Becker, Jürgen C; Lapa, Constantin; Kreissl, Michael C; Schirbel, Andreas; Herrmann, Ken; Schnack, Alexander; Bröcker, Eva-Bettina; Goebeler, Matthias; Buck, Andreas K

2014-01-01

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. To non-invasively assess SSTR expression in MCC using PET and the radiotracers [ 68 Ga]DOTA-D-Phe 1 -Tyr 3 -octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%). SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management

Iodine-131 labelled octreotide: not an option for somatostatin receptor therapy

International Nuclear Information System (INIS)

Bakker, W.H.; Breeman, W.A.P.; Pluijm, M.E. van der; Jong, M. de; Visser, T.J.; Krenning, E.P.

1996-01-01

This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from 131 I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of 131 I in cancer treatment and out previous experience with [ 111 In-DTPA-D-Phe 1 ]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq 131 I has to be coupled to a maximum of ∼100 μg peptide, representing only a slight excess of peptide over 131 I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated form unreacted iodide, and from di-iodinated and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 μg unlabelled peptide with 370 MBq 131 I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher β-flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated 131 I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain. (orig./VHE)

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

International Nuclear Information System (INIS)

Trejtnar, F.; Novy, Z.; Petrik, M.; Laznickova, A.; Melicharova, L.; Vankova, M.; Laznicek, M.

2008-01-01

Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA 0 , Tyr 3 , Thr 8 ]-octreotide (DOTA-TATE) and [DOTA 0 , 1-Nal 3 ]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods. The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells. The renal clearance of 111 In-DOTA-NOC in the perfused rat kidney was significantly lower than that of 111 In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. 111 In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than 111 In-DOTA-TATE (ratio 3:1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin

PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy

International Nuclear Information System (INIS)

Hofmann, M.; Gazdhar, A.; Weitzel, T.; Schmid, R.; Krause, T.

2006-01-01

Localized information on region-selective gene expression in small animals is widely obtained by use of reporter genes inducing light emission. Using these reporter genes for imaging deep inside the human body fluorescent probes are hindered by attenuation, scattering and possible fluorescence quenching. This can be overcome by use of radio-peptide receptors as reporter genes. Therefore, the feasibility of the somatostatin receptor 2 expression vector system for expression imaging was checked against a control vector containing luciferase gene. For in vivo transduction of vector DNA into the rat forelimb muscles the in vivo electroporation technique was chosen because of its high regio-selectivity. The gene expression was imaged by high-sensitive CCD camera (luciferase activity) and by PET/CT using a Ga-68-DOTATOC as radio peptide probe. The relative sstr2 expression was enhanced by gene transduction at maximum to a factor of 15. The PET/CT images could be fully quantified. The above demonstrated feasibility of radio-peptide PET/CT reporter gene imaging may serve in the future as a tool for full quantitative understanding of regional gene expression, especially in large animals and humans

PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy

Energy Technology Data Exchange (ETDEWEB)

Hofmann, M. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland)]. E-mail: Michael.Hofmann@insel.ch; Gazdhar, A. [Division of Pulmonary Medicine, University Hospital Bern (Switzerland); Weitzel, T. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland); Schmid, R. [Division of Thoracic Surgery, University Hospital Bern (Switzerland); Krause, T. [Molecular Imaging and Therapy Group (MIT-Bern), Clinic of Nuclear Medicine, Inselspital, Medical School Bern (Switzerland)

2006-12-20

Localized information on region-selective gene expression in small animals is widely obtained by use of reporter genes inducing light emission. Using these reporter genes for imaging deep inside the human body fluorescent probes are hindered by attenuation, scattering and possible fluorescence quenching. This can be overcome by use of radio-peptide receptors as reporter genes. Therefore, the feasibility of the somatostatin receptor 2 expression vector system for expression imaging was checked against a control vector containing luciferase gene. For in vivo transduction of vector DNA into the rat forelimb muscles the in vivo electroporation technique was chosen because of its high regio-selectivity. The gene expression was imaged by high-sensitive CCD camera (luciferase activity) and by PET/CT using a Ga-68-DOTATOC as radio peptide probe. The relative sstr2 expression was enhanced by gene transduction at maximum to a factor of 15. The PET/CT images could be fully quantified. The above demonstrated feasibility of radio-peptide PET/CT reporter gene imaging may serve in the future as a tool for full quantitative understanding of regional gene expression, especially in large animals and human000.

Evaluation of (64)Cu-labeled DOTA-D-Phe(1)-Tyr (3)-octreotide ((64)Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors.

Science.gov (United States)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich; Paudyal, Pramila; Iida, Yasuhiko; Watanabe, Shigeki; Paudyal, Bishnuhari; Higuchi, Tetsuya; Oriuchi, Noboru; Endo, Keigo

2009-08-01

In-111 ((111)In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ((64)Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a (64)Cu-labeled octreotide analog, (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D: -Phe(1)-Tyr(3)-octreotide ((64)Cu-DOTA-TOC). (64)Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 degrees C. The stability of (64)Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of (64)Cu-DOTA-TOC and (111)In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of (64)Cu-DOTA-TOC or (64)Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC). The tumor was imaged using (64)Cu-DOTA-TOC, (64)Cu-TETA-OC, and FDG with an animal PET scanner. (64)Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. (64)Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of (64)Cu was higher than that of (111)In in all organs except kidney. In tumor-bearing mice, (64)Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 +/- 1.17 at 6 h after administration. (64)Cu-DOTA-TOC showed significantly higher accumulation in the tumor than (64)Cu-TETA-OC. (64)Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of (18)F-FDG PET and very similar to that of (64)Cu

Evaluation of 64Cu-labeled DOTA-D-Phe1-Tyr3-octreotide (64Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors

International Nuclear Information System (INIS)

Hanaoka, Hirofumi; Tominaga, Hideyuki; Yamada, Keiich

2009-01-01

In-111 ( 111 In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 ( 64 Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a 64 Cu-labeled octreotide analog, 64 Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-D-Phe 1 -Tyr 3 -octreotide ( 64 Cu-DOTA-TOC). 64 Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45 deg C. The stability of 64 Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by high performance liquid chromatography (HPLC) analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of 64 Cu-DOTA-TOC and 111 In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of 64 Cu-DOTA-TOC or 64 Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ( 64 Cu-TETA-OC). The tumor was imaged using 64 Cu-DOTA-TOC, 64 Cu-TETA-OC, and fluorodeoxyglucose (FDG) with an animal PET scanner. 64 Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. 64 Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of 64 Cu was higher than that of 111 In in all organs except kidney. In tumor-bearing mice, 64 Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81±1.17 at 6 h after administration. 64 Cu-DOTA-TOC showed significantly higher accumulation in the tumor than 64 Cu-TETA-OC. 64 Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of 18 F-FDG PET and

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes (''chimney sign'') in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

International Nuclear Information System (INIS)

Behr, T.M.; Gratz, S.; Markus, P.M.; Dunn, R.M.; Huefner, M.; Becker, H.; Becker, W.

1997-01-01

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the ''chimney sign'' may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis. (orig.). With 2 figs., 1 tab

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

Energy Technology Data Exchange (ETDEWEB)

Antunes, P.; Ginj, M.; Zhang, H.; Maecke, H. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Waser, B.; Reubi, J.C. [University of Bern, Institute of Pathology, Bern (Switzerland); Baum, R.P. [Zentralklinik Bad Berka, Department of Nuclear Medicine/PETCT-Center, Bad Berka (Germany)

2007-07-15

Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [{sup 68}Ga-DOTA,Tyr{sup 3}]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its {sup 111}In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. All peptides showed high affinities on hsst2, with the highest affinity for the Ga{sup III}-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga{sup III} peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all {sup 67}Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the {sup 111}In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [{sup 67}Ga-DOTA,1-Nal{sup 3}]octreotide in comparison to [{sup 111}In-DOTA,1-Nal{sup 3}]octreotide and [{sup 67}Ga-DOTA,Tyr{sup 3}]octreotide showed a significantly higher and receptor-mediated uptake of the two{sup 67}Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. This study demonstrates that {sup 67/68}Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the {sup 111}In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

International Nuclear Information System (INIS)

Antunes, P.; Ginj, M.; Zhang, H.; Maecke, H.; Waser, B.; Reubi, J.C.; Baum, R.P.

2007-01-01

Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [ 68 Ga-DOTA,Tyr 3 ]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111 In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. All peptides showed high affinities on hsst2, with the highest affinity for the Ga III -complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga III peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67 Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111 In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [ 67 Ga-DOTA,1-Nal 3 ]octreotide in comparison to [ 111 In-DOTA,1-Nal 3 ]octreotide and [ 67 Ga-DOTA,Tyr 3 ]octreotide showed a significantly higher and receptor-mediated uptake of the two 67 Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. This study demonstrates that 67/68 Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111 In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies. (orig.)

Ectopic ACTH secretion due to a bronchopulmonary carcinoid localized by somatostatin receptor scintigraphy.

Science.gov (United States)

Iser, G; Pfohl, M; Dörr, U; Weiss, E M; Seif, F J

1994-11-01

We present the case of a 65-year-old woman with an adrenocorticotropic hormone (ACTH) secreting bronchopulmonary carcinoid. This patient showed the typical long history of Cushing's syndrome, including hypokaliemia, impaired glucose tolerance, high levels of ACTH and beta-endorphin, and coproduction of other peptides. At the onset of clinical symptoms in 1979 an adrenal adenoma was suspected, and left-sided adrenalectomy was performed. The symptoms soon recurred, and the diagnosis of ACTH-dependent Cushing's syndrome was made. As no ACTH-secreting tumor was found, the right adrenal was resected, and the patient was followed up regularly. Fourteen years later chest roentgenography and computed tomography revealed a para-aortic pulmonary lesion, which was suspicious for a bronchopulmonary carcinoid. ACTH and beta-endorphin were excessively, pancreatic polypeptide slightly elevated at that time. The final diagnosis was made using somatostatin receptor scintigraphy which confirmed the hormonal activity of the suspicious lesion; no additional focus was found. This method turned out to be not only a useful additional localization technique but also a promising tool for characterization and staging of a suspected ACTH-producing carcinoid. The tumor was resected curatively, and the diagnosis was confirmed histologically.

Current knowledge on the sensitivity of the 68Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours

OpenAIRE

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; von Guggenberg, Elisabeth; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, llanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-01-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three 68Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these 68Ga-sstr-binding peptides in the imaging setting. On 68Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake val...

Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy. A potential novel treatment based on molecular pathology

International Nuclear Information System (INIS)

Salavati, A.; Prasad, V.; Baum, R.P.; Schneider, C.P.; Herbst, R.

2012-01-01

Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of 177 Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by 18 F-fluorodeoxyglucose ( 18 F-FDG) and 68 gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up positron emission tomography (PET)/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and 68 Ga-somatostatin-receptor PET/CT in the management of MCC. (author)

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

Science.gov (United States)

Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin sst4 Receptor in the Antinociceptive and Anti-inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide

Directory of Open Access Journals (Sweden)

István Z. Bátai

2018-02-01

Full Text Available Transient receptor potential ankyrin 1 (TRPA1 non-selective ligand-gated cation channels are mostly expressed in primary sensory neurons. Polysulfides (POLYs are Janus-faced substances interacting with numerous target proteins and associated with both protective and detrimental processes. Activation of TRPA1 in sensory neurons, consequent somatostatin (SOM liberation and action on sst4 receptors have recently emerged as mediators of the antinociceptive effect of organic trisulfide dimethyl trisulfide (DMTS. In the frame of the present study, we set out to compare the participation of this mechanism in antinociceptive and anti-inflammatory effects of inorganic sodium POLY and DMTS in carrageenan-evoked hind-paw inflammation. Inflammation of murine hind paws was induced by intraplantar injection of carrageenan (3% in 30 µL saline. Animals were treated intraperitoneally with POLY (17 µmol/kg or DMTS (250 µmol/kg or their respective vehicles 30 min prior paw challenge and six times afterward every 60 min. Mechanical pain threshold and swelling of the paws were measured by dynamic plantar aesthesiometry and plethysmometry at 2, 4, and 6 h after initiation of inflammation. Myeloperoxidase (MPO activity in the hind paws were detected 6 h after challenge by luminescent imaging. Mice genetically lacking TRPA1 ion channels, sst4 receptors and their wild-type counterparts were used to examine the participation of these proteins in POLY and DMTS effects. POLY counteracted carrageenan-evoked mechanical hyperalgesia in a TRPA1 and sst4 receptor-dependent manner. POLY did not influence paw swelling and MPO activity. DMTS ameliorated all examined inflammatory parameters. Mitigation of mechanical hyperalgesia and paw swelling by DMTS were mediated through sst4 receptors. These effects were present in TRPA1 knockout animals, too. DMTS inhibited MPO activity with no participation of the sensory neuron–SOM axis. While antinociceptive effects of

Radioimmunoassay of somatostatin: methodological problems and physiological investigations

International Nuclear Information System (INIS)

Penman, E.; Wass, J.A.H.

1981-01-01

Somatostatin, a tetradecapeptide, has a wide distribution throughout the central nervous system and the gastrointestinal tract and a broad spectrum of biological actions. In order to investigate its various physiological roles in man, a radioimmunoassay was developed for somatostatin in human blood plasma, which is described here. This RIA was used to investigate possible factors influencing somatostatin secretion. Changes in somatin levels produced by changes in insulin, glucagon and growth hormone levels were studied via the response of plasma immunoreactive somatostatin to hormonal stimuli in normal man. The influence of fasting and food consumption was studied; and the site of origin of circulating immunoreactive somatostatin was investigated in patients. (Auth.)

Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration

NARCIS (Netherlands)

A.C. Lambooij (Antoinette); R.W.A.M. Kuijpers (Robert); E.G. van Lichtenauer-Kaligis; M. Kliffen (Mike); G.S. Baarsma (Seerp); P.M. van Hagen (Martin); C.M. Mooy (Cornelia)

2000-01-01

textabstractPURPOSE: The growth of ocular neovascularization is regulated by a balance between stimulating and inhibiting growth factors. Somatostatin affects angiogenesis by inhibiting the growth hormone-insulin-like growth factor axis and also has a direct

Immuno-reactive somatostatin in the cerebro-spinal fluid

International Nuclear Information System (INIS)

Kohler, J.

1983-01-01

In the present work the lumbar cerebro-spinal fluid of 178 patients with different neurological affections was examined with the aid of a specific radioimmunoassay for somatostatin. 18 patients without any pathologic neurological findings served as controls. In degenerative diseases of the brain, reduced somatostatin levels in the cerebro-spinal fluid as compared to the controls were measured. In 3 patients with isolated cerebellar atrophy no reduction of the somatostatin content was found; rather the values were highly normal. Huntington-Chorea also is a case apart. In patients with manifest affections, the somatostatin reduction, amounting to 54.6%, was particularly notable as compared to the controls. By contrast, degenerative diseases with predominant medullary and spastic affection are characterized by significantly increased somatostatin levels. Again, in non-spastic patients the values were not significantly different from those of the controls. Patients with inflammations of the brain and meminges as well as with tumors of the nervous system showed somatostatin levels increased by about 60.8% respectively 51.8% as compared to the controls. Epileptic patients normally exhibit a reduced somatostatin level in the cerebro-spinal fluid, but the reduction is not significant. Disseminated encephalomyclitis, whether chromic or acute, is not found to be associated with significant modifications of the somatostatin level in the cerebro-spinal fluid. Strikingly, however, patients in which the disease took a serious or very serious clinical course showed also the lowest somatostatin levels in the cerebro-spinal fluid. In patients exhibiting the roof compression symptom in consequence of a prolapse of the disk, no significant modifications were found. By contrast, in patients with the symptoms of a transverse lesion, significantly increased somatostatin values were measured. (orig./MG) [de

Somatostatin in the caudal spinal cord

DEFF Research Database (Denmark)

Schrøder, H D

1984-01-01

. In all of these regions somatostatin-positive cell bodies were also observed. In the intermediate gray matter stained terminals were present around the central canal in a varying number. The most prominent stainability was found in the lumbosacral transition zone. Many terminals were also observed...... was particularly low in the motoneuron neuropil. However, a dense somatostatin network was found in the sixth lumbar segment in relation to the neurons in Onuf's nucleus X complex, the nucleus that innervates the small pelvic muscles including the striated sphincters. It is concluded that somatostatin, besides...

99m Tc- la bed somatostatin analogs for imaging somatostatin-receptor-positive tumors

International Nuclear Information System (INIS)

Gandomkar, M.; Najafi, R.; Shafiei, A.; Sadat Ebrahimi, E.; Babaie, M.H.; Rabani, M.

2002-01-01

Over the least few years, 111 In-DTPA- Octreotide has found widespread clinical applicability, especially in oncology. However limitation, especially concerning availability, imaging properties, and costs, remain and have stimulated research on radiolabeling with many alternative radionuclides. The purpose of this investigation was to labeling somatostatin analogs with 99 m Tc and evaluate their suitability as an agents for in vivo use. Octreotide and Tyr-3-Octreotide were labeled by 99 mTc with direct and indirect methods. Sodium ascorbate and sodium dithionite were used for reduction of cystine bridge and HYNIC was used as bifunctional agents and different co ligands used for labeling by 99 mTc. Yield of labeling, purity, stability, internalisation, binding affinity and biodistribution of peptide conjugates were studied. Direct labeling of octreotide was simple, rapid, efficient and yield was good (%60). K d for binding affinity as high (10 -9 ) but stability was low. Labeling for HYNIC-Tyr-Octreotide had a high yield (>%90), good stability, internalisation and biodistribution. with more experimental work and some improve this peptide-based radiopharmaceuticals can be employed in all nuclear medicine centers as a useful agent for imaging of tumors

Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients.

Science.gov (United States)

Faggiano, Antongiulio; Tavares, Lidice Brandao; Tauchmanova, Libuse; Milone, Francesco; Mansueto, Gelsomina; Ramundo, Valeria; De Caro, Maria Laura Del Basso; Lombardi, Gaetano; De Rosa, Gaetano; Colao, Annamaria

2008-11-01

In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated. To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP. Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled. The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy. Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR. After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%). Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.

Receptor scintigraphy using the Tc-99M-labelled somatostatin analogue EDDA-TRYCINE-HYNIC-TOC: clinical results in different tumor types and comparison with In-111 DOTATOC during Y-90 DOTATOC radioreceptor therapy

International Nuclear Information System (INIS)

Baum, R.P.; Schmuecking, M.; Fischer, S.; Przetak, C.; Niesen, A.; Maecke, H.R.

2002-01-01

Aim: To evaluate Tc-99m EDDA-TRYCINE-HYNIC-TOC in patients with somatostatin receptor positive tumours (staging, pre-therapeutic dosimetry for radioreceptor therapy and restaging after therapy) in comparison with In-111 DOTATOC. Material and Methods: The Tc-99m labelled somatostatin analogue was synthesized by an optimized procedure in our pharmaceutical laboratory using lyophilized kits (radiochemical purity by HPLC, TLC > 95%, product stability in vitro 4 to 6h). So far, 58 patients (60 examinations) were studied after injection of 580-890 MBq (median 673 MBq) EDDA-TRYCINE-HYNIC-TOC. The histologically proven tumours were neuroendocrine neoplasias, renal carcinomas, bronchial carcinoma, mesothelioma and malignant fibrous histiocytoma. The imaging protocol consisted of whole-body scans and planar images of the tumor region (15 min, 1 h, 2 h, 4 h, 8 h, 24 h p.i.) and additionally SPECT-images (1 h und 4 h p.i.). For semi-quantitative assessment, individual regions of interest (ROI) were drawn in order to generate time-activity curves and to calculate tumour-to-tissue/background ratios which were compared by visual grading (scala 0 to 3+). Furthermore, pharmacokinetic analyses were carried out (radioactivity kinetics in plasma and urine). In some selected patients, image fusion of whole-body scans was performed with CT and/or MRT and/or PET using a NUD software and a HERMES computer. Results: 10 out of 58 patients showed an intense tracer accumulation in the SSTR-positive tumours (visual 3+, tumour/background ratio >2,5). In these patients, radioreceptor therapy was carried out using Y-90 DOTATOC (simultaneous injection von 150 MBq In-111 DOTATOC). All pretherapeutic scans with the Tc-99m labelled ligand (4 h p.i.) showed a similar overall pattern of biodistribution and tumour uptake in comparison to the therapy scans with In-111 / Y-90 DOTATOC (24 h p.i.). The Tc-99m EDDA-TRYCINE-HYNIC-TOC scans (incl. SPECT) offered superior imaging properties with earlier tumour

Guideline for PET/CT imaging of neuroendocrine neoplasms with {sup 68}Ga-DOTA-conjugated somatostatin receptor targeting peptides and {sup 18}F-DOPA

Energy Technology Data Exchange (ETDEWEB)

Bozkurt, Murat Fani [Hacettepe University Faculty of Medicine Department of Nuclear Medicine, Ankara (Turkey); Virgolini, Irene; Decristoforo, Clemens [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Balogova, Sona [Comenius University and St. Elisabeth Oncology Institute, Department of Nuclear Medicine, Bratislava (Slovakia); Tenon Hospital AP-HP and Universite Pierre et Marie Curie, Department of Nuclear Medicine, Paris (France); Beheshti, Mohsen [St. Vincent' s Hospital, PET-CT Center, Department of Nuclear Medicine and Endocrinology, Linz (Austria); Paracelsus Medical University, Department of Nuclear Medicine, Salzburg (Austria); Rubello, Domenico [Santa Maria della Misericordia Hospital, Department of Nuclear Medicine, PET Center and Medical Physics and Radiology, Rovigo (Italy); Ambrosini, Valentina; Fanti, Stefano [University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Bologna (Italy); Kjaer, Andreas [National University Hospital and University of Copenhagen, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Delgado-Bolton, Roberto [San Pedro Hospital and Centre for Biomedical Research of La Rioja (CIBIR), Department of Diagnostic Imaging (Radiology) and Nuclear Medicine, Logrono (Spain); Kunikowska, Jolanta [Medical University of Warsaw, Nuclear Medicine, Warsaw (Poland); Oyen, Wim J.G. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London (United Kingdom); Chiti, Arturo [Humanitas University, Nuclear Medicine Department, Rozzano, MI (Italy); Giammarile, Francesco [University of Lyon, Nuclear Medicine, Lyon (France)

2017-08-15

Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using {sup 68}Ga-DOTA-conjugated peptides, as well as {sup 18}F-DOPA imaging for various neuroendocrine neoplasms. The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with {sup 68}Ga-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts. (orig.)

Selective central activation of somatostatin receptor 2 increases food intake, grooming behavior and rectal temperature in rats.

Science.gov (United States)

Stengel, A; Goebel, M; Wang, L; Rivier, J; Kobelt, P; Monnikes, H; Tache, Y

2010-08-01

The consequences of selective activation of brain somatostatin receptor-2 (sst2) were assessed using the sst2 agonist, des-AA(1,4-6,11-13)-[DPhe(2),Aph7(Cbm),DTrp(8)]-Cbm-SST-Thr-NH2. Food intake (FI) was monitored in ad libitum fed rats chronically implanted with an intracerebroventricular (i.c.v.) cannula. The sst(2) agonist injected i.c.v. at 0.1 and 1 microg/rat dose-dependently increased light phase FI from 2 to 6 hours post injection (2.3+/-0.5 and 7.5+/-1.2 respectively vs. vehicle: 0.2+/-0.2 g/300 g bw, P<0.001). Peptide action was reversed by i.c.v. injection of the sst2 antagonist, des-AA(1,4-6,11-13)-[pNO(2)-Phe(2),DCys(3),Tyr(7),DAph(Cbm)8]-SST-2Nal-NH(2) and not reproduced by intraperitoneal injection (30 microg/rat). The sst(2) antagonist alone i.c.v. significantly decreased the cumulative 14-hours dark phase FI by 29.5%. Other behaviors, namely grooming, drinking and locomotor activity were also increased by the sst(2) agonist (1 microg/rat, i.c.v.) as monitored during the 2(nd) hour post injection while gastric emptying of solid food was unaltered. Rectal temperature rose 1 hour after the sst(2) agonist (1 microg/rat, i.c.v.) with a maximal response maintained from 1 to 4 hours post injection. These data show that selective activation of the brain sst(2) receptor induces a feeding response in the light phase not associated with changes in gastric emptying. The food intake reduction following sst(2) receptor blockade suggests a role of this receptor in the orexigenic drive during the dark phase.

SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

Science.gov (United States)

Dalm, Simone U; Haeck, Joost; Doeswijk, Gabriela N; de Blois, Erik; de Jong, Marion; van Deurzen, Carolien H M

2017-10-01

Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111 In-DOTA-Tyr 3 -octreotate (SSTR agonist) and 111 In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177 Lu-DOTA-Tyr 3 -octreotate or 177 Lu-DOTA-JR11. Results: 111 In-DOTA-JR11 binding to human BC tissue was significantly higher than 111 In-DOTA-Tyr 3 -octreotate binding ( P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer

Studies in rats on octreotide labelled with Ga-67: A potential radiopharmaceutical agent for the treatment of somatostatin receptor-positive tumours

International Nuclear Information System (INIS)

Lazniekova, A.; Laznieek, M.; Trejtnar, F.; Maecke, H.R.

2001-01-01

The paper presents the preparation, biodistribution and analysis of elimination mechanisms of 67 Ga-[DFO]-octreotide in rats. For labelling of the ligand with 67 Ga, desferrioxamine B (DFO) coupled to octreotide via the succinyl linker has been shown to form a stable chelating agent for binding of 67 Ga. The radiopharmaceutical was prepared by direct chelating of 67 Ga 3+ with [DFO]-octreotide in a slightly acidic reaction medium with high radiochemical purity. Pharmacokinetics of 67 Ga-[DFO]-octreotide of radioactivity in rats has shown relatively rapid elimination of the compound from the body with a long-term retention in the kidney and organs with high somatostatin receptor density. The agent was eliminated mostly by urine predominantly by the mechanism of glomerular filtration. (author)

Regulation of somatostatin release in the nervous system of the rat

International Nuclear Information System (INIS)

Sheppard, M.

1979-08-01

This thesis represents the work done to study the release of somatostatin from the rat central nervous system in vitro, providing some evidence for a physiological role for somatostatin. Somatostatin was measured by a sensitive and specific radioimmunoassay devoloped in the laboratory. Chapter 2 reviews the literature on hypothalamic peptides and control of an anterior pituitary function, somatostatin, other central nervous system peptides and neurosecretion. Chapter 3 describes the central nervous system tissue dissection technique, the radioimmunoassay for somatostatin and the tissue levels of somatostatin immunoreactivity in different areas of the central nervous system. Chapter 4 deals with the release of immunoreactive somatostatin from incubated rat hypothalamus in vitro and the influence of other hormones and neuropeptides on this release. Chapter 5 describes the preparation of isolated nerve endings (synaptosomes) from four different areas of rat brain, the localisation of somatostatin to the synaptosome fraction of brain homogenates and the release of somatostatin from these synaptosomes. Chapter 6 deals with the release of somatostatin from incubated rat spinal cord in vitro. Chapter 7 presents the results of the characterisation of released immunoreactive material, the technique utilised being serial dilution of immunoreactive material and comparison to the standard curve, Sephadex gel chromatography, affinity chromatography, and the effect of released immunoreactive somatostatin on growth hormone release from perifused hemipituitaries in vitro, i.e. biological activity. Chapter 8 provides a summary of the main conclusions reached in this study and is followed by the Appendix describing chemical and biochemical methods, histological techniques, and statistical methods

Union of 99m Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer

International Nuclear Information System (INIS)

Rodriguez C, J.; Ramirez I, M.T.; Ferro F, G.; Pedraza L, M.

2005-01-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide 99m Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with 99m Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The 99m Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide 99m Tc-UBI and the 99m TcO 4 . The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the 99m Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the 99m Tc-UBI and the 99m TcO 4 one doesn

Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells

DEFF Research Database (Denmark)

Egerod, Kristoffer L; Engelstoft, Maja S; Lund, Mari L

2015-01-01

In the stomach, somatostatin (SST) acts as a general paracrine negative regulator of exocrine secretion of gastric acid and pepsinogen and endocrine secretion of gastrin, ghrelin, and histamine. Using reporter mice expressing red fluorescent protein (RFP) under control of the SST promotor, we hav...

Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors.

Science.gov (United States)

Mirzaei, Siroos; Bastati, Brigitte; Lipp, Rainer W; Knoll, Peter; Zojer, Niklas; Ludwig, Heinz

2011-01-01

Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. All patients demonstrated (177)Lu-DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc-EDDA/HYNIC-TOC. Copyright © 2011 S. Karger AG, Basel.

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors

DEFF Research Database (Denmark)

Malmberg, Catarina; Ripa, Rasmus Sejersten; Johnbeck, Camilla Bardram

2015-01-01

UNLABELLED: The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We...

Ectopic Expression of α6 and δ GABAA Receptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

Science.gov (United States)

Tong, Xiaoping; Peng, Zechun; Zhang, Nianhui; Cetina, Yliana; Huang, Christine S.; Wallner, Martin; Otis, Thomas S.

2015-01-01

The role of GABAA receptor (GABAAR)-mediated tonic inhibition in interneurons remains unclear and may vary among subgroups. Somatostatin (SOM) interneurons in the hilus of the dentate gyrus show negligible expression of nonsynaptic GABAAR subunits and very low tonic inhibition. To determine the effects of ectopic expression of tonic GABAAR subtypes in these neurons, Cre-dependent viral vectors were used to express GFP-tagged GABAAR subunits (α6 and δ) selectively in hilar SOM neurons in SOM-Cre mice. In single-transfected animals, immunohistochemistry demonstrated strong expression of either the α6 or δ subunit; in cotransfected animals, both subunits were consistently expressed in the same neurons. Electrophysiology revealed a robust increase of tonic current, with progressively larger increases following transfection of δ, α6, and α6/δ subunits, respectively, indicating formation of functional receptors in all conditions and likely coassembly of the subunits in the same receptor following cotransfection. An in vitro model of repetitive bursting was used to determine the effects of increased tonic inhibition in hilar SOM interneurons on circuit activity in the dentate gyrus. Upon cotransfection, the frequency of GABAAR-mediated bursting in granule cells was reduced, consistent with a reduction in synchronous firing among hilar SOM interneurons. Moreover, in vivo studies of Fos expression demonstrated reduced activation of α6/δ-cotransfected neurons following acute seizure induction by pentylenetetrazole. The findings demonstrate that increasing tonic inhibition in hilar SOM interneurons can alter dentate gyrus circuit activity during strong stimulation and suggest that tonic inhibition of interneurons could play a role in regulating excessive synchrony within the network. SIGNIFICANCE STATEMENT In contrast to many hippocampal interneurons, somatostatin (SOM) neurons in the hilus of the dentate gyrus have very low levels of nonsynaptic GABAARs and exhibit

Morphological Imaging in the Localization of Neuroendocrine Gastroenteropancreatic Tumors Found by Somatostatin Receptor Scintigraphy

International Nuclear Information System (INIS)

Saga, T.; Doi, R.; Endo, K.; Shimatsu, A.; Koizumi, K.; Ichikawa, T.; Yamamoto, K.; Noguchi, S.; Ishibashi, M.; Machinami, R.; Nakamura, K.; Sakahara, H.

2005-01-01

Purpose: To evaluate the necessity of morphological images (MI) in reading somatostatin receptor scintigraphy (SRS) in patients with suspected neuroendocrine gastroenteropancreatic (GEP) tumors. Material and Methods: A Japanese multicenter clinical trial of SRS was conducted in 40 patients with suspected GEP tumors. Three experienced radiologists interpreted the images in three separate sessions in a blinded manner (1: SRS images alone, 2: MI alone, 3: SRS and MI analyzed simultaneously), and the reading results of each session were compared. In addition, the diagnostic abilities of SRS, MI and SRS alone and simultaneous SRS and MI readings were compared for patients where final diagnosis was obtained. Results: SRS detected more suspected lesions (positive or inconclusive uptake) than morphological images did (51 vs 27 lesions), but included many physiological uptakes detected as positive or inconclusive uptakes. Combined reading of SRS and morphological images helped to correctly recognize these physiological uptakes, and also helped in determining the anatomical localization of the abnormal uptakes. Combined reading of SRS and morphological images gave the highest diagnostic impact. Conclusion: The sensitivity of SRS with regard to GEP is high. However the specificity is very low. Morphologic imaging is necessary for the exclusion of physiological uptake and correct anatomic location of an abnormal tracer uptake. The combined reading of SRS and morphologic imaging studies gives the highest diagnostic impact

Somatostatin receptor scintigraphy and magnetic resonance imaging in recurrent medullary thyroid carcinoma: A comparative study

International Nuclear Information System (INIS)

Doerr, U.; Wuerstlin, S.; Frank-Raue, K.; Raue, F.; Hehrmann, R.; Iser, G.; Scholz, M.; Guhl, L.; Buhr, H.J.; Bihl, H.

1993-01-01

In a prospective study, 18 patients with recurrent medullary thyroid carcinoma (MTC) underwent magnetic resonance imaging (MRI) of the neck and mediastinum and somatostatin receptor scintigraphy (SRS) with 111 In-labeled pentetreotide. In nine patients with macroscopic MTC, 17 corresponding lesions were found on MRI and SRS; in addition, 13 suspicious lesions were seen on SRS only. Histological confirmation was available for 19 metastatic lesions, showing MRI to be true positive in 13 metastases, SRS in 18. In minimal residual disease (n=10), MRI and SRS were compared with the histological findings in three patients and with selective venous catheterization (SVC) in seven patients. Corresponding findings on MRI and SVC were seen in one of seven, whereas SRS and SVC showed concordant localization of tumor recurrence in five of seven. Histological examination demonstrated MTC tissue in one of three cases; MRI and SRS were false positive in one of three cases, while in the others the interpretation remained uncertain. In conclusion, SRS is a promising imaging modality for localization of MTC recurrence. MRI provides better spatial resolution and thus facilitates the planning of surgery for macroscopic metastases. In minimal residual disease, SRS turned out to be superior in detecting occult MTC recurrence, confirming SVC findings. (orig.)

Quantitative Assessment of 99mTc-Depreotide Uptake in Oesophageal Cancer and Precursor Conditions and Its Reflection in Immunohistochemically Detected Somatostatin Receptors

International Nuclear Information System (INIS)

Herlin, G.; Aspelin, P.; Axelsson, R.; Herlin, G.; Aspelin, P.; Axelsson, R.; Lundell, L.; Ost, A.; Svensson, L.

2012-01-01

Background. Somatostatin receptors (SSTRs) are over-expressed in several tumors making it possible for imaging with labelled SSTR. A previous study showed feasibility to image oesophageal cancer with SSTR analogue 99m Tc-depreotide. Purpose. (1) To investigate expression of the SSTRs in different types of esophageal carcinoma and (2) to correlate such an expression with 99m Tc-depreotide uptake in these lesions. Material and Methods. Total 28 patients (17 with esophageal cancer and 11 with Barrett’s esophagus) were examined with 99m Tc-depreotide scintigraphy. The SSTR2A, SSTR2B, SSTR3, and SSTR5 were analyzed immunohistochemically in the lesion samples. Results. Among the patients with adenocarcinoma 10/11 expressed different amounts of SSTRs, while SSTRs were absent in 5/6 patients with Squamous cell carcinoma (Sqcc). There was no correlation neither between the 99m Tc-depreotide uptake and the amount of SSTRs nor between the amount of SSTRs and differentiation grade of the tumor. Conclusions. (1) SSTRs are expressed in esophageal carcinoma and more abundantly so in adenocancer specimens; (2) in vivo 99m Tc-depreotide uptake does not obviously correlate with the immunohistochemically detection of SSTRs of different subtypes in esophageal carcinoma.

Quantitative Assessment of 99mTc-Depreotide Uptake in Oesophageal Cancer and Precursor Conditions and Its Reflection in Immunohistochemically Detected Somatostatin Receptors

International Nuclear Information System (INIS)

Herlin, Gunnar; Lundell, Lars; Öst, Åke; Aspelin, Peter; Svensson, Leif; Axelsson, Rimma

2012-01-01

Background. Somatostatin receptors (SSTRs) are over-expressed in several tumors making it possible for imaging with labelled SSTR. A previous study showed feasibility to image oesophageal cancer with SSTR analogue 99m Tc-depreotide. Purpose. (1) To investigate expression of the SSTRs in different types of esophageal carcinoma and (2) to correlate such an expression with 99m Tc-depreotide uptake in these lesions. Material and Methods. Total 28 patients (17 with esophageal cancer and 11 with Barrett's esophagus) were examined with 99m Tc-depreotide scintigraphy. The SSTR2A, SSTR2B, SSTR3, and SSTR5 were analyzed immunohistochemically in the lesion samples. Results. Among the patients with adenocarcinoma 10/11 expressed different amounts of SSTRs, while SSTRs were absent in 5/6 patients with Squamous cell carcinoma (Sqcc). There was no correlation neither between the 99m Tc-depreotide uptake and the amount of SSTRs nor between the amount of SSTRs and differentiation grade of the tumor. Conclusions. (1) SSTRs are expressed in esophageal carcinoma and more abundantly so in adenocancer specimens; (2) in vivo 99m Tc-depreotide uptake does not obviously correlate with the immunohistochemically detection of SSTRs of different subtypes in esophageal carcinoma

Calcitonin gene-related peptide and somatostatin releases correlated with the area under the lafutidine concentration-time curve in human plasma.

Science.gov (United States)

Ikawa, K; Shimatani, T; Azuma, Y; Inoue, M; Morikawa, N

2006-08-01

To examine the effects of the histamine H(2)-receptor antagonist, lafutidine, at clinical dosage (10 mg tablet after a standardized meal) on plasma levels of the gastrointestinal peptides, calcitonin gene-related peptide (CGRP), somatostatin and gastrin. Six healthy male volunteers ate a standardized meal, and received either lafutidine orally at a dose of 10 mg or water only (control). Blood samples were taken before and up to 4 h after the drug administration. Plasma lafutidine concentrations were determined by high pressure liquid chromatography. Pharmacokinetic analysis of lafutidine was performed using one-compartmental model. The levels of immunoreactive substances of plasma CGRP, somatostatin and gastrin were measured by enzyme immunoassay, and the amount of peptide release was calculated by the trapezoidal method. Lafutidine significantly increased plasma CGRP levels at 1, 1.5, 2.5 and 4 h and the total amount of CGRP release (192 +/- 14.0 pg.h/mL) compared with the control group (128 +/- 21.5 pg.h/mL). Lafutidine significantly increased the plasma somatostatin levels at 1 and 1.5 h, and the total amount of somatostatin released (107 +/- 18.2 pg.h/mL) compared with the control (78.4 +/- 7.70 pg.h/mL). The area under the drug concentration-time curve (AUC) from 0 to 4 h after administration correlated well with the Delta-CGRP and Delta-somatostatin release but not with total amount of gastrin released. However, plasma gastrin levels were significantly elevated at 1.5 h after drug administration. Lafutidine at clinical dosage increases plasma CGRP and the somatostatin. The amounts released correlated with the AUC of lafutidine in humans. These results suggest that the increased release of CGRP and somatostatin may contribute to its gastroprotective and anti-acid secretory effect.

Cysteamine induces cholecystokinin release from the duodenum. Evidence for somatostatin as an inhibitory paracrine regulator of cholecystokinin secretion in the rat

International Nuclear Information System (INIS)

Abucham, J.; Reichlin, S.

1990-01-01

To determine whether cholecystokinin secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced in vivo with cysteamine (250 mg/kg body wt, IV) or anti-somatostatin antiserum in anaesthetized rats and in vitro with cysteamine (30 micrograms/mL) in a rat duodenum-incubation system. Cholecystokinin secretion was assessed in vivo by measuring amylase in duodenal perfusates collected at 10-minute intervals for 1 hour and in vitro by a carboxy-terminal radioimmunoassay. Cysteamine induced a marked decrease in duodenal immunoreactive somatostatin both in vivo (50%) and in vitro (60%). The rate of amylase secretion increased from 9.7 +/- 2.1 U (mean +/- SE) to 28.0 +/- 4.8 U at 20 minutes (P less than 0.001). The cholecystokinin-receptor antagonist CR-1392 abolished amylase response for 30 minutes, whereas the more potent antagonists Asperlicin (18.0 mg/kg body wt, IV) and L-364,718 (0.25 mg/kg body wt, IV) caused prolonged blockade. The rate of amylase secretion in gastrectomized animals increased from 7.2 +/- 2.0 U to 15.0 +/- 2.2 U 20 minutes after cysteamine administration (P less than 0.01), indicating that the effect was not due to the presence of gastrin. In vitro, cysteamine caused a nearly fourfold increase in cholecystokinin secretion compared with controls (63.1 +/- 4.9 vs. 15.2 +/- 3.7, respectively; P less than 0.001). In vivo immunoneutralization of circulating somatostatin with a high-affinity and high-capacity antiserum produced no significant change in the rate of amylase secretion. These results suggest that cholecystokinin secretion is tonically inhibited by somatostatin and that this effect is mediated by locally secreted (paracrine) but not by circulating somatostatin

Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

NARCIS (Netherlands)

J. Nonnekens (Julie); M. van Kranenburg (Melissa); C.E.M.T. Beerens (Cecile); M. Suker (Mustafa); M. Doukas (Michael); C.H.J. van Eijck (Casper); M. de Jong (Marcel); D.C. van Gent (Dik)

2016-01-01

textabstractMetastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with

99mTc labelled peptide for imaging of peripheral receptors

International Nuclear Information System (INIS)

Mishra, A.K.; Mishra, P.; Chuttani, K.; Sharma, R.K.; Lazar Mathew, T.

2001-01-01

Conjugates of somatostatin analogues, RC-160 with different bifunctional chelators to label with 99m Tc, were synthesized. Conjugates with hydrazinonicotinamide (HYNIC) and compounds (benzoyl MAG-3 and CITC-DTPA) were prepared on a small scale with high purity and evaluated as different types of chelators on RC-160. Stability studies performed under physiological conditions showed high stability. Peptide conjugates could be labelled at high specific activities (307inCi/umol) with 99m Tc and different transchelator were used for the HYNIC conjugates. The resulting radiolabelled with ( 99m Tc and 1251) complexes were highly stable and showed binding affinity to somatostatin receptors in the nanomolar range. The radioconjugates were administered to rabbits and mice in order to study their in vivo stability, biokinetics and biodistribution. (author)

Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: First comparative results using the somatostatin analogues Lu-177 DOTA-NOC and Lu-177 DOTA-TATE

International Nuclear Information System (INIS)

Wehrmann, C.; Senftleben, S.; Baum, R.P.

2005-01-01

Peptide receptor radionuclide therapy (PRRT) is used in our department since 5 years (approx. 400 applications) for the treatment of patients with metastatic neuroendocrine tumors. Of all known peptides, the somatostatin analogue DOTA-NOC shows in vitro the highest affinity to somatostatin receptors (sstr) 3 and 5 and a very high affinity to sstr 2. We studied the in vivo behaviour of the two peptides DOTA-NOC and DOTA-TATE (highest affinity to sstr 2) by the use of different parameters like tumor and organ uptake, effective half-lifes (kinetics) and mean absorbed organ and tumor doses. We studied 27 patients with metastatic neuroendocrine tumors with high somatostatin expression, as verified prior to treatment by Ga-68 DOTA-NOC receptor PET/CT or somatostatin receptor scintigraphy (Tc-99m EDDA-Hynic TOC or In-111 OctreoScan, planar and SPECT). 22 patients (8M and 14F; aged 619 years) were treated with 2500 6790 MBq Lu-177 DOTA-TATE. Another 5 patients (1M and 4F, aged 6310 years) were treated with 4000 7400 MBq Lu-177 DOTA-NOC. Labelling efficiency and radiochemical purity using Lutetium-177 chloride (obtained from PerkinElmer Life Sciences, USA) were constantly over 99.5%. Whole-body scans (anterior/posterior) were performed at 0.5h, 3h, 24h, 48h, 72h and 96h p.i. ROIs were drawn over the whole-body, organs, and different metastases (mainly in the liver). Blood samples were obtained in 12 patients after therapy with Lu-177 DOTA-TATE over 5 days for calculating the kinetics in blood. The ROI results were used to determine the uptake and effective half-life in different organs (kidney, spleen, liver, bone etc.) and the tumor residence times. By means of geometric mean, and after background correction, the ROI results were also used to calculate the estimated absorbed organ and tumor doses using the OLINDA software. Compared to Lu-177 DOTA-TATE (=100%), the uptake of Lu-177 DOTA-NOC was higher for the whole-body (45%) and for normal tissues (28%), and also in the

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue

NARCIS (Netherlands)

Fiebrich, H. -B.; van den Berg, G.; Kema, I. P.; Links, T. P.; Kleibeuker, J. H.; van Beek, A. P.; Walenkamp, A. M. E.; Sluiter, W. J.; de Vries, E. G. E.

2010-01-01

P>Background Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels

Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Melis, Marleen; Krenning, Eric P.; Bernard, Bert F.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Barone, Raffaella [UCL, Centre of Nuclear Medicine and Laboratory of PET, Brussels (Belgium); Visser, Theo J. [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)

2005-10-01

Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1-24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [{sup 111}In-DTPA]octreotide, the effects of three inhibitory substances were explored in rats. Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The anti-megalin immunohistochemical staining pattern showed a strong similarity with the renal [{sup 111}In-DTPA]octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged d-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [{sup 111}In-DTPA]octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Renal retention of [{sup 111}In-DTPA]octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part. (orig.)

Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR

Science.gov (United States)

Grace, Christy Rani R.; Erchegyi, Judit; Koerber, Steven C.; Reubi, Jean Claude; Rivier, Jean; Riek, Roland

2008-01-01

The three-dimensional NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II’ β-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8 and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is therefore different from that proposed by others for sst2/3/5 analogues. PMID:16854054

Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy

Science.gov (United States)

Kaemmerer, Daniel; Träger, Tina; Hoffmeister, Maike; Sipos, Bence; Hommann, Merten; Sänger, Järg; Schulz, Stefan; Lupp, Amelie

2015-01-01

Introduction Somatostatin receptors (SSTR) are widely distributed in well-differentiated neuroendocrine neoplasms (NEN) and serve as primary targets for diagnostics and treatment. An overexpression of the chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. Comparative data are still lacking, however, for neuroendocrine carcinomas (NEC). Methods SSTR subtype (1, 2A, 3, 5) and CXCR4 expression was evaluated in G1 (n = 31), G2 (n = 47), and low (G3a; Ki-67: 21–49%; n = 21) and highly proliferative (G3b; Ki-67: >50%, n = 22) G3 (total n = 43) gastroenteropancreatic NEN samples by performing immunohistochemistry with monoclonal rabbit anti-human anti-SSTR and anti-CXCR4 antibodies, respectively, and was correlated with clinical data. Results Both CXCR4 and SSTR were widely expressed in all tumors investigated. CXCR4 expression differed significantly between the G1 and G3 specimens and within the G3 group (G3a to G3b), and was positively correlated with Ki-67 expression. SSTR2A, in contrast, exhibited an inverse association with Ki-67. SSTR2A was highly expressed in G1 and G2 tumors, but was significantly less abundant in G3 carcinomas. Additionally, SSTR1 expression was higher in G3a than in G3b tumors. Conclusion We observed an elevation in CXCR4 and a decrease in SSTR2A expression with increasing malignancy. Interestingly, 23% of the G3 specimens had strong SSTR2A expression. Because CXCR4 was strongly expressed in highly proliferative G3 carcinomas, it is an interesting new target and needs to be validated in larger studies. PMID:26259237

Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in endocrine gastro-entero-pancreatic tumours

International Nuclear Information System (INIS)

Lebtahi, R.; Genin, R.; Rouzet, F.; Bleicner-Perez, S.; Lievre, A.; Scigliano, S.; Vialle, C.; Le Guludec, D.; Cadiot, G.; Sobhani, I.; Mignon, M.

2005-01-01

Somatostatin receptors scintigraphy (SRS) is a sensitive method for the detection of endocrine gastro-entero-pancreatic tumors. The aim of this study was to evaluate the sensitivity of anterior and posterior planar associated to single photon emission computerized tomography (SPECT) compared to anterior and posterior planar associated to additional lateral and oblique views in the detection of abdominal endocrine tumors. One hundred and sixty four patients with endocrine gastro-entero-pancreatic tumors were included in this study. Scintigraphic images were performed after injection of 189 ± 23 MBq of 111 In-Pentetreotide. Abdominal planar images were performed 4 h and 24 hours after injection. Abdominal SPECT was performed at 24 hours. The combination of anterior and posterior abdominal planar images with SPECT using iterative reconstruction detected significantly more tumoral sites compared to multiple planar images (298 versus 280 for the liver, p = 0.01 and 90 versus 88 for coeliac area). In particular liver lesions were better delineated on tomographic slices. The combination of 111 In-Pentetreotide SPECT with anterior and posterior planar images is more sensitive than multiple planar images to detect abdominal endocrine tumors. (author)

Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals

International Nuclear Information System (INIS)

Storch, D.; Schmitt, J.S.; Waldherr, C.; Maecke, H.R.; Waser, B.; Reubi, J.C.

2007-01-01

Radiometallated analogues of the regulatory peptide somatostatin are of interest in the in vivo localization and targeted radiotherapy of somatostatin receptor-overexpressing tumors. An important aspect of their use in vivo is a fast and efficient labeling (complexation) protocol for radiometals along with a high specific activity. We describe in this manuscript synthetic methods for the coupling of two chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid = DOTA) to the bioactive peptide [Tyr 3 ,Thr 8 ]-octreotide (TATE) in order to increase the specific activity (radioactivity in Bq per mole peptide). The full chelator-linker-peptide conjugate was assembled on solid support using standard Fmoc chemistry. Two DOTA-chelators were linked to the peptide using lysine or N,N'-bis(3-aminopropyl)-glycine (Apg); in addition, pentasarcosine (Sar 5 ) was used as a spacer between the chelators and the peptide to probe its influence on biology and pharmacology. Complexation rates with In 3+ and Y 3+ salts and the corresponding radiometals were high, the bis-DOTA-derivatives showed higher complexation rates and gave higher specific activity than DOTA-TATE. Pharmacological and biological data of the complexed molecules did not show significant differences if compared to the parent peptide [ 111/nat In-DOTA]-TATE except for [( 111/nat In-DOTA) 2 -Apg]-TATE which showed a lower binding affinity and rate of internalization into tumor cells. The biodistribution of [( 111/nat In-DOTA)-Lys( 111/nat In-DOTA)]-TATE in the rat tumor model (AR4-2J) showed a high and specific (as shown by a blocking experiment) tracer uptake in somatostatin receptor-positive tissue but a lower tumor uptake compared to [ 111/nat In-DOTA]-TATE. (orig.)

Somatostatin receptor scintigraphy to predict the clinical evolution and therapeutic response of thyroid-associated ophthalmopathy

International Nuclear Information System (INIS)

Nocaudie, M.; Bailliez, A.; Itti, E.; Marchandise, X.

1999-01-01

Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves' disease, four Hashimoto's thyroiditis, two isolated in appearance: Means' syndrome). Each patient underwent hormonal (free T 3 and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and 111 In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. At 4 and 24 h after the intravenous injection of 111 MBq of 111 In-pentetreotide, planar imaging centred on the head and neck (anterior and both lateral views) was carried out. Retrobulbar uptake was assessed by visual semi-quantitative analysis (score given by two independent trained observers) and by quantitative analyses (regions of interest, orbit/brain uptake indices). Patients were ophthalmologically followed up for 6 months and then classified as improved or not. Visual semi-quantitative analysis of 4-h/24-h planar images was correlated with the ophthalmological evolution (χ 2 test, P 111 In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed. (orig.)

Somatostatin receptor scintigraphy and intraoperative gamma probe detection in the localisation and treatment of pancreatic insulinoma

International Nuclear Information System (INIS)

Loh, Nelson K.; Macdonald, William B.; Dunne, Marina L.; Rao, Sudhakar

2009-01-01

Full text: Aims: We report a case of insulinoma that was successfully enucleated under radio-guidance after an initial unsuccessful laparotomy. This case highlights the utility of Somatostatin Receptor Scintigraphy (SRS) and gamma probe in the localisation and treatment of neuroendocrine tumours. Methods: The patient presented with recurrent hypoglycaemia. An abdominal CT scan identified a lesion in the uncinate process of the pancreas, however, laparotomy with use of intraoperative ultrasound failed to localise the lesion. SRS with SPECTICT was then requested by the surgical team with a view to radio-guided surgery. Results: SRS demonstrated an octreotide-avid tumour in the posterior uncinate process of the pancreas, and confirmed suitability for radio-guided surgery. At re-exploration, the surgeon was again unable to palpate the lesion or localise it with intraoperative ultrasound, however, the lesion was successfully detected and removed with the use of a gamma probe. A postoperative SRS confirmed complete excision and histopathology was diagnostic of insulinoma. Conclusion: This case highlights the utility of SRS in the intraoperative localisation and surgical excision of neuroendocrine tumours. The lesion was unable to be localised clinically or with intraoperative ultrasound but was successfully detected with scintigraphic techniques. The surgical team acknowledge that the use of a gamma probe enabled enucleation of the insulinoma, which obviated the need for an invasive Whipple's procedure.

In vivo somatostatin, vasopressin, and oxytocin synthesis in diabetic rat hypothalamus

International Nuclear Information System (INIS)

Fernstrom, J.D.; Fernstrom, M.H.; Kwok, R.P.

1990-01-01

The in vivo labeling of somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin was studied in rat hypothalamus after third ventricular administration of [35S]cysteine to streptozotocin-diabetic and normal rats. Immunoreactive somatostatin levels in hypothalamus were unaffected by diabetes, as was the incorporation of [35S]cysteine into hypothalamic somatostatin-14 and somatostatin-28. In contrast, immunoreactive vasopressin levels in hypothalamus and posterior pituitary (and oxytocin levels in posterior pituitary) were below normal in diabetic rats. Moreover, [35S]cysteine incorporation into hypothalamic vasopressin and oxytocin (probably mainly in the paraventricular nucleus because of its proximity to the third ventricular site of label injection) was significantly above normal. The increments in vasopressin and oxytocin labeling were reversed by insulin administration. In vivo cysteine specific activity and the labeling of acid-precipitable protein did not differ between normal and diabetic animals; effects of diabetes on vasopressin and oxytocin labeling were therefore not caused by simple differences in cysteine specific activity. These results suggest that diabetes (1) does not influence the production of somatostatin peptides in hypothalamus but (2) stimulates the synthesis of vasopressin and oxytocin. For vasopressin at least, the increase in synthesis may be a compensatory response to the known increase in its secretion that occurs in uncontrolled diabetes

CXCL14-like Immunoreactivity Exists in Somatostatin-containing Endocrine Cells, and in the Lamina Propria and Submucosal Somatostatinergic Nervous System of Mouse Alimentary Tract.

Science.gov (United States)

Suzuki, Hirohumi; Yamada, Kentaro; Matsuda, Yasuhiro; Onozuka, Minoru; Yamamoto, Toshiharu

2017-12-26

In the present study, we investigated the distribution of CXCL14 immunoreactive endocrine cells and neurons in mouse alimentary tract by immunohistochemistry. CXCL14 immunoreactive endocrine cells were found as closed-type cells in the stomach and open-type cells in the small intestine. The immunostaining of these endocrine cells corresponded with that of the somatostatin-containing endocrine cells. Only a few CXCL14 immunoreactive endocrine cells were seen in the large intestine. CXCL14 immunoreactive fibers were observed in the muscular layer from the stomach to the rectum with most abundance in the rectum. Many CXCL14 immunoreactive fibers were observed in the lamina propria and submucosal layer from the duodenum to the rectum with most abundance in the rectum; these fibers corresponded to the somatostatin-containing nerve fibers. Some CXCL14 immunoreactive neuronal somata that were also immuno-positive for somatostatin, were noted in the submucosal layer of the rectum. However, the remaining parts of the alimentary tract presented with almost negligible immunoreactive somata. The co-localization of CXCL14 and somatostatin suggests that CXCL14 contributes to the function of somatostatin, which include the inhibition of other endocrine and exocrine cells and the enteric nervous systems.

Does somatostatin have a role in the regulation of cortisol secretion in primary pigmented nodular adrenocortical disease (PPNAD)? A clinical and in vitro investigation

NARCIS (Netherlands)

Z. Bram (Zakariae); P. Xekouki (Paraskevi); E. Louiset (Estelle); M. Keil (Mark); D. Avgeropoulos (Dimitrios); C. Giatzakis (Christoforos); M. Nesterova (Maria); N. Sinaii (Ninet); L.J. Hofland (Leo); R. Cherqaoui (Rabia); H. Lefebvre (Hervé); C.A. Stratakis (Constantine)

2014-01-01

textabstractContext: Somatostatin (SST) receptors (SSTRs) are expressed in a number of tissues, including the adrenal cortex, but their role in cortisol secretion has not been well characterized. Objectives: The objective of the study was to investigate the expression of SSTRs in the adrenal cortex

Experience with indium-111 and yttrium-90-labeled somatostatin analogs.

Science.gov (United States)

Virgolini, I; Traub, T; Novotny, C; Leimer, M; Füger, B; Li, S R; Patri, P; Pangerl, T; Angelberger, P; Raderer, M; Burggasser, G; Andreae, F; Kurtaran, A; Dudczak, R

2002-01-01

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide / lanreotide analogs as tumor tracers in nuclear medicine. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or immunologic diseases such as thyroid-associated ophthalmology. The vast majority of human tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-DTPA-DPhe(1)-octreotide (OctreoScan(R)) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (K(d) 10-100 nM) and does not bind to hSSTR1 and hSSTR4, (111)In / (90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d) 200 nM). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to (111)In-DTPA-DPhe(1)-octreotide and (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higherrdquuo; high-affinity binding of (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide to hSSTR2 (K(d) 0.1-1 nM). Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as (99m)Tc-depreotide (NeoSpect(R); NeoTect(R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or nonsmall cell

Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig

DEFF Research Database (Denmark)

Schmidt, P T; Hansen, L; Hilsted, L

2004-01-01

BACKGROUND: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin....... METHODS: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. RESULTS: CCK infusion...... at 10(-9) M and 10(-8) M decreased gastrin output to 70.5% +/- 7.6% (n = 8) and 76.3% +/- 3.6% (n = 7) of basal output, respectively. CCK at 10(-10) M had no effect (n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 +/- 38.2% (n = 7) of basal secretion...

Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

Energy Technology Data Exchange (ETDEWEB)

Kelly, Catriona, E-mail: catriona.kelly@qub.ac.uk [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom); Flatt, Peter R.; McClenaghan, Neville H. [SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine (United Kingdom)

2010-08-20

Research highlights: {yields} TGP52 cells display enhanced functionality in pseudoislet form. {yields} Somatostatin content was reduced, but secretion increased in high glucose conditions. {yields} Cellular interactions and environment alter the somatostatin status of TGP52 cells. -- Abstract: Introduction: Somatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. Methods: This study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5 mM glucose) or DMEM (25 mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. Results: TGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P < 0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P < 0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. Conclusions: Somatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

Cell-to-cell communication and cellular environment alter the somatostatin status of delta cells

International Nuclear Information System (INIS)

Kelly, Catriona; Flatt, Peter R.; McClenaghan, Neville H.

2010-01-01

Research highlights: → TGP52 cells display enhanced functionality in pseudoislet form. → Somatostatin content was reduced, but secretion increased in high glucose conditions. → Cellular interactions and environment alter the somatostatin status of TGP52 cells. -- Abstract: Introduction: Somatostatin, released from pancreatic delta cells, is a potent paracrine inhibitor of insulin and glucagon secretion. Islet cellular interactions and glucose homeostasis are essential to maintain normal patterns of insulin secretion. However, the importance of cell-to-cell communication and cellular environment in the regulation of somatostatin release remains unclear. Methods: This study employed the somatostatin-secreting TGP52 cell line maintained in DMEM:F12 (17.5 mM glucose) or DMEM (25 mM glucose) culture media. The effect of pseudoislet formation and culture medium on somatostatin content and release in response to a variety of stimuli was measured by somatostatin EIA. In addition, the effect of pseudoislet formation on cellular viability (MTT and LDH assays) and proliferation (BrdU ELISA) was determined. Results: TGP52 cells readily formed pseudoislets and showed enhanced functionality in three-dimensional form with increased E-cadherin expression irrespective of the culture environment used. However, culture in DMEM decreased cellular somatostatin content (P < 0.01) and increased somatostatin secretion in response to a variety of stimuli including arginine, calcium and PMA (P < 0.001) when compared with cells grown in DMEM:F12. Configuration of TGP52 cells as pseudoislets reduced the proliferative rate and increased cellular cytotoxicity irrespective of culture medium used. Conclusions: Somatostatin secretion is greatly facilitated by cell-to-cell interactions and E-cadherin expression. Cellular environment and extracellular glucose also significantly influence the function of delta cells.

Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

Science.gov (United States)

de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

2012-01-01

For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

Somatostatin-like peptide and regeneration capacities in planarians.

Science.gov (United States)

Bautz, A; Schilt, J

1986-11-01

The presence of a neuropeptide immunologically related to somatostatin (SRIF) has been investigated in the neurosecretory cells of two regenerating planarian species (Dugesia lugubris and Dendrocoelum lacteum). A correlation has been shown between the discharge of the SRIF-like-immunoreactive cells during the first hours after amputation and the capacity to regenerate, and between the persistence of numerous positive cells and the lack of regeneration. These results suggest that somatostatin might play a regulatory (inhibitory) role on the cellular proliferation which leads to the blastema edification.

Ultrastructural autoradiographic localization of somatostatin-28 in the rat pituitary gland

International Nuclear Information System (INIS)

Morel, G.; Leroux, P.; Pelletier, G.

1985-01-01

To identify the anterior pituitary cell type(s) containing somatostatin-28 (SS-28)-binding sites and to study the internalization processes of this peptide by the target cells, autoradiography was performed on rat anterior pituitaries removed at specific intervals (2-60 min) after iv injection of the [ 125 I]iodo-SS-28 agonist [Leu8,D-Trp22,Tyr25]SS-28 into intact, adrenalectomized, or castrated male rats. At the light microscopic level, the silver grains were found in 75% of cells. Concomitant injection of an excess of unlabeled peptide prevented the binding of label, verifying the specificity of binding. No specific labeling could be detected in the adrenocorticotrophs of adrenalectomized rats or gonadotrophs (castration cells) of castrated rats. At the electron microscopic level, three cell types (somatotrophs, thyrotrophs, and mammotrophs) appear to contain radiolabeled SS-28. The time-course study in somatotrophs of intact animals showed that 2 min after injection, most silver grains were associated with the plasma membrane. Five to 15 min after injection, label was found over both the plasma membrane and cytoplasmic organelles, especially the Golgi apparatus, lysosomes, and secretory granules. At the longest time interval (60 min), labeling was mostly associated with the cytoplasmic organelles. These results indicate that SS-28-binding sites are present only in those cell types in which somatostatin is known to regulate secretory functions. The present data also show that a rapid internalization of the radiolabeled peptide occurs

Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions.

Science.gov (United States)

Perianes-Cachero, A; Burgos-Ramos, E; Puebla-Jiménez, L; Canelles, S; Frago, L M; Hervás-Aguilar, A; de Frutos, S; Toledo-Lobo, M V; Mela, V; Viveros, M P; Argente, J; Chowen, J A; Arilla-Ferreiro, E; Barrios, V

2013-11-12

Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain

Excessive grooming induced by somatostatin or its analog SMS 201-995

NARCIS (Netherlands)

Wimersma Greidanus, T.B. van; Maigret, C.; Krechting, B.

1987-01-01

Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS

Depletion of somatostatin-like immunoreactivity in the rat central nervous system by cysteamine

International Nuclear Information System (INIS)

Sagar, S.M.; Landry, D.; Millard, W.J.; Badger, T.M.; Arnold, M.A.; Martin, J.B.

1982-01-01

Selective neurotoxins have been of value in providing a means for specifically interfering with the actions of endogenous neurotransmitter candidates. Others have shown cysteamine (CSH) to deplete the gastrointestinal tract and hypothalamus of rats of immunoreactive somatostatin, suggesting a toxic action of that compound directed against somatostatin-containing cells. The present study further defines the actions of cysteamine on somatostatin in the central nervous system. (CNS). Cysteamine hydrochloride administered subcutaneously results in a depletion of somatostatin-like immunoreactivity (SLI) in the retina, brain, and cervical spinal cord of rats. The effect is demonstrable at doses of 30 mg/kg of body weight and above, occurs within 2 to 4 hr of a single injection of the drug, and is largely reversible within 1 week. The mean depletion of SLI observed within the CNS varies from 38% in cerebral cortex to 65% in cervical spinal cord 24 hr following administration of CSH, 300 mg/kg of body weight, s.c. By gel permeation chromatography, all molecular weight forms of SLI are affected, with the largest reductions in those forms that co-chromatograph with synthetic somatostatin-14 and somatostatin-28. These results indicate that CSH has a generalized, rapid, and largely reversible effect in depleting SLI from the rat CNS

Contribution of scintigraphy for somatostatin receptors in case of non-iodine-fixating metastases of thyroid epithelioma

International Nuclear Information System (INIS)

Couty, H.; Andrieu, J.M.; Baudet, L.; Faurous, P.; Artus, J.C.; Jaffiol, C.

1997-01-01

The objective of this work was to evaluate the sensitivity and importance of scintigraphy of somatostatin receptors (SSR) in the detection of non iodine-fixating metastases of thyroid epithelioma. We have studied retrospectively 7 patients with a detectable thyroglobulin under hormonal hindrance, amounting after cessation of treatment up to 72 - 1500 μ g/l and a normal post-irradiation therapy (3.7 GBq of 131 I) scintigraphy. These patients (4 F / 3 M), aged from 27 to 74 years (average age, 54 years), were treated by total and ganglionic curettage for papillary cancer of thyroid. Their evolutive surveillance extended from 1 to 24 years (on average, 8.4 years) and they received curative cumulated 131 I activities of 13 to 26 GBq. Each of them benefited by an osseous scintigraphy, of a cervico-thoraco-abdominal TDM and of a 111 In Pentetreotide SSR. The SSR was positive for 4/7 patients showing cervico-mediastinal fixations, the localizations being not detected by TDM. The osseous scintigraphy revealed once to be positive showing a costal lesion already detected by SSR. Cervical non-palpable adenopathies were detected by TDM for one patient. The anatomical-pathological analysis confirmed their thyroid origin. For other two patients the TDM showed suspect pulmonary nodules. These cervical and pulmonary localization were not detected by SSR. The SSR + TDM couple was positive for 6/7 patients. In conclusion, in this series the sensitivity of SSR was estimated to be 57%. Besides, the results obtained showed a net complementarity between the detection performances of SSR and TDM

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

Directory of Open Access Journals (Sweden)

Heiko Löhr

2018-05-01

Full Text Available Summary: Anorexigenic pro-opiomelanocortin (Pomc/alpha-melanocyte stimulating hormone (αMSH neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin (Sst-neurons that express the melanocortin receptor Mc4r, elevated growth hormone (GH expression in the pituitary, and enhanced somatic growth. Mc4r expression and αMSH responsiveness are conserved in Sst-expressing hypothalamic neurons of mice. Thus, acquired leptin resistance and attenuation of pomca transcription in response to excessive caloric intake may represent an ancient mechanism to promote somatic growth when food resources are plentiful. : The melanocortin system controls energy homeostasis and somatic growth, but the underlying mechanisms are elusive. Löhr et al. identify a functional neural circuit in which Pomc neurons stimulate hypothalamic somatostatin neurons, thereby inhibiting hypophyseal growth hormone production. Excessive feeding and acquired leptin resistance attenuate this pathway, allowing faster somatic growth when food resources are rich. Keywords: Pomc neuron, somatostatin neuron, somatic growth, growth hormone, melanocortin system, high-fat diet, obesity, leptin resistance, zebrafish, mouse

Technetium-99m somatostatin analogues: effect of labelling methods and peptide sequence

International Nuclear Information System (INIS)

Decristoforo, C.; Mather, S.J.

1999-01-01

In this paper the preclinical evaluation of the somatostatin analogue RC160 labelled with technetium-99m using bifunctional chelators (BFCs) based on the hydrazinonicotinamide (HYNIC) and N 3 S system is described and a comparison made with [Tyr 3 ]-octreotide (TOC). Conjugates of both peptides with HYNIC, and of RC160 with benzoyl-MAG 3 and an N 3 S-adipate derivative were prepared and radiolabelling performed at high specific activities using tricine, tricine/nicotinic acid and ethylenediamine-N,N'-diacetic adic (EDDA) as co-ligands for HYNIC conjugates. All conjugates and 99m Tc-labelled peptides showed preserved binding affinity for the somatostatin receptor (IC50, Kd 99m Tc-RC160 derivatives compared with 99m Tc-EDDA/HYNIC-[Tyr 3 ]-octreotide (0.2%-3.5%ID/g vs 9.7%ID/g) and correlated well with the reduced internalisation rate for RC160 derivatives. Our results show that the selection of the labelling approach as well as the right choice of the peptide structure are crucial for labelling peptides with 99m Tc to achieve complexes with favourable biodistribution. Despite the relatively low tumour uptake compared with 99m Tc-EDDA/HYNIC-[Tyr 3 ]-octreotide, 99m Tc-RC160 could play a role in imaging tumours that do not bind octreotide derivatives. (orig.)

Effect of somatostatin on glucose homeostasis in conscious long-fasted dogs

International Nuclear Information System (INIS)

Stevenson, R.W.; Steiner, K.E.; Hendrick, G.K.; Cherrington, A.D.

1987-01-01

The effects of somatostatin plus intraportal insulin and glucagon replacement (pancreatic clamp) on carbohydrate metabolism were studied in conscious dogs fasted for 7 days so that gluconeogenesis was a major contributor to total glucose production. By use of [3- 3 H]glucose, glucose production (R a ) and utilization (R d ) and glucose clearance were assessed before and after implementation of the pancreatic clamp. After an initial control period, somatostatin (0.8 μg·kg -1 ·min -1 ) was infused with intraportal replacement amounts of glucagon and insulin. The insulin infusion rate was varied to maintain euglycemia and then kept constant for 250 min. Plasma glucagon was similar before and during somatostatin infusion, while plasma insulin was lower. Plasma glucose levels remained similar while R a and R d and the ratio of glucose clearance to plasma insulin were significantly increased. Net hepatic lactate uptake and [ 14 C]alanine plus [ 14 C]lactate conversion to [ 14 C]glucose increased. In conclusion, somatostatin alters glucose clearance in 7-day fasted dogs, resulting in changes in several indices of carbohydrate metabolism

99mTc labelled peptides for imaging of peripheral receptors

International Nuclear Information System (INIS)

Mustanser, J.; Anjum, A.

2001-01-01

Several peptides are being used as radiopharmaceuticals for receptor imaging scintigraphy. The peptide receptors are found in the tumours of various sites in the human body. Somatostatin is one of those, which is expressed by a variety of tumours say in brain cortex, medullary carcinoma of thyroid, adrenal glands, pancreas and gut. Therefore neuropeptides based on somatostatin analogues are labelled with different radionuclide, 123 I and 111 In. Efforts are underway to label RC-160 (an analogue of somatostatin) with 99m Tc because of its favourable radiation dosimetry, short half-life, low price, high count rate and better diagnostic efficacy. In this project various methods of labelling RC-160 with different radionuclides 125 I and 99m Tc have been studied in detail. Radioiodination of RC-160 was tried with 125 I using the iodogen method as directed and then with Chloramine T method. Labelling of RC-160 peptide with 99m Tc was done using two different aspects. Direct labelling with 99m Tc and indirect labelling with 99m Tc using double chelating agents. Radiochemical quality control was carried out applying instant thin layer chromatography using ITLC-SG strips in 85% of methanol. Later the HPLC analysis was used for its evaluation. To label RC-160 with 99m Tc the approach of direct labelling was attempted first. 46% labelling could be achieved with 95% of radiochemical purity. The biodistribution of 99m Tc-RC-160 complex in rats has also been studied to determine uptake in various sites of somatostatin receptors. Eventually, attempt was made to synthesize biomolecule by conjugating Boc protected RC-160 with benzoyl MAG-3. As a result 80% of Boc-RC-160 went under conjugation with benzoyl MAG-3. (author)

Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

Science.gov (United States)

Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

2016-06-01

In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Breast cancer imaging using radiolabelled somatostatin analogues

International Nuclear Information System (INIS)

Dalm, Simone U.; Melis, Marleen; Emmering, Jasper; Kwekkeboom, Dik J.; Jong, Marion de

2016-01-01

Imaging and therapy using radiolabelled somatostatin analogues are methods successfully used in patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Since these techniques were first introduced, many improvements have been made. SSTR expression has also been reported on breast cancer (BC). Currently mammography, magnetic resonance imaging and ultrasound are the most frequent methods used for BC imaging. Since SSTR expression on BC was demonstrated, clinical studies examining the feasibility of visualizing primary BC using SSTR radioligands have been performed. However, to date SSTR-mediated nuclear imaging is not used clinically in BC patients. The aim of this review is to assess whether recent improvements made within nuclear medicine may enable SSTR-mediated imaging to play a role in BC management. For this we critically analysed results of past studies and discussed the potential of the improvements made within nuclear medicine on SSTR-mediated nuclear imaging of BC. Seven databases were searched for publications on BC imaging with SSTR radioligands. The papers found were analysed by 3 individual observers to identify whether the studies met the pre-set inclusion criteria defined as studies in which nuclear imaging using radiolabelled SST analogues was performed in patients with breast lesions. Twenty-four papers were selected for this review including studies on SSTR-mediated nuclear imaging in BC, neuroendocrine BC and other breast lesions. The analysed studies were heterogeneous with respect to the imaging method, imaging protocol, patient groups and the radiolabelled SST analogues used. Despite the fact that the analysed studies were heterogeneous, sensitivity for primary BC ranged from 36–100%. In a subset of the studies LN lesions were visualized, but sensitivity was lower compared to that for primary tumours. A part of the studies included benign lesions and specificity ranged from 22–100%. Furthermore, false negatives and

Synthesis and evaluation in vitro in cancer cells AR42J of the radiopharmaceutical 99mTc-Tyr3-Octreotide-dendrimer similar of somatostatin

International Nuclear Information System (INIS)

Orocio R, E.

2013-01-01

The objective of this project was preparing a multimeric system through the conjugation of several molecules of the peptide Tyr 3 -Octreotide to a dendrimer molecule based on Poly-amidoamine (PAMAM), as well as radiolabeled with 99m Tc and evaluating its behavior like new radiopharmaceutical similar of somatostatin. The dendrimer PAMAM generation 3.5 that possesses terminal groups of sodium carboxylate, was functionalized to peptide Tyr 3 -Octreotide through a reaction of peptide coupling with HATU (hexafluorophosphate (V) of 1-oxide-3-(bis(dimethylamino)methylene)-3H-[1,2,3]triazole[4,5-b]pyridine) as activating agent of carboxylate groups using the Size Exclusion Chromatography (Sec) as purification method. The product was characterized by Ultraviolet visible spectrophotometry, Mid-infrared and Far-infrared, Elemental analysis, Energy dispersive X-ray spectroscopy, Scanning electron microscopy, Thermogravimetry and Differential scanning calorimetry. The radiolabeled with 99m Tc was carried out using a direct method that involves the reduction of the anion TcO 4 - with stannous chloride, so that the dendrimer is capable of coordinating to the technetium forming a chelate compound. The radiochemical purity of the radiolabeled compound was determined by thin layer chromatography using a sodium chloride solution to 20% (m/v) as mobile phase and was verified by molecular exclusion chromatography. The radiolabeled compound was possible to obtain it with a radiochemical purity superior to 90%. Also, the specific and not specific union was evaluated of the synthesized compound in mouse pancreas cancer cells AR42J, positive to somatostatin receptors, showing specific recognition for this receptors type with high cellular internalization. The biodistribution studies were carried out in BALB/c mice at different post injection times and in nude mice with induced tumors AR42J. The results showed that the 99m Tc-PAMAM-Tyr 3 -Octreotide is excreted by via renal as hepatobiliary

Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms

DEFF Research Database (Denmark)

Engelund Luna, Iben; Monrad, Nina; Binderup, Tina

2016-01-01

, and biochemical features as well as treatment and prognosis. DESIGN: Twenty-three patients with p-dSOM (9 duodenal, 12 pancreatic, 2 unknown primary tumour) were identified from our prospective neuroendocrine tumour (NET) database, and data according to the study aims were recorded. RESULTS: Of the 9 patients...... with duodenal SOM the m/f ratio was 4/5. All males and one female had NF-1. Seven patients had stage 1A-B and 2 had stage 2B disease. The Ki-67 index was 1-5% (median 2%). Plasma somatostatin was elevated in patients with 2B disease. Of the 14 patients with pancreatic SOM or unknown primary tumour the m/f ratio...... was 2/12. One male had MEN-1. Five had stage 1A-2B and nine had stage 4. The Ki-67 index was 1-40% (median 7%). Plasma somatostatin was elevated in seven patients. Patients reported symptoms related to the somatostatinoma syndrome, but none fulfilled the criteria for a full syndrome. Primary tumour...

Somatostatin receptor scintigraphy to predict the clinical evolution and therapeutic response of thyroid-associated ophthalmopathy

Energy Technology Data Exchange (ETDEWEB)

Nocaudie, M.; Bailliez, A.; Itti, E. [Centre Hospitalier Regional et Universitaire, Lille (France). Service Central de Medecine Nucleaire et Imagerie Fonctionnelle; Bauters, C.; Wemeau, J.L. [Clinique d`Endocrinologie, Centre Hospitalier Regional et Universitaire de Lille (France); Marchandise, X.

1999-05-01

Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves` disease, four Hashimoto`s thyroiditis, two isolated in appearance: Means` syndrome). Each patient underwent hormonal (free T{sub 3} and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and {sup 111}In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. At 4 and 24 h after the intravenous injection of 111 MBq of {sup 111}In-pentetreotide, planar imaging centred on the head and neck (anterior and both lateral views) was carried out. Retrobulbar uptake was assessed by visual semi-quantitative analysis (score given by two independent trained observers) and by quantitative analyses (regions of interest, orbit/brain uptake indices). Patients were ophthalmologically followed up for 6 months and then classified as improved or not. Visual semi-quantitative analysis of 4-h/24-h planar images was correlated with the ophthalmological evolution ({chi}{sup 2} test, P<0.01). All ten patients in whom scintigraphy was considered positive were clinically improved at 6 months, and of the seven patients in whom scintigraphy was negative, six were not improved. Nevertheless, objective quantitative analysis did not succeed in confirming these results. We conclude that {sup 111}In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed

99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives.

Science.gov (United States)

Decristoforo, C; Mather, S J; Cholewinski, W; Donnemiller, E; Riccabona, G; Moncayo, R

2000-09-01

[111In-diethylene triamine penta-acetic acid-D-Phe1]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99mTc-EDDA/HYNIC-TOC were compared with those of 111In-DTPA-octreotide in six cases, and with those of 111In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111In-DTPA-octreotide but faster than that of 111In-DOTA-TOC, while urinary excretion was lower compared with the 111In derivatives. Semi-quantitative region of interest analysis showed that 99mTc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99mTc images. We conclude that 99mTcEDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111In-labelled octreotide derivatives.

99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours: first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives

International Nuclear Information System (INIS)

Decristoforo, C.; Cholewinski, W.; Donnemiller, E.; Riccabona, G.; Moncayo, R.

2000-01-01

[ 111 In-diethylene triamine penta-acetic acid-d-Phe 1 ]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99m Tc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99m Tc-EDDA/HYNIC-TOC were compared with those of 111 In-DTPA-octreotide in six cases, and with those of 111 In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111 In-DTPA-octreotide but faster than that of 111 In-DOTA-TOC, while urinary excretion was lower compared with the 111 In derivatives. Semi-quantitative region of interest analysis showed that 99m Tc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111 In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99m Tc images. We conclude that 99m Tc-EDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111 In-labelled octreotide derivatives. (orig.)

[111In-DOTA]LTT-SS28, a first pansomatostatin radioligand for in vivo targeting of somatostatin receptor-positive tumors.

Science.gov (United States)

Maina, Theodosia; Cescato, Renzo; Waser, Beatrice; Tatsi, Aikaterini; Kaloudi, Aikaterini; Krenning, Eric P; de Jong, Marion; Nock, Berthold A; Reubi, Jean Claude

2014-08-14

Radiolabeled pansomatostatin-like analogues are expected to enhance the diagnostic sensitivity and to expand the clinical indications of currently applied sst2-specific radioligands. In this study, we present the somatostatin mimic [DOTA]LTT-SS28 {[(DOTA)Ser1,Leu8,D-Trp22,Tyr25]SS28} and its 111In radioligand. [DOTA]LTT-SS28 exhibited a pansomatostatin-like profile binding with high affinity to all five hsst1-hsst5 subtypes (IC50 values in the lower nanomolar range). Furthermore, [DOTA]LTT-SS28 behaved as an agonist at hsst2, hsst3, and hsst5, efficiently stimulating internalization of the three receptor subtypes. Radioligand [111In-DOTA]LTT-SS28 showed good stability in the mouse bloodstream. It displayed strong and specific uptake in AR42J tumors 4 h postinjection (9.3±1.6% ID/g vs 0.3±0.0% ID/g during sst2 blockade) in mice. Significant and specific uptake was also observed in HEK293-hsst2-, HEK293-hsst3-, and HEK293-hsst5-expressing tumors (4.43±1.5, 4.88±1.1, and DOTA]LTT-SS28 specifically localizes in sst2-, sst3-, and sst5-expressing xenografts in mice showing promise for multi-sst1-sst5 targeted tumor imaging.

Patient-specific dosimetry in peptide receptor radionuclide therapy: a clinical review

International Nuclear Information System (INIS)

Chalkia, M.T.; Stefanoyiannis, A.P.; Chatziioannou, S.N.; Efstathopoulos, E.P.; Round, W.H.; Nikiforidis, G.C.

2015-01-01

Neuroendocrine tumours (NETs) belong to a relatively rare class of neoplasms. Nonetheless, their prevalence has increased significantly during the last decades. Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment approach for inoperable or metastasised NETs. The therapeutic effect is based on the binding of radiolabelled somatostatin analogue peptides with NETs’ somatostatin receptors, resulting in internal irradiation of tumours. Pre-therapeutic patient-specific dosimetry is essential to ensure that a treatment course has high levels of safety and efficacy. This paper reviews the methods applied for PRRT dosimetry, as well as the dosimetric results presented in the literature. Focus is given on data concerning the therapeutic somatostatin analogue radiopeptides 111 In-[DTPA o , D -Phe 1 ]-octreotide ( 111 In-DTPA-octreotide), 90 Y-[DOTA o ,Tyr 3 ]-octreotide ( 90 Y-DOTATOC) and 177 Lu-[DOTA o ,Tyr 3 ,Thr 8 ]-octreotide ( 177 Lu-DOTATATE). Following the Medical Internal Radiation Dose (MIRD) Committee formalism, dosimetric analysis demonstrates large interpatient variability in tumour and organ uptake, with kidneys and bone marrow being the critical organs. The results are dependent on the image acquisition and processing protocol, as well as the dosimetric imaging radiopharmaceutical.

Multiparametric PET imaging in thyroid malignancy characterizing tumour heterogeneity: somatostatin receptors and glucose metabolism

Energy Technology Data Exchange (ETDEWEB)

Traub-Weidinger, Tatjana [Medical University of Vienna, Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Putzer, Daniel; Bale, Reto [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Guggenberg, Elisabeth von; Dobrozemsky, Georg; Nilica, Bernhard; Kendler, Dorota; Virgolini, Irene Johanna [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

2015-12-15

Radiolabelled somatostatin (SST) analogues have proven useful in diagnosing tumours positive for SST receptor (SSTR). As different subtypes of SSTR are expressed on the tumour cell surface, the choice of appropriate therapeutic SST analogue is crucial. We evaluated the SSTR status of thyroid cancer patients who had signs of progressive disease comparing different SSTR ligands for PET imaging to evaluate possible further therapeutic options. PET with {sup 68}Ga-radiolabelled SSTR ligands DOTA lanreotide (DOTA-LAN), DOTA-Tyr{sup 3} octreotide (DOTA-TOC) and {sup 18}F-FDG was performed in 31 patients with thyroid cancer (TC). These 31 patients comprised 18 with radioiodine non-avid differentiated TC (DTC) including 6 papillary TC (PTC), 8 follicular TC (FTC) and 4 oxyphilic TC (oxyTC), 5 with anaplastic TC (ATC), and 8 with medullary TC (MTC). The PET results were compared in a region-based evaluation. All patients underwent a PET study with {sup 68}Ga-DOTA-LAN, 28 patients with {sup 68}Ga-DOTA-TOC and 28 patients with {sup 18}F-FDG. A lack of SSTR expression was found in 13 of the 31 patients (42 %) with negative results with both SSTR tracers in 12 patients. Ambiguous results with both SSTR tracers were observed in one patient. High tracer uptake in SSTR PET images was seen in seven DTC patients (39 %; two PTC, three FTC, two oxyTC), in four ATC patients (80 %) and in six MTC patients (75 %). Lesions showing aerobic glycolysis on {sup 18}F-FDG PET were found in 24 of 28 patients (86 %) with corresponding positive results with {sup 68}Ga-DOTA-LAN in 35 % and with {sup 68}Ga-DOTA-TOC in 29 %. The heterogeneous SSTR profile of TC tumour lesions needs to be evaluated using different SSTR PET tracers to characterize more closely the SSTR subtype affinities in patients with progressive TC in order to further stratify therapy with SSTR therapeutics. (orig.)

Angiotensin type 2 receptor (AT2R) and receptor Mas

DEFF Research Database (Denmark)

Villela, Daniel; Leonhardt, Julia; Patel, Neal

2015-01-01

The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striki...

The radioimmunoassay and physiology of somatostatin in the pancreas and gastrointestinal tract.

Science.gov (United States)

McIntosh, C; Arnold, R

1978-05-01

Radioimmunoassays for somatostain have demonstrated that high concentrations of the polypeptide are present in the pancreas and gastrointestinal tract of a number of species. Although measurement in tissue extracts is relatively unproblematic, detection and characterization of somatostatin-like material in plasma has proved technically difficult. Studies of pancreatic somatostatin release in vitro suggest a possible function in the regulation of islet hormone secretion, but the mode of action remains to be elucidated. Although, at present, no clinical relevance can be attributed to the somatostain radioimmunoassay reports of somatostatin secreting tumors and changes in stomach tissue content in patients with ulcer disease indicate a contributory role in the pathophysiology of certain disease states.

Chemokine receptors and cortical interneuron dysfunction in schizophrenia.

Science.gov (United States)

Volk, David W; Chitrapu, Anjani; Edelson, Jessica R; Lewis, David A

2015-09-01

Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; pschizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

Science.gov (United States)

Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

2003-01-01

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA

Pertussis toxin inhibits somatostatin-induced K+ conductance in human pituitary tumor cells

International Nuclear Information System (INIS)

Yamashita, N.; Kojima, I.; Shibuya, N.; Ogata, E.

1987-01-01

The effect of pertussis toxin on somatostatin-induced K + current was examined in dissociated human pituitary tumor cells obtained from two acromegalic patients. Somatostatin-induced hyperpolarization or K + current was observed in 20 of 23 cells in adenoma 1 and 10 of 11 cells in adenoma 2. After treatment with pertussis toxin for 24 h, these responses were completely suppressed (0/14 in adenoma, 1, 0/10 in adenoma 2). Spontaneous action potentials, K + , Na + , and Ca 2+ currents were well preserved after pertussis toxin treatment. When crude membrane fraction was incubated with [ 32 P]NAD, a 41K protein was ADP-ribosylated by pertussis toxin. Hormone release was inhibited by somatostatin and this inhibition was blocked by pertussis toxin treatment

Preliminary PET/CT Imaging with Somatostatin Analogs [68Ga]DOTAGA-TATE and [68Ga]DOTAGA-TOC.

Science.gov (United States)

Satpati, Drishty; Shinto, Ajit; Kamaleshwaran, K K; Sarma, Haladhar Dev; Dash, Ashutosh

2017-12-01

Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs. Herein, the potential of ([ 68 Ga]DOTAGA, Tyr 3 , Thr 8 ) octreotide ([ 68 Ga]DOTAGA-TATE) and ([ 68 Ga]DOTAGA, Tyr 3 ) octreotide ([ 68 Ga]DOTAGA-TOC) as NET imaging agents has been investigated. Amenability of [ 68 Ga]DOTAGA-(TATE/TOC) to kit-type formulation has been demonstrated. Biodistribution studies were carried out in normal rats at 1 h post-injection (p.i.). [ 68 Ga]DOTAGA-(TATE/TOC) PET/CT scans were carried out in patients (70-170 MBq, 1 h p.i.) with histologically confirmed well-differentiated NETs. [ 68 Ga]DOTAGA-TATE exhibited hydrophilicity similar to [ 68 Ga]DOTA-TATE (log P = -3.51 vs -3.69) whereas [ 68 Ga]DOTAGA-TOC was more hydrophilic than [ 68 Ga]DOTA-TOC (log P = -3.27 vs -2.93). [ 68 Ga]DOTAGA-TATE and [ 68 Ga]DOTA-TATE showed almost identical blood and kidney uptake in normal rats whereas significantly fast clearance (p TOC also demonstrated rapid clearance from blood and kidneys (p TOC. The metastatic lesions in NET patients were well identified by [ 68 Ga]DOTAGA-TATE and [ 68 Ga]DOTAGA-TOC. The phenomenal analogy was observed between [ 68 Ga]DOTAGA-TATE and [ 68 Ga]DOTA-TATE as well as between [ 68 Ga]DOTAGA-TOC and [ 68 Ga]DOTA-TOC in biodistribution studies in rats. The good lesion detection ability of the two radiotracers indicates their potential as NET imaging radiotracers.

Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

Energy Technology Data Exchange (ETDEWEB)

Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

1986-06-01

The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

Neurotensin receptors in human neoplasms: high incidence in Ewing's sarcomas.

Science.gov (United States)

Reubi, J C; Waser, B; Schaer, J C; Laissue, J A

1999-07-19

Receptors for regulatory peptides, such as somatostatin or vasoactive intestinal peptide (VIP), expressed at high density by neoplastic cells, can be instrumental for tumor diagnosis and therapy. Little is known about the expression of neurotensin receptors in human tumors. In the present study, 464 human neoplasms of various types were investigated for their neurotensin receptor content by in vitro receptor autoradiography on tissue sections using 125I-[Tyr3]-neurotensin as radioligand. Neurotensin receptors were identified and localized in tumor cells of 11/17 Ewing's sarcomas, 21/40 meningiomas, 10/23 astrocytomas, 5/13 medulloblastomas, 7/24 medullary thyroid cancers and 2/8 small cell lung cancers. They were rarely found in non-small cell lung cancers and breast carcinomas; they were absent in prostate, ovarian, renal cell and hepatocellular carcinomas, neuroendocrine gut tumors, pituitary adenomas, schwannomas, neuroblastomas and lymphomas. When present, the receptors bound with nanomolar affinity neurotensin and acetyl-neurotensin-(8-13), with lower affinity neuromedin N, diethylenetriamine penta-acetic acidneurotensin-(8-13) and SR 48692, but not neurotensin-(1-11). They were all of the NT1 type, without high affinity for levocabastine. Further, in 2 receptor-positive Ewing's sarcomas, neurotensin mRNA was detected by in situ hybridization techniques. Since neurotensin is known to stimulate cell proliferation, the presence of neurotensin receptors in human neoplasia may be of biological relevance, possibly as an integrative part of an autocrine feedback mechanism of tumor growth stimulation.

Tumour uptake of the radiolabelled somatostatin analogue [DOTA0,TYR3]octreotide is dependent on the peptide amount

International Nuclear Information System (INIS)

Jong, M. de; Breeman, W.A.P.; Bernard, B.F.; Gameren, A. van; Bruin, E. de; Bakker, W.H.; Van der Pluijm, M.E.; Krenning, E.P.; Visser, T.J.; Maecke, H.R.

1999-01-01

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr 3 ]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in somatostatin receptor subtype 2 (sst 2 )-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111 In-labelled [DOTA 0 ,Tyr 3 ]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA 0 ,Tyr 3 ]octreotide in sst 2 -positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pancreas) μg. Uptake in the tumour was highest at 0.5 μg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [ 111 In-DTPA 0 ]octreotide (d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound

Identification of the receptors for somatostatin (SST) and cortistatin (CST) in chickens and investigation of the roles of cSST28, cSST14, and cCST14 in inhibiting cGHRH1-27NH2-induced growth hormone secretion in cultured chicken pituitary cells.

Science.gov (United States)

Meng, Fengyan; Huang, Guian; Gao, Shunyu; Li, Juan; Yan, Zhenxin; Wang, Yajun

2014-03-25

Somatostatin receptors (SSTRs) are proposed to mediate the actions of somatostatin (SST) and its related peptide, cortistatin (CST), in vertebrates. However, the identity, functionality, and tissue expression of these receptors remain largely unknown in most non-mammalian vertebrates including birds. In this study, five SSTRs (named cSSTR1, cSSTR2, cSSTR3, cSSTR4, cSSTR5) were cloned from chicken brain by RT-PCR. Using a pGL3-CRE-luciferase reporter system, we demonstrated that activation of each cSSTR expressed in CHO cells by cSST28, cSST14 and cCST14 treatment could inhibit forskolin-induced luciferase activity of CHO cells, indicating the functional coupling of all cSSTRs to Gi protein(s). Interestingly, cSSTR1-4 expressed in CHO cells could be activated by cSST28, cSST14 and cCST14 with high potencies, suggesting that they may function as the receptors common for these peptides. In contrast, cSSTR5 could be potently activated by cSST28 only, indicating that it is a cSST28-specific receptor. Using RT-PCR, wide expression of cSSTRs was detected in chicken tissues including pituitary. In accordance with their expression in pituitary, cSST28, cSST14, and cCST14 were demonstrated to inhibit basal and novel cGHRH1-27NH2-induced GH secretion in cultured chicken pituitary cells dose-dependently (0-10nM) by Western blot analysis, suggesting the involvement of cSSTR(s) common for these peptides in mediating their inhibitory actions. Collectively, our study establishes a molecular basis to elucidate the roles of SST/CST in birds and provide insights into the roles of SST/CST in vertebrates, such as their conserved actions on pituitary. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Somatostatin and serum gastrin in normal subjects and in patients with pernicious anaemia, chronic liver and renal disease

Energy Technology Data Exchange (ETDEWEB)

Le Roith, D; Vinik, A I; Epstein, S; Baron, P; Olkenitzky, M N; Pimstone, B L

1975-09-13

The effects of somatostatin (growth hormone release inhibiting hormone) on basal gastrin were studied in patients suffering from pernicious anaemia and chronic renal and liver disease, and during sequential arginine/insulin-stimulated gastrin release in normal subjects. When basal gastrin concentrations were normal (10-50 pg/ml) in controls and in patients who were in renal and liver failure, somatostatin had no effect on gastrin levels. Raised basal gastrin levels in pernicious anaemia and in 2 cases of chronic renal disease, were significantly inhibited by somatostatin with a half-life (T-half) of 3 to 4 minutes. Arginine infusion caused an insignificant rise in serum gastrin which was unaffected by somatostatin, whereas insulin hypoglycaemia significantly stimulated gastrin release, which was inhibited by somatostatin.

The clinical impact of a combined gamma camera/CT imaging system on somatostatin receptor imaging of neuroendocrine tumours

International Nuclear Information System (INIS)

Hillel, P.G.; Beek, E.J.R. van; Taylor, C.; Lorenz, E.; Bax, N.D.S.; Prakash, V.; Tindale, W.B.

2006-01-01

AIM: With a combined gamma camera/CT imaging system, CT images are obtained which are inherently registered to the emission images and can be used for the attenuation correction of SPECT and for mapping the functional information from these nuclear medicine tomograms onto anatomy. The aim of this study was to evaluate the clinical impact of SPECT/CT using such a system for somatostatin receptor imaging (SRI) of neuroendocrine tumours. MATERIALS AND METHODS: SPECT/CT imaging with 111 In-Pentetreotide was performed on 29 consecutive patients, the majority of whom had carcinoid disease. All SPECT images were first reported in isolation and then re-reported with the addition of the CT images for functional anatomical mapping (FAM). RESULTS: Fifteen of the 29 SPECT images were reported as abnormal, and in 11 of these abnormal images (73%) FAM was found to either establish a previously unknown location (7/11) or change the location (4/11) of at least one lesion. The revised location could be independently confirmed in 64% of these cases. Confirmation of location was not possible in the other patients due to either a lack of other relevant investigations, or the fact that lesions seen in the SPECT images were not apparent in the other investigations. FAM affected patient management in 64% of the cases where the additional anatomical information caused a change in the reported location of lesions. CONCLUSION: These results imply that FAM can improve the reporting accuracy for SPECT SRI with significant impact on patient management

Study of pharmacokinetics and biodistribution of radiolabelled receptor specific peptides in laboratory animals

International Nuclear Information System (INIS)

Laznickova, A.; Laznicek, M.; Trejtnar, F.; Maecke, H.R.; Mather, S.J.

2001-01-01

Somatostatin analogues labelled with different radionuclides could be employed for visualization or treatment of somatostatin receptor-positive tumours. An octapeptide 111 In [DTPA] octreotide is a synthetic radiolabelled somatostatin analogue which is currently in clinical use for detecting small neuroendocrine tumours and metastases not detectable by conventional means. However, several other somatostatin analogues have been under development and testing. The aim of this study was to radiolabel selected somatostatin receptor-binding octapeptides by different radionuclides and to report the results of their biodistribution in rats. The study was focused on the direct labelling of vapreotide (RC-160) with 99m Tc, on the conjugates of octreotide with DFO (desferrioxamine) for labelling with 67 Ga, and on the conjugates of octreotide and TOC with DOTA (tetraazacyclo-dodecane tetraacetic acid) for labelling with 88 Y. In the present study, 88 Y isotope instead of 90 Y was used as a label as 88 Y exhibits a longer half life of decay and emits gamma radiation which can be much more easily detected in biological samples than beta emission. The labelling of octreotide analogues with metal radionuclides using derived bifunctional chelates was simple, straightforward and consistently resulted in high radiochemical purity of the product. On the other hand, the application of the direct labelling method for labelling of RC-160 with 99m Tc was difficult because all procedures had to be made under nitrogen atmosphere and an attainment of high yield proved to be highly dependent on the accurate observation of reaction conditions. The labelling efficiency makes an immediate use of the radiolabelled RC-160 for biological studies impossible and it is necessary to involve the purification step into the labelling procedure. All radiolabelled receptor specific peptides under study exhibited rapid radioactivity clearance from the blood and most organs and tissues. On the other hand

High molecular somatostatin, an interfering factor in radioimmunoassay

International Nuclear Information System (INIS)

Diel, F.; Schneider, E.; Baumann, H.

1977-01-01

Cyclic Tyr 1 -somatostatin (Tyr 1 -SRIF) is radioiodinated by the lactoperoxidase method. Purification is achieved by Sephadex G-25 adsorption chromatography. Specific anti-SRIF serum (FA1) has been raised in rabbits. A dose response curve is obtained in the range of 5 - 5,000 pg per tube using an antiserum dilution of 1:2,000. There is little cross-reaction with linear somatostatin and none with ocytocin, (lys-, arg-) vasopressin, valinomycin, polymyxin, insulin, glucagon, human growth hormone (hGH), and thyrotropin-releasing hormone (TRH). For recovery tests, extraction procedures are necessary. Thin-layer chromatography (TLC) and polyacrylamide-disc-electrophoresis (Disc-PAGE) are performed to identify the presumed high molecular 125 I-Tyr 1 -SRIF associate. This high molecular associate may represent an interfering factor in the radioimmunoassay for cyclic SRIF. (orig./AJ) [de

The influence of somatostatin receptor scintigraphy during preoperative staging of non-functioning pancreatic neuroendocrine tumours

International Nuclear Information System (INIS)

Jilesen, A.P.J.; Hoefnagel, S.J.M.; Busch, O.R.C.; Bennink, R.J.; Gouma, D.J.; Nieveen van Dijkum, E.J.M.

2016-01-01

Aim: To determine whether somatostatin receptor scintigraphy (SRS) influences the preoperative staging and clinical management of non-functioning pancreatic neuroendocrine tumours (NF-pNETs). Materials and methods: All SRS examinations performed between 2002–2013 were selected. Patients with NF-pNET were included if both computed tomography (CT) and SRS was performed during preoperative staging. The diagnostic accuracy of CT and SRS for detecting NF-pNET metastases was analysed. Altered TNM classification and changed clinical management were calculated. Changed management was defined as a change from surgical resection into systemic treatment or vice versa. NF-pNETs were defined as tumours without clinical symptoms of hormonal hypersecretion. Results: Overall, 62 patients with NF-pNET were included with a mean age of 57 years (SD: 12.4) 2 . In 28 patients (45%), CT and SRS were correct and in agreement in the detection of primary tumour/metastases. In 34 patients (55%), one of the techniques was incorrect and therefore, there was no agreement. SRS altered the TNM classification in 14 patients (23%) and clinical management in nine patients (15%). In patients without metastases on CT, SRS detected lymph node metastases in one patient. The sensitivity to detect the primary tumour with CT was 95% and with SRS was 73%. In detecting metastases, the sensitivity and specificity were both 85% for CT versus 80% and 90% for SRS. Conclusion: Overall, CT and SRS were in agreement in the detection of NF-pNET. In NF-pNET without suspicious metastatic lesions on CT, SRS has limited value. SRS may be indicated to confirm lesions suspicious for neuroendocrine tumours metastases. - Highlights: • In 28 patients (45%), CT and SRS were correct and in agreement in the detection of primary tumor/metastases. • In 34 patients (55%) one of the modalities was incorrect and therefore, there was no agreement. • Sensitivity to detect the primary tumor with CT and SRS were 95% versus 73

GH and IGF-I induction by passive immunization of rainbow trout Oncorhynchus mykiss Walbaum using a somatostatin 14 antibody

Science.gov (United States)

Inhibition of the growth axis by somatostatin was studied in juvenile rainbow trout using passive immunization with a previously isolated somatostatin antibody (antiSS-14). Upon subcutaneously injection of laying hens (Gallus domesticus) with conjugated somatostatin-14 (SS-14), the antiSS-14 was iso...

Somatostatin analogue scintigraphy and tuberculosis: case report

International Nuclear Information System (INIS)

Biancheri, I.; Rudenko, B.; Vautrin, P.; Raddoul, J.; Lamfichek, N.; Kantelip, B.; Mantion, G.

2005-01-01

Scintigraphy using a radiolabelled somatostatin analogue (111 In-pentetreotide) is useful in the detection of neuroendocrine tumors. But this radiopharmaceutical accumulates also in solid tumours or in inflammatory diseases such as granulomatosis. We present a case of 111 In-pentetreotide uptake in a tuberculous adenopathy. (author)

Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

Science.gov (United States)

Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

1998-01-01

hippocampal formation. Only calretinin and somatostatin showed an appreciable degree of co-localization with m2 (20% and 15%, respectively). Using retrograde tracing, some of the m2-positive cells in stratum oriens were shown to project to the medial septum, accouting for 38% of all projection neurons. The present results demonstrate that there is a differential distribution of m2 receptor immunoreactivity on the axonal vs the somadendritic membranes of distinct interneuron types and suggest that acetylcholine via m2 receptors may reduce GABA release presynaptically from the terminals of perisomatic inhibitory cells, while it may act to increase the activity of another class of interneuron, which innervates the dendritic region of pyramidal cells.

Design, Synthesis, and Biological Evaluation of 68Ga-DOTA-PA1 for Lung Cancer: A Novel PET Tracer for Multiple Somatostatin Receptor Imaging.

Science.gov (United States)

Liu, Fei; Liu, Teli; Xu, Xiaoxia; Guo, Xiaoyi; Li, Nan; Xiong, Chiyi; Li, Chun; Zhu, Hua; Yang, Zhi

2018-02-05

Most of the radiolabeled somatostatin analogues (SSAs) are specific for subtype somatostatin receptor 2 (SSTR 2 ). Lack of ligands targeting other subtypes of SSTRs, especially SSTR 1, SSTR 3 , and SSTR 5 , limited their applications in tumors of low SSTR 2 expression, including lung tumor. In this study, we aimed to design and synthesize a positron emission tomography (PET) radiotracer targeting multi-subtypes of SSTRs for PET imaging. PA1 peptide and its conjugate with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator or fluorescein isothiocyanate (FITC) at the N-terminal of the lysine position were synthesized. 68 Ga was chelated to DOTA-PA1 to obtain 68 Ga-DOTA-PA1 radiotracer. The stability, lipophilicity, binding affinity, and binding specificity of 68 Ga-DOTA-PA1 and FITC-PA1 were evaluated by various in vitro experiments. Micro-PET imaging of 68 Ga-DOTA-PA1 was performed in nude mice bearing A549 lung adenocarcinoma, as compared with 68 Ga-DOTA-(Tyr3)-octreotate ( 68 Ga-DOTA-TATE). Histological analysis of SSTR expression in A549 tumor tissues and human tumor tissues was conducted using immunofluorescence staining and immunohistochemical assay. 68 Ga-DOTA-PA1 had high radiochemical yield and radiochemical purity of over 95% and 99%, respectively. The radiotracer was stable in vitro in different buffers over a 2 h incubation period. Cell uptake of 68 Ga-DOTA-PA1 was 1.31-, 1.33-, and 1.90-fold that of 68 Ga-DOTA-TATE, which has high binding affinity only for SSTR 2 , after 2 h incubation in H520, PG, and A549 lung cancer cell lines, respectively. Micro-PET images of 68 Ga-DOTA-PA1 showed that the PET imaging signal correlated with the total expression of SSTRs, instead of SSTR 2 only, which was measured by Western blotting and immunofluorescence analysis in mice bearing A549 tumors. In summary, a novel PET radiotracer, 68 Ga-DOTA-PA1, targeting multi-subtypes of SSTRs, was successfully synthesized and was confirmed to be useful for PET

Effect of somatostatin on nonesterified fatty acid levels modifies glucose homeostasis during fasting

International Nuclear Information System (INIS)

Hendrick, G.K.; Frizzell, R.T.; Cherrington, A.D.

1987-01-01

In the 7-days fasted conscious dog, unlike the postabsorptive conscious dog, somatostatin infusion results in decreased levels of nonesterified fatty acids (NEFA) and increased glucose utilization (R d ) even when insulin and glucagon levels are held constant. The aim of this study was to determine whether NEFA replacement in such animals would prevent the increase in R d . In each of three protocols there was an 80-min tracer equilibration period, a 40-min basal period, and a 3-h test period. During the test period in the first protocol saline was infused, in the second protocol somatostatin was infused along with intraportal replacement amounts of insulin and glucagon (hormone replacement), while in the third protocol somatostatin plus the pancreatic hormones were infused with concurrent heparin plus Intralipid infusion. Glucose turnover was assessed using [3- 3 H]glucose. The peripheral levels of insulin, glucagon, and glucose were similar and constant in all three protocols; however, during somatostatin infusion, exogenous glucose infusion was necessary to maintain euglycemia. The NEFA level was constant during saline infusion and decreased in the hormone replacement protocol. In the hormone replacement plus NEFA protocol, the NEFA level did not change during the first 90-min period and then increased during the second 90-min period. After a prolonged fast in the dog, (1) somatostatin directly or indirectly inhibits adipose tissue NEFA release and causes a decrease in the plasma NEFA level, and (2) this decrease in the NEFA level causes an increase in R d

Association of SSTR2 Polymorphisms and Glucose Homeostasis Phenotypes

OpenAIRE

Sutton, Beth S.; Palmer, Nicholette D.; Langefeld, Carl D.; Xue, Bingzhong; Proctor, Alexandria; Ziegler, Julie T.; Haffner, Steven M.; Norris, Jill M.; Bowden, Donald W.

2009-01-01

OBJECTIVE This study evaluated the influence of somatostatin receptor type 2 (SSTR2) polymorphisms on measures of glucose homeostasis in the Insulin Resistance Atherosclerosis Family Study (IRASFS). SSTR2 is a G-protein?coupled receptor that, in response to somatostatin, mediates inhibition of insulin, glucagon, and growth hormone release and thus may affect glucose homeostasis. RESEARCH DESIGN AND METHODS Ten single nucleotide polymorphisms (SNPs) spanning the gene were chosen using a SNP de...

A 12-month phase 3 study of pasireotide in Cushing's disease

DEFF Research Database (Denmark)

Colao, Annamaria; Petersenn, Stephan; Newell-Price, John

2012-01-01

Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5.......Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5....

Somatostatin-immunoreactive senile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques.

Science.gov (United States)

Yamashita, Akiko; Fuchs, Eberhard; Taira, Masato; Yamamoto, Takamitsu; Hayashi, Motoharu

2012-06-01

Previously, we demonstrated decreased expression of somatostatin mRNA in aged macaque brain, particularly in the prefrontal cortex. To investigate whether or not this age-dependent decrease in mRNA is related to morphological changes, we analyzed somatostatin cells in the cerebra of aged Japanese macaques and compared them with those in rats and tree shrews, the latter of which are closely related to primates. Brains of aged macaques, tree shrews, and rats were investigated by immunohistochemistry with special emphasis on somatostatin. We observed degenerating somatostatin-immunoreactive cells in the cortices of aged macaques and tree shrews. Somatostatin-immunoreactive senile plaque-like structures were found in areas 6 and 8 and in the nucleus accumbens of macaques, as well as in the nucleus accumbens and the cortex of aged tree shrews, where amyloid accumulations were observed. Somatostatin degenerations may be related to amyloid accumulations and may play roles in impairments of cognitive functions during aging. © 2012 John Wiley & Sons A/S.

Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry.

Science.gov (United States)

Hörsch, Dieter; Ezziddin, Samer; Haug, Alexander; Gratz, Klaus Friedrich; Dunkelmann, Simone; Krause, Bernd Joachim; Schümichen, Carl; Bengel, Frank M; Knapp, Wolfram H; Bartenstein, Peter; Biersack, Hans-Jürgen; Plöckinger, Ursula; Schwartz-Fuchs, Sabine; Baum, R P

2013-01-01

Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.

Receptor-mediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group.

Science.gov (United States)

Chinol, Marco; Bodei, Lisa; Cremonesi, Marta; Paganelli, Giovanni

2002-04-01

High concentrations of subtype 2 somatostatin tumor receptors (sst(2)) are expressed in numerous tumors, enabling primary and metastatic masses to be localized by scintigraphy after injecting (111)In-labeled somatostatin analogue octreotide. In addition to neuroendocrine tumors, somatostatin receptors have been identified on cancers of the central nervous system, breast, lung, and lymphatic tissue, and the use of radionuclide-labeled somatostatin analogues appeared promising for therapy as well as for diagnosis of such malignancies. The somatostatin analogue [DOTA-(D)Phe(1)-Tyr(3)] octreotide (DOTATOC) possesses favorable characteristics for its potential therapeutic use in that it shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3), high hydrophilicity, stable and facile labeling with (111)In and (90)Y. We began to investigate the potential therapeutic applications of (90)Y DOTATOC in 1997 by performing a thorough dosimetric study in 18 patients who were administered (111)In DOTATOC to estimate the absorbed doses during(90)Y-DOTATOC therapy. Then, we moved on and treated an overall number of 256 patients, mostly recruited in 2 distinct protocols with and without the administration of kidney protecting agents, with (90)Y DOTATOC. No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The MTD per cycle was defined as 5.18 GBq. Objective therapeutic responses were documented in more than 20% of patients in terms of partial and complete responses. The present article reports in details our clinical experience (still ongoing) and outcomes with the use of (90)Y DOTATOC. Copyright 2002, Elsevier Science (USA). All rights reserved.

Identification of type II and type III pyoverdine receptors from Pseudomonas aeruginosa.

Science.gov (United States)

de Chial, Magaly; Ghysels, Bart; Beatson, Scott A; Geoffroy, Valérie; Meyer, Jean Marie; Pattery, Theresa; Baysse, Christine; Chablain, Patrice; Parsons, Yasmin N; Winstanley, Craig; Cordwell, Stuart J; Cornelis, Pierre

2003-04-01

Pseudomonas aeruginosa produces, under conditions of iron limitation, a high-affinity siderophore, pyoverdine (PVD), which is recognized at the level of the outer membrane by a specific TonB-dependent receptor, FpvA. So far, for P. aeruginosa, three different PVDs, differing in their peptide chain, have been described (types I-III), but only the FpvA receptor for type I is known. Two PVD-producing P. aeruginosa strains, one type II and one type III, were mutagenized by a mini-TnphoA3 transposon. In each case, one mutant unable to grow in the presence of the strong iron chelator ethylenediaminedihydroxyphenylacetic acid (EDDHA) and the cognate PVD was selected. The first mutant, which had an insertion in the pvdE gene, upstream of fpvA, was unable to take up type II PVD and showed resistance to pyocin S3, which is known to use type II FpvA as receptor. The second mutant was unable to take up type III PVD and had the transposon insertion in fpvA. Cosmid libraries of the respective type II and type III PVD wild-type strains were constructed and screened for clones restoring the capacity to grow in the presence of PVD. From the respective complementing genomic fragments, type II and type III fpvA sequences were determined. When in trans, type II and type III fpvA restored PVD production, uptake, growth in the presence of EDDHA and, in the case of type II fpvA, pyocin S3 sensitivity. Complementation of fpvA mutants obtained by allelic exchange was achieved by the presence of cognate fpvA in trans. All three receptors posses an N-terminal extension of about 70 amino acids, similar to FecA of Escherichia coli, but only FpvAI has a TAT export sequence at its N-terminal end.

Receptor imaging with a new Tc-99m labelled somatostatin analogue (Tc-99m EDDA-TRYCINE-HYNIC-TOC): first clinical results and comparison with In-111 Dotatoc during radioreceptor therapy with Y-90 Dotatoc

International Nuclear Information System (INIS)

Baum, R.P.; Schmuecking, M.; Fischer, S.; Przetak, C.; Niesen, A.; Maecke, H.R.

2002-01-01

Full text: To evaluate Tc-99m EDDA-TRYCINE-HYNIC-TOC (TET-H-TOC) in patients with somatostatin receptor (SSTR)-positive tumors (staging, pretherapeutic indication for radioreceptor therapy and restaging after therapy) in comparison with In-111 DOTATOC. The Tc-99m labelled somatostatin analogue was synthesized by an optimized procedure in our pharmaceutical lab using lyophilized kits (radiochemical purity by HPLC, TLC > 95 %, product stability in vitro 4 to 6 h). So far, 46 patients (53 examinations) were studied after injection of 580-890 MBq (median 673 MBq) TET-H-TOC. The histologically proven tumors were endocrine neoplasias, renal carcinomas, bronchial carcinoma, mesothelioma and malignant fibrous histiocytoma. The imaging protocol consisted of whole-body scans and planar images of the tumor region (15 min, 1 h, 2 h, 4 h, 8 h, 24 h p.i.) and additionally SPECT-images (1 h and 4 h p.i.). For semi-quantitative assessment, individual regions of interest (ROI) were drawn in order to generate time-activity curves and to calculate tumor-to-tissue/background ratios which were compared by visual grading (scale 0 to 3+). Furthermore, pharmacokinetic analyses were carried out (radioactivity kinetics in plasma and urine). In some selected patients, image fusion of the whole-body scans was performed with CT and/or MRT and/or PET using a HERMES computer. 7 out of 46 patients showed an intense tracer accumulation in the SSTR-positive tumors (visual 3+, tumor / background ratio >2,5). In these patients, radioreceptor therapy was carried out using Y-90 DOTATOC (simultaneous injection of 150 MBq In-111 DOTATOC). All pretherapeutic scans with the Tc-99m labelled ligand (4 h p.i.) showed a similar overall pattern of biodistribution and tumor uptake in comparison to the therapy scans with In-111 / Y-90 DOTATOC 24 h p.i. The Tc-99m EDDA-HYNIC-TOC scans (incl. SPECT) offered superior imaging properties with earlier tumor visualization (all lesions were detected 1 h p.i.) as compared

Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands

DEFF Research Database (Denmark)

Poulsen, Steen Seier

1984-01-01

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output......, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited...... growth factor and bicarbonate from Brunner's glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner's gland secretion is suggested....

Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma.

Science.gov (United States)

Müssig, K; Gallwitz, B; Honegger, J; Strasburger, C J; Bidlingmaier, M; Machicao, F; Bornemann, A; Ranke, M B; Häring, H-U; Petersenn, S

2007-03-01

Gigantism is rare with the majority of cases caused by a growth hormone (GH)-secreting pituitary adenoma. Treatment options for GH-secreting pituitary adenomas have been widened with the availability of long-acting dopamine agonists, depot preparations of somatostatin analogues, and recently the GH receptor antagonist pegvisomant. A 23-year-old male patient presented with continuous increase in height during the past 6 years due to a GH-secreting giant pituitary adenoma. Because of major intracranial extension and failure of octreotide treatment to shrink the tumour, the tumour was partially resected by a trans-frontal surgical approach. At immunohistochemistry, the tumour showed a marked expression of GH and a sparsely focal expression of prolactin. Somatostatin receptors (sst) 1-5 were not detected. Tumour tissue weakly expressed dopamine receptor type 2. The Gs alpha subunit was intact. Conversion from somatostatin analogue to pegvisomant normalized insulin-like-growth-factor-I (IGF-I) levels and markedly improved glucose tolerance. Pegvisomant is a potent treatment option in patients with pituitary gigantism. In patients who do not respond to somatostatin analogues, knowledge of the SST receptor status may shorten the time to initiation of pegvisomant treatment.

Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications

Directory of Open Access Journals (Sweden)

Meike eKörner

2012-12-01

Full Text Available Peptide hormones of the glucagon-like peptide (GLP family play an increasing clinical role, such as GLP-1 in diabetes therapy. Moreover, GLP receptors are over-expressed in various human tumor types and therefore represent molecular targets for important clinical applications. In particular, virtually all benign insulinomas highly over-express GLP-1 receptors (GLP-1R. Targeting GLP-1R with the stable GLP-1 analogs 111In-DOTA/ DPTA-exendin-4 offers a new approach to successfully localize these small tumors. This non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. Malignant insulinomas, in contrast to their benign counterparts, express GLP-1R in only one third of the cases, while they more often express the somatostatin type 2 receptors. Importantly, one of the two receptors appears to be always expressed in malignant insulinomas. The GLP-1R overexpression in selected cancers is worth to be kept in mind with regard to the increasing use of GLP-1 analogs for diabetes therapy. While the functional role of GLP-1R in neoplasia is not known yet, it may be safe to monitore patients undergoing GLP-1 therapy carefully.

Regulation of ATP-sensitive K+ channels in insulinoma cells: Activation by somatostatin and protein kinase C and the role of cAMP

International Nuclear Information System (INIS)

De Weille, J.R.; Schmid-Antomarchi, H.; Fosset, M.; Lazdunski, M.

1989-01-01

The actions of somatostatin and of the phorbol ester 4β-phorbol 12-myristate 13-acetate (PMA) were studied in rat insulinoma (RINm5F) cells by electrophysiological and 86 Rb + flux techniques. Both PMA and somatostatin hyperpolarize insulinoma cells by activating ATP-sensitive K + channels. The presence of intracellular GTP is required for the somatostatin effects. PMA- and somatostatin-induced hyperpolarization and channel activity are inhibited by the sulfonylurea glibenclamide. Glibenclamide-sensitive 86 Rb + efflux from insulinoma cells is stimulated by somatostatin in a dose-dependent manner (half maximal effect at 0.7 nM) and abolished by pertussis toxin pretreatment. Mutual roles of a GTP-binding protein, of protein kinase C, and of cAMP in the regulation of ATP-sensitive K + channels are discussed

In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours - impact of peptide mass

International Nuclear Information System (INIS)

Velikyan, Irina; Sundin, Anders; Eriksson, Barbro; Lundqvist, Hans; Soerensen, Jens; Bergstroem, Mats; Langstroem, Bengt

2010-01-01

Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [ 68 Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [ 68 Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 μg of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [ 68 Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. Results: [ 68 Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 μg of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Discussion: Three sequential PET-CT examinations using 68 Ga-based tracer was carried out in 1 day. The use of high SRA [ 68 Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [ 68 Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management.

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

DEFF Research Database (Denmark)

Engelstoft, Maja S; Park, Won-Mee; Sakata, Ichiro

2013-01-01

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro......, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi....../o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi...

General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Treatment Options for Pancreatic Neuroendocrine Tumors

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors)

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

Stages of Pancreatic Neuroendocrine Tumors

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... also called nuclear magnetic resonance imaging (NMRI). Somatostatin receptor scintigraphy : A type of radionuclide scan that may ...

An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors.

Science.gov (United States)

Gabriel, Michael; Decristoforo, Clemens; Donnemiller, Eveline; Ulmer, Hanno; Watfah Rychlinski, Christine; Mather, Stephen J; Moncayo, Roy

2003-05-01

The aim of this study was to compare the imaging abilities of the recently developed somatostatin analog, (99m)Tc-hydrazinonicotinyl-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC [(99m)Tc-TOC]), with (111)In-diethylenediaminepentaacetic acid-D-Phe(1)-octreotide ((111)In-OCT [Octreoscan]) in patients undergoing routine somatostatin receptor (SSTR) scintigraphy. Forty-one patients (20 men, 21 women; age range, 29-75 y; mean age, 56.7 y) with either histologically proven or biologically and clinically suspected endocrine tumors were enrolled in the study. Four groups were distinguished: (a) patients being evaluated for the detection and localization of neuroendocrine tumors (n = 6), (b) tumor staging (n = 19), (c) patients being investigated to determine the SSTR status of tumor lesions (n = 11), and (d) patient follow-up studies (n = 5). Each patient received a mean activity of 150 MBq (111)In-OCT and 350-400 MBq (99m)Tc-TOC. Scintigraphy with (99m)Tc-TOC was performed 4 h after injection and scintigraphy with (111)In-OCT was performed 4 and 24 h after injection. SPECT studies of areas of interest were performed 4 h after injection for both tracers as well as at 24 h after injection for (111)In-OCT. The time interval between the studies using each tracer ranged from 2 to 22 d (mean interval, 9.3 d). (111)In-OCT and (99m)Tc-TOC showed an equivalent scan result in 32 patients (78%), 9 cases showed discrepancies (22%), false-negative results with (111)In-OCT were seen in 6 cases (14.6%), whereas (99m)Tc-TOC was false-positive in 2 cases (4.9%). (111)In-OCT was true-negative in both cases. The false-positive findings of the (99m)Tc-TOC studies were caused by nonspecific uptake in the bowel. In 1 case, (99m)Tc-TOC correctly identified a metastasis in the lumbar spine but both scan results were false-positive because of an inflammatory process. In 21 patients with SSTR-expressing tumors, the semiquantitative region-of-interest analysis showed that (99m)Tc-TOC achieved higher tumor

Chimeric opioid peptides: Tools for identifying opioid receptor types

International Nuclear Information System (INIS)

Xie, G.; Miyajima, A.; Yokota, T.; Arai, K.; Goldstein, A.

1990-01-01

The authors synthesized several chimeric [125J-labelled] peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the κ opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surface or membrane preparation, these peptides could still bind specifically to the monoclonal antibody. These chimeric peptides should be useful for isolating μ, δ, and κ opioid receptors and for identifying opioid receptors on transfected cells in expression cloning procedures. The general approach using chimeric peptides should be applicable to other peptide receptors

Receptor PET/CT for determining the somatostatin receptor status of neuroendocrine tumors before and after peptide receptor radionuclide therapy (PRRT): Clinical experience after 1,500 studies

International Nuclear Information System (INIS)

Baum, R.P.; Prasad, V.; Leonhardi, J.; Kroeger, R.; Wortmann, R.; Mueller, D.

2007-01-01

Full text: The octapeptide [DOTA]-1-Nal3-octreotide (DOTA-NOC) has 3 to 4 times higher binding affinity to sstr2 than DOTATOC (Wild 2003). We labeled this peptide with the Ga-68 (t1/2 68 min) and used it in pts with metastatic NET before/after PRRT for evaluating the sstr status by semiquantitative PET/CT imaging. Methods: Ga-68 was eluted from a Ge-68/Ga-68 generator using 0.1 M HCl. Following purifications, Ga-68 was eluted into a labeling vial containing 0.05 mg DOTA-NOC. Radiolabeling yields of >80% were achieved within 15 min at >95C. After purification (C18 cartridge) and a final elution, 370-700 MBq of Ga-68 DOTA-NOC were obtained with 100% radiochemical purity within 20 min (about 70% yield). Results: 1,500 PET/CT studies were performed in pts with histologically proven NET and progressive metastases before and after PRRT. Acquisition was started 20-270 min after injection of a mean of 100 MBq (46-260 MBq) Ga-68 DOTA-NOC using an LSO-based PET/CT (biograph DUO, Siemens). SUV were determined for all tumor lesions and normal tissues. SUV in metastases was as high as 152 whereas normal tissue was in the range of 0.4 (lung) to 33 (spleen). Outstanding PET/CT images of all known tumor lesions and in addition very small lymph node and bone metastases (<5 mm) were easily visualized as early as 20 min p.i. Clearly more lesions were detected as compared to Tc-99m EDDA-HYNIC-TOC or In-111 DOTA-NOC SPECT or as seen on CT or MRI images (especially regarding lymph node metastases, bone lesions and unknown primaries). Conclusions: Molecular receptor PET/CT imaging using the Ga-68-labeled somatostatin analogue DOTA-NOC detects neuroendocrine tumor metastases with very high diagnostic sensitivity and specificity. Semiquantitative uptake measurements (SUV) allow predicting the tumor uptake of Y-90 or Lu-177- labeled peptides before PRRT and are highly useful for therapy control to determine the 'molecular tumor response' which can precede the morphologic responses by months

Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel

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Kang Zhang

2017-05-01

Full Text Available The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca2+ channel is still unclear. Considering both sigma-1 receptors and N-type Ca2+ channels are involved in intracellular calcium homeostasis and neurotransmission, we undertake studies to explore the possible interaction between these two proteins. In the experiment, we confirmed the expression of the sigma-1 receptors and the N-type calcium channels in the cholinergic interneurons (ChIs in rat striatum by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR and immunofluorescence staining. N-type Ca2+ currents recorded from ChIs in the brain slice of rat striatum was depressed when sigma-1 receptor agonists (SKF-10047 and Pre-084 were administrated. The inhibition was completely abolished by sigma-1 receptor antagonist (BD-1063. Co-expression of the sigma-1 receptors and the N-type calcium channels in Xenopus oocytes presented a decrease of N-type Ca2+ current amplitude with an increase of sigma-1 receptor expression. SKF-10047 could further depress N-type Ca2+ currents recorded from oocytes. The fluorescence resonance energy transfer (FRET assays and co-immunoprecipitation (Co-IP demonstrated that sigma-1 receptors and N-type Ca2+ channels formed a protein complex when they were co-expressed in HEK-293T (Human Embryonic Kidney -293T cells. Our results revealed that the sigma-1 receptors played a negative modulation on N-type Ca2+ channels. The mechanism for the inhibition of sigma-1 receptors on

Union of {sup 99m} Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer; Union del {sup 99m} Tc-HYNIC-TOC a los receptores de somatostatina en celulas de cancer de pancreas

Energy Technology Data Exchange (ETDEWEB)

Rodriguez C, J. [Facultad de Medicina, UAEM, 50000 Toluca, Estado de Mexico (Mexico); Ramirez I, M.T. [INCMNSZ, Vasco de Quiroga Num. 15, Tlalpan, 14000 Mexico D.F. (Mexico); Ferro F, G.; Pedraza L, M. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

2005-07-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide {sup 99m}Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with {sup 99m}Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The {sup 99m}Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide {sup 99m}Tc-UBI and the {sup 99m}TcO{sub 4}. The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the {sup 99m}Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the {sup 99m

Union of {sup 99m} Tc-HYNIC-TOC at the somatostatin receptors in cells of pancreas cancer; Union del {sup 99m} Tc-HYNIC-TOC a los receptores de somatostatina en celulas de cancer de pancreas

Energy Technology Data Exchange (ETDEWEB)

Rodriguez C, J [Facultad de Medicina, UAEM, 50000 Toluca, Estado de Mexico (Mexico); Ramirez I, M T [INCMNSZ, Vasco de Quiroga Num. 15, Tlalpan, 14000 Mexico D.F. (Mexico); Ferro F, G; Pedraza L, M [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)

2005-07-01

The radiation toxic effects have been used in therapy however much 50 years. The absorbed radiation dose can be determined at cellular level using cancerous cell cultures. If the deposited In vitro radiation dose coming from similar activities of several therapeutic radiopharmaceuticals it can compare it will be possible to choose the therapeutic radiopharmaceutical that it offers better dosimetric characteristics for the patient. The objective of this original investigation was to determine the union percentage of the octreotide {sup 99m}Tc-HYNlC-TOC to the somatostatin receivers in cells of cancer pancreas as well as the internalization, externalization and cellular viability. It was used the octapeptide, (octreotide, TOC) labelled with {sup 99m}Tc by means of the HYNIC chelating agent (6-hydrazine pyridine-3-carboxylic acid) and 3 cellular lines of murine pancreas cancer (AR42J), of cancer of human pancreas (CAPAN) and of one negative cellular line for somatostatin receivers (WRL-68). The {sup 99m}Tc-HYNIC-TOC was compared against two negative proofs for somatostatin receivers: the peptide {sup 99m}Tc-UBI and the {sup 99m}TcO{sub 4}. The cellular lines were conserved in the synthetic media Dulbecco-Eagle. After 2, 4 and 24 h of exhibition to the radiation, the cells are picked up and its are determined the viability by count in a Neubauer camera using tripan blue. In the same times it was calculated the union percentage of the radiopharmaceutical to the cells and the internalization (union to the cytoplasm) and the externalization (union to membrane receivers). With those figures it was calculated the absorbed radiation dose at cellular level. Results: At 4 hours the union percentage of the {sup 99m}Tc-HYNlC-TOC to the AR42-J cells was 6.83 times greater than for the WRL-68 control cells of human papilloma, (without receivers of the somatostatin) and for the CAPAN them 4 times greater than for the same cells used as negative control, for the case of the {sup 99m

Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β--emitting 177Lu in human pancreatic adenocarcinoma cells

International Nuclear Information System (INIS)

Nayak, Tapan K.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Prossnitz, Eric R.; Stabin, Michael G.; Atcher, Robert W.

2007-01-01

Introduction: Advance clinical cancer therapy studies of patients treated with somatostatin receptor (sstr)-targeted [DOTA 0 -Tyr 3 ]octreotide (DOTATOC) labeled with low-linear-energy-transfer (LET) β - -emitters have shown overall response rates in the range of 15-33%. In order to improve outcomes, we sought to compare the therapeutic effectiveness of sstr-targeted high-LET α-emitting 213 Bi to that of low-LET β - -emitting 177 Lu by determining relative biological effectiveness (RBE) using the external γ-beam of 137 Cs as reference radiation. Methods: Sstr-expressing human pancreatic adenocarcinoma Capan-2 cells and A549 control cells were used for this study. The effects of different radiation doses of 213 Bi and 177 Lu labeled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and sstr-targeted DOTATOC were investigated with a clonogenic cell survival assay. Apoptosis was measured using the Cell Death Detection ELISA PLUS 10x kit. Results: Using equimolar DOTATOC treatment with concurrent irradiation with a 137 Cs source as reference radiation, the calculated RBE of [ 213 Bi]DOTATOC was 3.4, as compared to 1.0 for [ 177 Lu]DOTATOC. As measured in terms of absorbance units, [ 213 Bi]DOTATOC caused a 2.3-fold-greater release of apoptosis-specific mononucleosomes and oligonucleosomes than [ 177 Lu]DOTATOC at the final treatment time of 96 h (P 213 Bi]DOTATOC is therapeutically more effective in decreasing survival than is [ 177 Lu]DOTATOC in human pancreatic adenocarcinoma cells due to its comparatively higher RBE

Chimeric opioid peptides: tools for identifying opioid receptor types.

OpenAIRE

Xie, G X; Miyajima, A; Yokota, T; Arai, K; Goldstein, A

1990-01-01

We synthesized several chimeric peptides in which the N-terminal nine residues of dynorphin-32, a peptide selective for the kappa opioid receptor, were replaced by opioid peptides selective for other opioid receptor types. Each chimeric peptide retained the high affinity and type selectivity characteristic of its N-terminal sequence. The common C-terminal two-thirds of the chimeric peptides served as an epitope recognized by the same monoclonal antibody. When bound to receptors on a cell surf...

Preliminary study on the inhibition of nuclear internalization of Tat peptides by conjugation with a receptor-specific peptide and fluorescent dyes

Science.gov (United States)

Shen, Duanwen; Liang, Kexiang; Ye, Yunpeng; Tetteh, Elizabeth; Achilefu, Samuel

2006-02-01

Numerous studies have shown that basic Tat peptide (48-57) internalized non-specifically in cells and localized in the nucleus. However, localization of imaging agents in cellular nucleus is not desirable because of the potential mutagenesis. When conjugated to the peptides that undergo receptor-mediated endocytosis, Tat peptide could target specific cells or pathologic tissue. We tested this hypothesis by incorporating a somatostatin receptor-avid peptide (octreotate, Oct) and two different fluorescent dyes, Cypate 2 (Cy2) and fluorescein 5'-carboxlic acid (5-FAM), into the Tat-peptide sequence. In addition to the Cy2 or 5-FAM-labeled Oct conjugated to Tat peptide (Tat) to produce Tat-Oct-Cypate2 or Tat-Oct-5-FAM, we also labeled the Tat the Tat peptide with these dyes (Tat-Cy2 and Tat-5-FAM) to serve as positive control. A somatostatin receptor-positive pancreatic tumor cell line, AR42J, was used to assess cell internalization. The results show that Tat-5-FAM and Tat-Cypate2 localized in both nucleus and cytoplasm of the cells. In contrast to Tat-Oct-Cypate2, which localized in both the cytoplasm and nucleus, Tat-Oct-5-FAM internalized in the cytoplasm but not in the nucleus of AR42J cells. The internalizations were inhibited by adding non-labeled corresponding peptides, suggesting that the endocytoses of each group of labeled and the corresponding unlabeled compounds occurred through a common pathway. Thus, fluorescent probes and endocytosis complex between octreotate and somatostatin receptors in cytoplasm could control nuclear internalization of Tat peptides.

Somatostatin ontogenesis in the gastrointestinal and pancreatic tract: study in normal rats and during a induced diabetes in neonates rats

International Nuclear Information System (INIS)

Cunha, M.C.

1980-01-01

The ontogenic studies of somatostatin of pancreas, ileum and duodenum of Wistar rats and the rats with induced diabetes were done. The radioimmunologic method to dose the somatostatin was used. (L.M.J.)

Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers.

Science.gov (United States)

Imhof, Anna; Brunner, Philippe; Marincek, Nicolas; Briel, Matthias; Schindler, Christian; Rasch, Helmut; Mäcke, Helmut R; Rochlitz, Christoph; Müller-Brand, Jan; Walter, Martin A

2011-06-10

To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers. In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [(90)Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface [(90)Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. Overall, 1,109 patients received 2,472 cycles of [(90)Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P TOC treatment in a large cohort. Response to [(90)Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [(90)Y-DOTA]-TOC treatment and occurrence of renal toxicity.

C-Type Lectin Receptors in Asthma

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Sabelo Hadebe

2018-04-01

Full Text Available Asthma is a heterogeneous disease that affects approximately 300 million people worldwide, largely in developed countries. The etiology of the disease is poorly understood, but is likely to involve specific innate and adaptive responses to inhaled microbial components that are found in allergens. Fungal-derived allergens represent a major contributing factor in the initiation, persistence, exacerbation, and severity of allergic asthma. C-type lectin like receptors, such as dectin-1, dectin-2, DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, and mannose receptor, recognize many fungal-derived allergens and other structurally similar allergens derived from house dust mites (HDM. In some cases, the fungal derived allergens have been structurally and functionally identified alongside their respective receptors in both humans and mice. In this review, we discuss recent understanding on how selected fungal and HDM derived allergens as well as their known or unknown receptors shape allergic airway diseases.

Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

Directory of Open Access Journals (Sweden)

Eva Ludvigsen

2011-01-01

Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

Role of 68Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study

International Nuclear Information System (INIS)

Prasad, Vikas; Sainz-Esteban, Aurora; Arsenic, Ruza; Ploeckinger, Ursula; Denecke, Timm; Pape, Ulrich-Frank; Pavel, Marianne; Pascher, Andreas; Kuehnen, Peter; Blankenstein, Oliver

2016-01-01

To explore the role of 68 Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. This explorative study suggests that SR PET in combination with CT may play a significant role in the detection

In vivo binding of [{sup 68}Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours - impact of peptide mass

Energy Technology Data Exchange (ETDEWEB)

Velikyan, Irina [Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala (Sweden); Uppsala Applied Science Lab, GEMS PET Systems, GE Healthcare, SE-752 28 Uppsala (Sweden); Sundin, Anders [Department of Radiology, Karolinska University Hospital, SE-171 76 Stockholm (Sweden); Eriksson, Barbro [Department of Endocrine Oncology, Uppsala University Hospital, SE-751 85 Uppsala (Sweden); Lundqvist, Hans [Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala (Sweden); Soerensen, Jens [Department of Medicinal Sciences, Clinical Physiology and Nuclear Medicine, Uppsala University Hospital, SE-751 85 Uppsala (Sweden); Bergstroem, Mats [Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala (Sweden); Langstroem, Bengt [Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala (Sweden)], E-mail: langstrom@biorg.uu.se

2010-04-15

Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [{sup 68}Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [{sup 68}Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 {mu}g of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [{sup 68}Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. Results: [{sup 68}Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 {mu}g of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Discussion: Three sequential PET-CT examinations using {sup 68}Ga-based tracer was carried out in 1 day. The use of high SRA [{sup 68}Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [{sup 68}Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management.

Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

DEFF Research Database (Denmark)

Damm, P; Binder, C

1989-01-01

Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... or with HbA1c. In conclusion, no major abnormalities in glucocorticoid receptor binding characteristics could be demonstrated in Type 1 diabetes mellitus....... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0...

Gastroenteropancreatic Neuroendocrine Tumors: Standardizing Therapy Monitoring with 68Ga-DOTATOC PET/CT Using the Example of Somatostatin Receptor Radionuclide Therapy

Directory of Open Access Journals (Sweden)

Wolfgang Luboldt

2010-11-01

Full Text Available The purpose of this study was to standardize therapy monitoring of hepatic metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs during the course of somatostatin receptor radionuclide therapy (SRRT. In 21 consecutive patients with nonresectable hepatic metastases of GEP-NETs, chromogranin A (CgA and 68Ga-DOTATOC PET/CT were compared before and after the last SRRT. On 68Ga-DOTATOC PET/CT, the maximum standard uptake values (SUVmax of normal liver and hepatic metastases were calculated. In addition, the volumes of hepatic metastases (volume of interest [VOI] were measured using four cut-offs to separate normal liver tissue from metastases (SUVmax of the normal liver plus 10% [VOIliver+10%], 20% [VOIliver+20%], 30% [VOIliver+30%] and SUV = 10 [VOI10SUV]. The SUVmaxof the normal liver was below 10 (7.2 ± 1.3 in all patients and without significant changes. Overall therapy changes (Δ per patient (mean [95% CI] were statistically significant with p < .01 for ΔCgA = −43 (−69 to −17, ΔSUVmax = −22 (−29 to −14, and ΔVOI10SUV = −53 (−68 to −38% and significant with p < .05 for ΔVOIliver+10% = −29 (−55 to −3%, ΔVOIliver+20% = −32 (−62 to −2 and ΔVOIliver+30% = −37 (−66 to −8. Correlations were found only between ΔCgA and ΔVOI10SUV (r = .595; p < .01, ΔSUVmax and ΔVOI10SUV (0.629, p < .01, and SUVmax and ΔSUVmax (r = .446; p < .05. 68Ga-DOTATOC PET/CT allows volumetric therapy monitoring via an SUV-based cut-off separating hepatic metastases from normal liver tissue (10 SUV recommended.

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-dPhe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

International Nuclear Information System (INIS)

Roesch, F.; Brockmann, J.; Koehle, M.

1999-01-01

[ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide ([ 90 Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was administered at two different peptide concentrations, namely 2 and 100 μg peptide per m 2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [ 86 Y]DOTA-dPhe 1 -Tyr 3 -octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide injected. For the 100 μg/m 2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide, respectively. The average effective dose equivalent amounted to 0.23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [ 90 Y]DOTA-dPhe 1 -Tyr 3 -octreotide in patients with somatostatin receptor-expressing tumours. (orig.)

In vitro effect of Δ9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2

International Nuclear Information System (INIS)

Rettori, V.; Aguila, M.C.; McCann, S.M.; Gimeno, M.F.; Franchi, A.M.

1990-01-01

Previous in vivo studies have shown that Δ 9 -tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E 2 (PGE 2 ) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE 2 suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE 2 synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release

Somatostatin analogues labelled with 99mTc

International Nuclear Information System (INIS)

Obenaus, E.; Crudo, J.; Edreira, M.; Viaggi, M.; De Castiglia, S.G.

2001-01-01

The aim of the present work was to study the biological and radiochemical behaviour of two somatostatin analogues, the RC-160 and Tyr3Octreotide(TOC) peptides when labelling with 99m Tc by two methods: direct and indirect using S-benzoyl- mercaptoacetyl triglycine (MAG-3) and hydrazinonicotinamide (HYNIC) as chelating agents. RC-160 was labelled with 125I (30% labelling yield) in order to examine its receptor specificity and to study the biodistribution in normal animals. A total binding of 30% and a non specific binding lower than 10% was obtained. On the other hand, the RC-160 was labelled with 99m Tc by a direct method (70% labelling yield), using sodium ascorbate and dithionite in order to reduce the peptide and 99m Tc, respectively. The synthesis of RC-160 with S-benzoyl MAG-3 and TOC with HYNIC, for labelling with 99m Tc are also described. The conjugates were prepared on a small scale and labelled with the radionuclide using tricine as co-ligands for HYNIC conjugates. Chromatographic studies were performed using HPLC system and radiochemical purities higher than 75% and 95% were obtained respectively. Biodistributions studies in normal Wistar rats were performed and results were correlated with chromatographic and protein binding properties. Lower lipophilicity of the labelled conjugates resulted in a higher renal excretion. HYNIC-TOC complex showed promising results when labelling with 99m Tc using tricine as co-ligand although higher stability should be found for ternary co-ligands compared to tricine. (author)

Macrophage galactose-type C-type lectin receptor for DC targeting of antitumor glycopeptide vaccines

DEFF Research Database (Denmark)

Nuti, M; Zizzari, I; Napoletano, C

2011-01-01

e13528 Background: Dendritic cells (DCs) are the most potent antigen presenting cells and are employed in cancer vaccination. Several receptors are being studied in order to identif strategies to increase DCs activating capacity. The C-type lectin macrophage galactose type C-type lectin (MGL...... of IFNg and IL-2 secretion by both CD8 and CD4 T cells. CONCLUSIONS: These results demonstrate that MGL engagement profoundly affects DC plasticity inducing and directing a Th1 immune response. Moreover, MGL receptor expressed on human DC can be targeted by glycopeptide based vaccines with adjuvant...

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly

Energy Technology Data Exchange (ETDEWEB)

Shen, Ming; Zhang, Qilin [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Liu, Wenjuan; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yang, Yeping [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Wang, Meng [Fudan University, Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Shanghai (China); Soochow University, Division of Endocrinology, the Second Affiliated Hospital, Suzhou (China); Zhu, Jingjing [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Neuropathology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Zhao, Yao; Wang, Yongfei [Fudan University, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Shanghai (China); Shanghai Pituitary Tumor Center, Shanghai (China); Yao, Zhenwei [Shanghai Pituitary Tumor Center, Shanghai (China); Fudan University, Department of Radiology, Huashan Hospital, Shanghai Medical College, Shanghai (China); Lu, Yun [Fudan University, Department of Nuclear Medicine, Huashan Hospital, Shanghai Medical College, Shanghai (China)

2016-11-15

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly. (orig.)

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly

International Nuclear Information System (INIS)

Shen, Ming; Zhang, Qilin; Liu, Wenjuan; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yang, Yeping; Wang, Meng; Zhu, Jingjing; Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Zhao, Yao; Wang, Yongfei; Yao, Zhenwei; Lu, Yun

2016-01-01

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly. (orig.)

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly.

Science.gov (United States)

Shen, Ming; Zhang, Qilin; Liu, Wenjuan; Wang, Meng; Zhu, Jingjing; Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yao, Zhenwei; Lu, Yun; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Yang, Yeping; Zhao, Yao; Wang, Yongfei

2016-11-01

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly.

PET/CT using 18-fluoro dihydroxyphenylalanine in neuroendocrine tumours according to their types

International Nuclear Information System (INIS)

Balogova, S.; Noskovicova, L.

2016-01-01

Amino acid analogue 18-fluoro dihydroxyphenylalanine (FDOPA) is a tracer of catecholamine metabolic pathway for functional imaging with positron emission tomography (PET). Diagnostic target for functional imaging of NET is a pathologically increased catecholamine or glucose metabolism or pathologically increased expression of somatostatin receptors, variably present according to type of NET. Due to heterogeneity of origin and biological properties of NET, there is no universal radiopharmaceutical permitting sufficient diagnostic accuracy of functional imaging NET of all types and of all grades of differentiation. However, the accurate staging is essential for optimal therapeutic management of NET. Diagnostic accuracy of functional nuclear medicine imaging relies upon the expression of diagnostic target by NET lesions, upon optimal choice of the tracer of diagnostic target and upon the technical performance of imaging. Commonly available comparators of FDOPA in NET are labelled somatostatin analogues for conventional scintigraphy and for PET, tracer of catecholamine synthesis and storage into secretory granules for conventional scintigraphy (123I-metaiodobenzylguanidine) and marker of glucose metabolism for PET (18-flu deoxyglucose). FDOPA shows better performances than comparators in medullary thyroid cancer, in well-differentiated catecholamine producing NETs, in well differentiated NET of mid-gut origin and in case of congenital hyperinsulinism in infants. Article summarises the documented indications of FDOPA according to type of NET and for each of them proposes currently the most performing sequence of functional imaging permitting the most accurate staging. (author)

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide

International Nuclear Information System (INIS)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna; Traub-Weidinger, Tatjana; Widmann, Gerlig

2013-01-01

The aim of this study was to evaluate the impact of 68 Ga-labelled DOTA 0 -lanreotide ( 68 Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or 68 Ga-labelled DOTA 0 ,Tyr 3 -octreotide ( 68 Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or 68 Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent 68 Ga-DOTA-LAN PET to evaluate a treatment option with 90 Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. 68 Ga-DOTA-LAN and 68 Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of 68 Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p 68 Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p 68 Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV max ) regarding the primary tumour in 25 patients (p 68 Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. 68 Ga-DOTA-TOC revealed more tumour sites than 68 Ga-DOTA-LAN (106 vs 53). The tumour to background ratios for tumour and liver calculated from SUV max measurements were significantly higher for 68 Ga-DOTA-TOC than 68 Ga

Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS

DEFF Research Database (Denmark)

Leonhardt, Julia; Villela, Daniel C.; Teichmann, Anke

2017-01-01

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may in...

Two peptide receptor ligands (99m)Tc-EDDA/HYNIC-Tyr(3)-octreotide and (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin for scintigraphy of medullary thyroid carcinoma.

Science.gov (United States)

Kosowicz, Jerzy; Mikołajczak, Renata; Czepczyński, Rafał; Ziemnicka, Katarzyna; Gryczyńska, Maria; Sowiński, Jerzy

2007-10-01

Somatostatin and gastrin receptors are overexpressed in medullary thyroid carcinoma (MTC) cells; hence, both of them are potential targets for peptide receptor scintigraphy and radiotherapy. Therefore, the aim of our study was to assess the clinical value of two technetium-99m-labeled peptides, a new gastrin analog, the EDDA/HYNIC-(D)Glu-octagastrin and a somatostatin analog, EDDA/HYNIC-Tyr(3)-octreotide (EDDA/HYNIC-TOC) for scintigraphy in patients with MTC to detect recurrences and metastases and select patients for peptide receptor radiotherapy. Thirty (30) patients, 20 females and 10 males, 22-83 years of age (mean, 52.7) with the diagnosis of MTC in different stages of the disease (preoperative, postsurgery, remission, recurrence, or metastatic disease) were included in this study. Before surgery, in all patients serum calcitonin concentrations were elevated. The diagnosis of MTC was confirmed in all cases by histopathology of the removed tumor and immunohistochemical staining giving positive reactions for calcitonin and chromogranin A. Imaging studies using (99m)Tc-EDDA/HYNIC-TOC and a new minigastrin analog, (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin, were performed in each patient and the results compared with each other and with other imaging methods. Scans of the whole body, head, neck, and chest were performed 2 and 4 hours after injections of the tracer, 500-600 MBq in each case, using a double-head Varicam (Elscint, Israel) gamma camera. (99m)Tc-EDDA/HYNIC-TOC detected somatostatin receptor-positive lesions in 20 patients with MTC, whereas (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin displayed gastrin receptors in 11 patients. In 9 cases, the scans were positive in both methods, although in 2 cases different pathologic foci were visualized. In 12 cases, only (99m)Tc-EDDA/HYNIC-TOC scintigraphy was positive, whereas in 3 other cases only (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin revealed pathologic lesions. Scintigraphy using (99m)Tc-HYNIC-TOC permits the visualization

False-positive 111In-pentetreotide Uptake in Gastritis

International Nuclear Information System (INIS)

Usmani, Sharjeel; Alshammari, Alshaima

2013-01-01

111 In-pentetreotide [ 111 In-octreoscan] is the most widely used radiolabeled somatostatin analog for evaluating neuroendocrine tumor overexpression of somatostatin receptors. False-positives studies of somatostatin receptor scintigraphy have been reported and often the cause is unexplained but assumed to be due to high number of somatostatin receptors in other pathologies. Causes of false-positives include visualization of the gallbladder, nasal mucosa and pulmonary hilar areas in respiratory infections, thyroid abnormalities, accessory spleens, recent Cerebrovascular accidents (CVA's) and activity at the site of a recent surgical incision. In infection or inflammation the cause of false-positive uptake is probably the result of tracer binding by somatostatin receptors on the inflammatory leukocytes. In this case report, we report, a 44-year-old male patient with false-positive 111 In-pentetreotide uptake due to gastritis

Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas

Directory of Open Access Journals (Sweden)

Wang JW

2014-01-01

Full Text Available Ji-wen Wang,1,2 Ying Li,3 Zhi-gang Mao,1,2 Bin Hu,1,2 Xiao-bing Jiang,1,2 Bing-bing Song,4 Xin Wang,4 Yong-hong Zhu,4 Hai-jun Wang1,21Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, 2Key Laboratory of Pituitary Adenoma in Guangdong Province, 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 4Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of ChinaAbstract: Excessive growth hormone (GH is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults. The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly. Control of serum GH and insulin-like growth factor (IGF 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity. Current pharmacotherapy includes somatostatin analogs (SAs and GH receptor antagonist; the former consists of lanreotide Autogel (ATG and octreotide long-acting release (LAR, and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4–6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated

DMPD: C-type lectin receptors in antifungal immunity. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18160296 C-type lectin receptors in antifungal immunity. Willment JA, Brown GD. Tre...nds Microbiol. 2008 Jan;16(1):27-32. Epub 2007 Dec 21. (.png) (.svg) (.html) (.csml) Show C-type lectin receptors in antifun...gal immunity. PubmedID 18160296 Title C-type lectin receptors in antifungal immunity. Author

Oligomerisation of C. elegans Olfactory Receptors, ODR-10 and STR-112, in Yeast

KAUST Repository

Tehseen, Muhammad; Liao, Chunyan; Dacres, Helen; Dumancic, Mira; Trowell, Stephen; Anderson, Alisha

2014-01-01

It is widely accepted that vertebrate G-Protein Coupled Receptors (GPCRs) associate with each other as homo- or hetero-dimers or higher-order oligomers. The C. elegans genome encodes hundreds of olfactory GPCRs, which may be expressed in fewer than a dozen chemosensory neurons, suggesting an opportunity for oligomerisation. Here we show, using three independent lines of evidence: co-immunoprecipitation, bioluminescence resonance energy transfer and a yeast two-hybrid assay that nematode olfactory receptors (ORs) oligomerise when heterologously expressed in yeast. Specifically, the nematode receptor ODR-10 is able to homo-oligomerise and can also form heteromers with the related nematode receptor STR-112. ODR-10 also oligomerised with the rat I7 OR but did not oligomerise with the human somatostatin receptor 5, a neuropeptide receptor. In this study, the question of functional relevance was not addressed and remains to be investigated.

Oligomerisation of C. elegans Olfactory Receptors, ODR-10 and STR-112, in Yeast

KAUST Repository

Tehseen, Muhammad

2014-09-25

It is widely accepted that vertebrate G-Protein Coupled Receptors (GPCRs) associate with each other as homo- or hetero-dimers or higher-order oligomers. The C. elegans genome encodes hundreds of olfactory GPCRs, which may be expressed in fewer than a dozen chemosensory neurons, suggesting an opportunity for oligomerisation. Here we show, using three independent lines of evidence: co-immunoprecipitation, bioluminescence resonance energy transfer and a yeast two-hybrid assay that nematode olfactory receptors (ORs) oligomerise when heterologously expressed in yeast. Specifically, the nematode receptor ODR-10 is able to homo-oligomerise and can also form heteromers with the related nematode receptor STR-112. ODR-10 also oligomerised with the rat I7 OR but did not oligomerise with the human somatostatin receptor 5, a neuropeptide receptor. In this study, the question of functional relevance was not addressed and remains to be investigated.

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

International Nuclear Information System (INIS)

Waser, Beatrice; Reubi, Jean Claude

2014-01-01

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Effects of the neuroprotective drugs somatostatin and brimonidine on retinal cell models of diabetic retinopathy.

Science.gov (United States)

Beltramo, Elena; Lopatina, Tatiana; Mazzeo, Aurora; Arroba, Ana I; Valverde, Angela M; Hernández, Cristina; Simó, Rafael; Porta, Massimo

2016-12-01

Diabetic retinopathy is considered a microvascular disease, but recent evidence has underlined early involvement of the neuroretina with interactions between microvascular and neural alterations. Topical administration of somatostatin (SST), a neuroprotective molecule with antiangiogenic properties, prevents diabetes-induced retinal neurodegeneration in animals. The α 2 -adrenergic receptor agonist brimonidine (BRM) decreases vitreoretinal vascular endothelial growth factor and inhibits blood-retinal barrier breakdown in diabetic rats. However, SST and BRM effects on microvascular cells have not yet been studied. We investigated the behaviour of these drugs on the crosstalk between microvasculature and neuroretina. Expression of SST receptors 1-5 in human retinal pericytes (HRP) was checked. We subsequently evaluated the effects of diabetic-like conditions (high glucose and/or hypoxia) with/without SST/BRM on HRP survival. Endothelial cells (EC) and photoreceptors were maintained in the above conditions and their conditioned media (CM) used to culture HRP. Vice versa, HRP-CM was used on EC and photoreceptors. Survival parameters were assessed. HRP express the SST receptor 1 (SSTR1). Glucose fluctuations mimicking those occurring in diabetic subjects are more damaging for pericytes and photoreceptors than stable high glucose and hypoxic conditions. SST/BRM added to HRP in diabetic-like conditions decrease EC apoptosis. However, neither SST nor BRM changed the response of pericytes and neuroretina-vascular crosstalk under diabetic-like conditions. Retinal pericytes express SSTR1, indicating that they can be a target for SST. Exposure to SST/BRM had no adverse effects, direct or mediated by the neuroretina, suggesting that these molecules could be safely evaluated for the treatment of ocular diseases.

Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein

DEFF Research Database (Denmark)

Jacobsen, Linda; Madsen, P; Moestrup, S K

1996-01-01

the corresponding cDNA. The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein. The receptor, designated sorLA-1, has a short cytoplasmic tail containing a tyrosine...... density lipoprotein receptor gene family receptors, and 3) six tandemly arranged fibronectin type III repeats also found in certain neural adhesion proteins. sorLA-1 may therefore be classified as a hybrid receptor. Northern blotting revealed specific mRNA transcripts in brain, spinal cord, and testis......The 39-40-kDa receptor-associated protein (RAP) binds to the members of the low density lipoprotein receptor gene family and functions as a specialized endoplasmic reticulum/Golgi chaperone. Using RAP affinity chromatography, we have purified a novel approximately 250-kDa brain protein and isolated...

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

Energy Technology Data Exchange (ETDEWEB)

Ogawa, Eiichi [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Hosokawa, Masaya [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Faculty of Human Sciences, Tezukayama Gakuin University, Osaka (Japan); Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Tsukiyama, Katsushi; Yamada, Yuichiro [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Department of Internal Medicine, Division of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita (Japan); Seino, Yutaka [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Kansai Electric Power Hospital, Osaka (Japan); Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); CREST of Japan Science and Technology Cooperation (JST), Kyoto (Japan)

2011-01-07

Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

International Nuclear Information System (INIS)

Ogawa, Eiichi; Hosokawa, Masaya; Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito; Tsukiyama, Katsushi; Yamada, Yuichiro; Seino, Yutaka; Inagaki, Nobuya

2011-01-01

Research highlights: → Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. → Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. → The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic β cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [ 14 C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [ 14 C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather

Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex.

NARCIS (Netherlands)

Gentet, L.J.; Kremer, Y.; Taniguchi, H.; Huang, Z.J.; Staiger, J.F.; Petersen, C.C.H.

2012-01-01

Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory

Concordance between results of somatostatin receptor scintigraphy with 111In-DOTA-DPhe1-Tyr3-octreotide and chromogranin A assay in patients with neuroendocrine tumours

International Nuclear Information System (INIS)

Rodrigues, Margarida; Gabriel, Michael; Heute, Dirk; Putzer, Daniel; Virgolini, Irene; Griesmacher, Andrea

2008-01-01

Somatostatin receptor scintigraphy (SRS) and chromogranin A (CgA) assay have successfully been implemented in the clinical work-up and management of neuroendocrine tumour (NET) patients. However, there is still a lack of studies comparing results in these patients. Our aim was to compare directly in NET patients SRS and CgA assay results with special regard to tumour features such as grade of malignancy, primary origin, disease extent and function. One hundred twenty consecutive patients with histological confirmed NETs were investigated with 111 In-DOTA-DPhe 1 -Tyr 3 -octreotide ( 111 In-DOTA-TOC) SRS and CgA immunoradiometric assay. Tumours were classified by cell characteristics [well-differentiated NETs, well-differentiated neuroendocrine carcinomas, poorly differentiated neuroendocrine carcinomas (PDNECs)], primary origin (foregut, midgut, hindgut, undetermined), disease extent (limited disease, metastases, primary tumour and metastases) and functionality (secretory, nonsecretory). SRS was positive in 107 (89%) patients; CgA levels were increased in 95 (79%) patients. Overall, concordance between SRS and CgA results was found in 84 patients. Positive SRS but normal CgA level were found in 24 patients, with higher prevalence (p 111 In-DOTA-TOC SRS proved to be more sensitive than CgA in NETs patients. Tumour differentiation, disease extent and presence of liver metastases impact both SRS and CgA results, whereas nonsecretory activity is a negative predictor of only CgA increase. PDNECs and hindgut origin of tumours predispose to discrepancies with negative SRS but increased CgA levels. (orig.)

Quantum Dot Immunocytochemical Localization of Somatostatin in Somatostatinoma by Widefield Epifluorescence, Super-resolution Light, and Immunoelectron Microscopy

Science.gov (United States)

Lai, Ken; Wu, Xiaojuan; Yong, Jim L. C.; Lee, C. Soon

2012-01-01

Quantum dot nanocrystal probes (QDs) have been used for detection of somatostatin hormone in secretory granules of somatostatinoma tumor cells by immunofluorescence light microscopy, super-resolution light microscopy, and immunoelectron microscopy. Immunostaining for all modalities was done using sections taken from an epoxy resin-embedded tissue specimen and a similar labeling protocol. This approach allowed assessment of labeling at light microscopy level before examination at super-resolution and electron microscopy level and was a significant aid in interpretation. Etching of ultrathin sections with saturated sodium metaperiodate was a critical step presumably able to retrieve some tissue antigenicity masked by processing in epoxy resin. Immunofluorescence microscopy of QD-immunolabeled sections showed somatostatin hormone localization in cytoplasmic granules. Some variable staining of tumor gland-like structures appeared related to granule maturity and dispersal of granule contents within the tumor cell cytoplasm. Super-resolution light microscopy demonstrated localization of somatostatin within individual secretory granules to be heterogeneous, and this staining pattern was confirmed by immunoelectron microscopy. PMID:22899862

Quantum dot immunocytochemical localization of somatostatin in somatostatinoma by Widefield Epifluorescence, super-resolution light, and immunoelectron microscopy.

Science.gov (United States)

Killingsworth, Murray C; Lai, Ken; Wu, Xiaojuan; Yong, Jim L C; Lee, C Soon

2012-11-01

Quantum dot nanocrystal probes (QDs) have been used for detection of somatostatin hormone in secretory granules of somatostatinoma tumor cells by immunofluorescence light microscopy, super-resolution light microscopy, and immunoelectron microscopy. Immunostaining for all modalities was done using sections taken from an epoxy resin-embedded tissue specimen and a similar labeling protocol. This approach allowed assessment of labeling at light microscopy level before examination at super-resolution and electron microscopy level and was a significant aid in interpretation. Etching of ultrathin sections with saturated sodium metaperiodate was a critical step presumably able to retrieve some tissue antigenicity masked by processing in epoxy resin. Immunofluorescence microscopy of QD-immunolabeled sections showed somatostatin hormone localization in cytoplasmic granules. Some variable staining of tumor gland-like structures appeared related to granule maturity and dispersal of granule contents within the tumor cell cytoplasm. Super-resolution light microscopy demonstrated localization of somatostatin within individual secretory granules to be heterogeneous, and this staining pattern was confirmed by immunoelectron microscopy.

Analysis of 125I-[Tyr3] octreotide receptors of NCI-H466 cell line

International Nuclear Information System (INIS)

Sun Junjie; Fan Wo; Xu Yujie; Zhang Youjiu; Zhu Ran

2002-01-01

Objective: To study the affinity of small cell lung carcinoma to [Tyr 3 ] octreotide (TOC). Methods: Taking 125 I-[Tyr 3 ] octreotide (labeled by chloramine-T method), as the ligand, small cell lung carcinoma NCI-H466 cell line was inspected for the receptor-binding points and affinity constant. Results: The radio-chemical purity of 125 I-TOC purified through sephadex G-10 was higher than 95%. Receptor analysis study showed that the expression of somatostatin receptors on NCI-H446 cells was numerous (Bmax = 1.17 x 10 5 /cell) with strong affinity to 125 I-TOC (Kd = 0.56 nM). Conclusion: Labeled TOC could be used for small cell lung carcinoma receptor imaging and radio-pharmaceutical therapy

Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells [v1; ref status: indexed, http://f1000r.es/8n

Directory of Open Access Journals (Sweden)

Ian LP Beales

2013-02-01

Full Text Available The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.

The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model

Science.gov (United States)

Rylova, Svetlana N.; Stoykow, Christian; Del Pozzo, Luigi; Abiraj, Keelara; Tamma, Maria Luisa; Kiefer, Yvonne; Fani, Melpomeni; Maecke, Helmut R.

2018-01-01

Copper-64 is an attractive radionuclide for PET imaging and is frequently used in clinical applications. The aim of this study was to perform a side-by-side comparison of the in vitro and in vivo performance of 64Cu-NODAGA-JR11 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid,4,7-acetic acid, JR11 = p-Cl-Phe-cyclo(D-Cys-Aph(Hor)-D-Aph(cbm)-Lys-Thr-Cys)D-Tyr-NH2), a somatostatin receptor 2 antagonist, with the clinically used sst2 agonist 64Cu-DOTA-TATE ((TATE = D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr). In vitro studies demonstrated Kd values of 5.7±0.95 nM (Bmax = 4.1±0.18 nM) for the antagonist 64/natCu-NODAGA-JR11 and 20.1±4.4. nM (Bmax = 0.48±0.18 nM) for the agonist 64/natCu-DOTA-TATE. Cell uptake studies showed the expected differences between agonists and antagonists. Whereas 64Cu-DOTA-TATE (the agonist) showed very effective internalization in the cell culture assay (with 50% internalized at 4 hours post-peptide addition under the given experimental conditions), 64Cu-NODAGA-JR11 (the antagonist) showed little internalization but strong receptor-mediated uptake at the cell membrane. Biodistribution studies of 64Cu-NODAGA-JR11 showed rapid blood clearance and tumor uptake with increasing tumor-to-relevant organ ratios within the first 4 hours and in some cases, 24 hours, respectively. The tumor washout was slow or non-existent in the first 4 hours, whereas the kidney washout was very efficient, leading to high and increasing tumor-to-kidney ratios over time. Specificity of tumor uptake was proven by co-injection of high excess of non-radiolabeled peptide, which led to >80% tumor blocking. 64Cu-DOTA-TATE showed less favorable pharmacokinetics, with the exception of lower kidney uptake. Blood clearance was distinctly slower and persistent higher blood values were found at 24 hours. Uptake in the liver and lung was relatively high and also persistent. The tumor uptake was specific and similar to that of 64Cu-NODAGA-JR11 at 1 h, but release from the tumor

Peptide receptor radionuclide therapy with {sup 90}Y-DOTATOC in recurrent meningioma

Energy Technology Data Exchange (ETDEWEB)

Bartolomei, Mirco; Bodei, Lisa; De Cicco, Concetta; Grana, Chiara Maria; Baio, Silvia Melania; Arico, Demetrio; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Botteri, Edoardo [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Radiometabolic Medicine Division, Meldola (Italy)

2009-09-15

Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using {sup 90}Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous {sup 90}Y-DOTATOC for 2-6 cycles for a cumulative dose in the range of 5-15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II-III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. PRRT with {sup 90}Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation. (orig.)

Application of single-vial ready-for-use formulation of 111In- or 177Lu-labelled somatostatin analogs.

Science.gov (United States)

de Blois, Erik; Chan, Ho Sze; de Zanger, Rory; Konijnenberg, Mark; Breeman, Wouter A P

2014-02-01

For the sake of safety it would be desirable to store and transport the ready-for-use liquid formulation (diagnostics and therapeutics) of radiolabelled peptides. The use of ethanol, in combination with a mixture of gentisic- and ascorbic acid, has superior effects on stabilizing radiolabelled somatostatin analogs. As a consequence, (111)In- and (177)Lu-labelled somatostatin analogs can be stored and transported in a single-vial ready-for-use liquid formulation up to 7 days after radiolabelling. © 2013 Published by Elsevier Ltd.

Development of 99mTc labelled somatostatin analogues and evaluation of their radiochemical and biological behaviour

International Nuclear Information System (INIS)

Gano, L.; Patricio, L.

2001-01-01

Conjugates of two somatostatin analogues, octreotide and RC-160, with HYNIC were synthesized, characterized and purified by reverse phase HPLC. Radiolabelling of the conjugates with 99m Tc was achieved using tricine as co-ligand. High labelling efficiencies were obtained and 99m Tc peptides with high radiochemical purity were found when analysed both by ITLC and HPLC. In vitro stability of 99m Tc-peptides in human serum and towards cysteine challenge was determined by Cellogel electrophoresis and HPLC after ultrafiltration of serum solution through a 20 kDa cut off membrane. Biodistribution studies were performed in healthy mice at 5 and 30 minutes and 1, 2, 4 and 24 h post-injection. Urine and blood samples were collected at sacrifice time. Samples of urine and ultrafiltrate murine serum were analysed by electrophoresis and reverse phase HPLC in order to get some information about radiocompounds metabolism. Biological distribution of 99m Tc octreotide was also assayed in mice pre-treated with an excess of unlabelled peptide. From our results we conclude that this labelling method led to stable 99m Tc complexes both in vitro and in vivo when high specific activities (37-72 GBq/μmole) were used. Biodistribution studies of both 99m Tc-peptides indicated a radioactivity distribution profile with significant differences especially in the liver uptake that is higher for 99m Tc RC-160. However, a rapid blood clearance was obtained for both radiolabelled peptides, and the urine analysis indicated that 99m Tc peptide is mostly excreted as the initial complex. Pre-treatment with unlabelled peptide did not affect renal excretion of 99m TOC but pancreas and intestine radioactive uptake was significantly lower, indicating saturation of somatostatin receptors and selective uptake. (author)

Somatostatin receptor expression in the human spleen - Answer to an enigma by ex-vivo and in-vitro autoradiography after 177Lu-DOTA-octreotate administration

International Nuclear Information System (INIS)

Melis, M.; Swart, J. de; Groen, H.C.; Konijnenberg, M.W.; Van der Graaf, L.M.; Kaemmerer, D.; Kulkami, H.R.; Baum, R.P.; Lupp, A.; Saenger, J.; Jong, M. de

2015-01-01

Full text of publication follows. Aim: radiolabelled somatostatin analogues are being used for diagnostic and therapeutic (PRRT) purposes in patients with somatostatin receptor (SSTR) expressing tumours. During PRRT a significant spleen uptake may lead to radiation doses of > 20 Gy. Yet, the threshold dose for spleen radiation induced toxicity is currently unknown. Based on previous 68 Ga-DOTATOC PET/CT studies, demonstrating higher uptake in spleen than in splenosis, white pulp (WP) localization of radioactivity was suggested. This hypothesis was investigated in the current pilot study using the longer lived 177 Lu-DOTA-octreotate. Methods: a patient diagnosed with neuroendocrine neoplasm of the pancreatic tail (SUV max on 68 Ga-DOTATOC PET/CT 100.4) with liver metastasis (SUV 47.3, normal liver SUV 12.5) and uptake in the spleen (SUV 41.0) received 1 GBq 177 Lu-DOTA-octreotate. 2 h after administration whole-body planar scintigraphy and SPECT/CT of the upper abdomen was performed, followed by laparoscopic resection of the pancreatic tumour and splenectomy the next day. After spleen transport from Bad Berka to Rotterdam ex-vivo micro-SPECT of the removed spleen was acquired for 73 min using 2.5 mm diameter pinholes. Spleen fragments (∼10 * 10 * 5 mm) were either snap-frozen in liquid nitrogen or fixed in 10% formalin and paraffin embedded. Ex-vivo autoradiography of 10 μm cryo-sections was performed and serial sections were used for 111 In-DOTA-octreotate in-vitro autoradiography after decay of 177 Lu. FFPE sections were used for HE- and immunostaining for SSTR2A and cell subsets CD4 (Th-cell), CD8 (Ts-cell), CD20 (B-cell) and CD68 (macrophage). Results: 177 Lu-DOTA-octreotate scintigraphy and SPECT/CT demonstrated high uptake in the pancreatic tumor, hepatic metastasis and homogeneously in the normal spleen. High resolution micro-SPECT imaging of the isolated spleen also revealed a relatively homogeneous uptake (calculated rest activity 60 MBq 177 Lu). The

Somatostatin receptor PET in neuroendocrine tumours: 68Ga-DOTA0,Tyr3-octreotide versus 68Ga-DOTA0-lanreotide.

Science.gov (United States)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Traub-Weidinger, Tatjana; Uprimny, Christian; von Guggenberg, Elisabeth; Decristoforo, Clemens; Warwitz, Boris; Widmann, Gerlig; Virgolini, Irene Johanna

2013-02-01

The aim of this study was to evaluate the impact of (68)Ga-labelled DOTA(0)-lanreotide ((68)Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or (68)Ga-labelled DOTA(0),Tyr(3)-octreotide ((68)Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or (68)Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent (68)Ga-DOTA-LAN PET to evaluate a treatment option with (90)Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 ± 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. (68)Ga-DOTA-LAN and (68)Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of (68)Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for (68)Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. (68)Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV(max)) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to (68)Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. (68)Ga-DOTA-TOC revealed more tumour sites than (68)Ga

β-arrestins negatively control human adrenomedullin type 1-receptor internalization.

Science.gov (United States)

Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Sekiguchi, Toshio; Danfeng, Jiang; Murakami, Manabu; Hattori, Yuichi; Kato, Johji

2017-05-27

Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM 1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure. Here, we examined the effects of β-arr-1 and β-arr-2 on human AM 1 receptor internalization. We constructed a V5-tagged chimera in which the cytoplasmic C-terminal tail (C-tail) of CLR was replaced with that of the β 2 -adrenergic receptor (β 2 -AR), and it was transiently transfected into HEK-293 cells that stably expressed RAMP2. The cell-surface expression and internalization of the wild-type or chimeric receptor were quantified by flow cytometric analysis. The [ 125 I]AM binding and the AM-induced cAMP production of these receptors were also determined. Surprisingly, the coexpression of β-arr-1 or -2 resulted in significant decreases in AM 1 receptor internalization without affecting AM binding and signaling prior to receptor internalization. Dominant-negative (DN) β-arr-1 or -2 also significantly decreased AM-induced AM 1 receptor internalization. In contrast, the AM-induced internalization of the chimeric AM 1 receptor was markedly augmented by the cotransfection of β-arr-1 or -2 and significantly reduced by the coexpression of DN-β-arr-1 or -2. These results were consistent with those seen for β 2 -AR. Thus, both β-arrs negatively control AM 1 receptor internalization, which depends on the C-tail of CLR. Copyright © 2017 Elsevier Inc. All rights reserved.

Immunohistochemical expression of insulin, glucagon, and somatostatin in pancreatic islets of horses with and without insulin resistance.

Science.gov (United States)

Newkirk, Kim M; Ehrensing, Gordon; Odoi, Agricola; Boston, Raymond C; Frank, Nicholas

2018-02-01

OBJECTIVE To assess insulin, glucagon, and somatostatin expression within pancreatic islets of horses with and without insulin resistance. ANIMALS 10 insulin-resistant horses and 13 insulin-sensitive horses. PROCEDURES For each horse, food was withheld for at least 10 hours before a blood sample was collected for determination of serum insulin concentration. Horses with a serum insulin concentration horses with a serum insulin concentration > 20 μU/mL underwent a frequently sampled IV glucose tolerance test to determine sensitivity to insulin by minimal model analysis. Horses with a sensitivity to insulin horses were euthanized with a barbiturate overdose, and pancreatic specimens were harvested and immunohistochemically stained for determination of insulin, glucagon, and somatostatin expression in pancreatic islets. Islet hormone expression was compared between insulin-resistant and insulin-sensitive horses. RESULTS Cells expressing insulin, glucagon, and somatostatin made up approximately 62%, 12%, and 7%, respectively, of pancreatic islet cells in insulin-resistant horses and 64%, 18%, and 9%, respectively, of pancreatic islet cells in insulin-sensitive horses. Expression of insulin and somatostatin did not differ between insulin-resistant and insulin-sensitive horses, but the median percentage of glucagon-expressing cells in the islets of insulin-resistant horses was significantly less than that in insulin-sensitive horses. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, in insulin-resistant horses, insulin secretion was not increased but glucagon production might be downregulated as a compensatory response to hyperinsulinemia.

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

Energy Technology Data Exchange (ETDEWEB)

Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

2014-06-15

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Impact of cell type and epitope tagging on heterologous expression of G protein-coupled receptor: a systematic study on angiotensin type II receptor.

Directory of Open Access Journals (Sweden)

Lili Jiang

Full Text Available Despite heterologous expression of epitope-tagged GPCR is widely adopted for functional characterization, there is lacking of systematic analysis of the impact of expression host and epitope tag on GPCR expression. Angiotensin type II (AT2 receptor displays agonist-dependent and -independent activities, coupling to a spectrum of signaling molecules. However, consensus has not been reached on the subcellular distributions, signaling cascades and receptor-mediated actions. To examine the contributions of host cell and epitope tag on receptor expression and activity, epitope-tagged AT2 receptor variants were transiently or stably expressed in HEK293, CHO-K1 and PC12 cells. The epitope-tagged AT2 receptor variants were detected both on the cell membrane and in the perinuclear region. In transiently transfected HEK293 cells, Myc-AT2 existed predominantly as monomer. Additionally, a ladder of ubiquitinated AT2 receptor proteins was detected. By contrast, stably expressed epitope-tagged AT2 receptor variants existed as both monomer and high molecular weight complexes, and the latter was enriched in cell surface. Glycosylation promoted cell surface expression of Myc-AT2 but had no effect on AT2-GFP in HEK293 cells. In cells that stably expressed Myc-AT2, serum starvation induced apoptosis in CHO-K1 cells but not in HEK293 or PC12 cells. Instead, HEK293 and PC12 cells stably expressing Myc-AT2 exhibited partial cell cycle arrest with cells accumulating at G1 and S phases, respectively. Taken together, these results suggest that expression levels, subcellular distributions and ligand-independent constitutive activities of AT2 receptor were cell type-dependent while posttranslational processing of nascent AT2 receptor protein was modulated by epitope tag and mode of expression.

In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

Energy Technology Data Exchange (ETDEWEB)

Rettori, V.; Aguila, M.C.; McCann, S.M. (Univ. of Texas Southwestern Medical Center at Dallas (United States)); Gimeno, M.F.; Franchi, A.M. (Centro de Estudios Farmacologicos y de Principios Naturales, Buenos Aires (Argentina))

1990-12-01

Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

Peripheral-type benzodiazepine receptors in the central nervous system: localization to olfactory nerves.

Science.gov (United States)

Anholt, R R; Murphy, K M; Mack, G E; Snyder, S H

1984-02-01

Binding levels of [3H]Ro5-4864, a ligand selective for peripheral-type benzodiazepine receptors, are substantially higher in homogenates of the olfactory bulb than in the rest of the brain. Among peripheral tissues evaluated, high levels of [3H]Ro5-4864 binding are found in the nasal epithelium. Drug displacement studies show that these binding sites are pharmacologically of the peripheral type. Their presence in the nasal epithelium and in the olfactory bulb can be demonstrated in several different mammalian species. Autoradiographic studies of murine nose reveal a bipolar staining pattern around the cell bodies of the olfactory receptor cells, suggesting the presence of peripheral-type benzodiazepine receptors on both processes of these bipolar neurons. In the brain a high density of [3H]Ro5-4864 binding sites occurs in the nerve fiber and glomerular layers of the olfactory bulb. Throughout the rest of the brain [3H]Ro5-4864-associated silver grains are diffusely distributed with intense staining over the choroid plexus and along the ependymal linings of the ventricles. Both the distribution and the ontogenic development of the peripheral-type benzodiazepine receptors differ from the central-type receptors. Intranasal irrigation with 5% ZnSO4 results in a 50% reduction of peripheral-type benzodiazepine receptors in the olfactory bulb without affecting the density of central-type benzodiazepine receptors. Thus, [3H]Ro5-4864 binding sites in the olfactory bulb appear in large part to be localized to olfactory nerves which originate in the nasal epithelium.

NCBI nr-aa BLAST: CBRC-TSYR-01-0849 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-TSYR-01-0849 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 87% ...

NCBI nr-aa BLAST: CBRC-PVAM-01-1207 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PVAM-01-1207 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 87% ...

NCBI nr-aa BLAST: CBRC-PHAM-01-1593 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PHAM-01-1593 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 0.0 86% ...

Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy

DEFF Research Database (Denmark)

Tarnow, L; Cambien, Francois; Rossing, P

1996-01-01

with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility...... is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied...... the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74...

NCBI nr-aa BLAST: CBRC-GGOR-01-1250 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-GGOR-01-1250 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-119 80% ...

NCBI nr-aa BLAST: CBRC-MEUG-01-0329 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MEUG-01-0329 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-160 73% ...

NCBI nr-aa BLAST: CBRC-MLUC-01-0637 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MLUC-01-0637 ref|NP_001020791.1| somatostatin receptor 3 [Canis lupus familiar...is] gb|AAV49129.1| somatostatin receptor subtype 3 [Canis lupus familiaris] NP_001020791.1 1e-165 90% ...

β-arrestins negatively control human adrenomedullin type 1-receptor internalization

International Nuclear Information System (INIS)

Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Sekiguchi, Toshio; Danfeng, Jiang; Murakami, Manabu; Hattori, Yuichi; Kato, Johji

2017-01-01

Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM 1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure. Here, we examined the effects of β-arr-1 and β-arr-2 on human AM 1 receptor internalization. We constructed a V5-tagged chimera in which the cytoplasmic C-terminal tail (C-tail) of CLR was replaced with that of the β 2 -adrenergic receptor (β 2 -AR), and it was transiently transfected into HEK-293 cells that stably expressed RAMP2. The cell-surface expression and internalization of the wild-type or chimeric receptor were quantified by flow cytometric analysis. The [ 125 I]AM binding and the AM-induced cAMP production of these receptors were also determined. Surprisingly, the coexpression of β-arr-1 or -2 resulted in significant decreases in AM 1 receptor internalization without affecting AM binding and signaling prior to receptor internalization. Dominant-negative (DN) β-arr-1 or -2 also significantly decreased AM-induced AM 1 receptor internalization. In contrast, the AM-induced internalization of the chimeric AM 1 receptor was markedly augmented by the cotransfection of β-arr-1 or -2 and significantly reduced by the coexpression of DN-β-arr-1 or -2. These results were consistent with those seen for β 2 -AR. Thus, both β-arrs negatively control AM 1 receptor internalization, which depends on the C-tail of CLR. - Highlights: • We found that β-arrestins 1 and 2 negatively control agonist-induced GPCR internalization. • β-arrestins 1 and 2 significantly inhibits the AM

DNA binding properties of dioxin receptors in wild-type and mutant mouse hepatoma cells

International Nuclear Information System (INIS)

Cuthill, S.; Poellinger, L.

1988-01-01

The current model of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) entails stimulation of target gene transcription via the formation of dioxin-receptor complexes and subsequent accumulation of the complexes within the cell nucleus. Here, the authors have analyzed the DNA binding properties of the dioxin receptor in wild-type mouse hepatoma (Hepa 1c1c7) cells and a class of nonresponsive mutant cells which fail to accumulate dioxin-receptor complexes within the nucleus in vivo. In vitro, both the wild-type and mutant [ 3 H]dioxin-receptor complexes exhibited low affinity for DNA-cellulose (5-8% and around 4% retention, respectively) in the absence of prior biochemical manipulations. However, following chromatography on heparin-Sepharose, the wild-type but not the mutant dioxin receptor was transformed to a species with an increased affinity for DNA (40-50% retention on DNA-cellulose). The gross molecular structure of the mutant, non DNA binding dioxin receptor did not appear to be altered as compared to that of the wild-type receptor. These results imply that the primary deficiency in the mutant dioxin receptor form may reside at the DNA binding level and that, in analogy to steroid hormone receptors, DNA binding of the receptor may be an essential step in the regulation of target gene transcription by dioxin

Decision-tree model for health economic comparison of two long-acting somatostatin receptor ligand devices in France, Germany, and the UK.

Science.gov (United States)

Marty, Rémi; Roze, Stéphane; Kurth, Hannah

2012-01-01

Long-acting somatostatin receptor ligands (SRL) with product-specific formulation and means of administration are injected periodically in patients with acromegaly and neuroendocrine tumors. A simple decision-tree model aimed at comparing cost savings with ready-to-use Somatuline Autogel(®) (lanreotide) and Sandostatin LAR(®) (octreotide) for the UK, France, and Germany. The drivers of cost savings studied were the reduction of time to administer as well as a reduced baseline risk of clogging during product administration reported for Somatuline Autogel(®). The decision-tree model assumed two settings for SRL administration, ie, by either hospital-based or community-based nurses. In the case of clogging, the first dose was assumed to be lost and a second injection performed. Successful injection depended on the probability of clogging. Direct medical costs were included. A set of scenarios were run, varying the cost drivers, such as the baseline risk of clogging, SRL administration time, and percentage of patients injected during a hospital stay. Costs per successful injection were less for Somatuline Autogel(®)/Depot, ranging from Euros (EUR) 13-45, EUR 52-108, and EUR 127-151, respectively, for France, Germany, and the UK. The prices for both long-acting SRL were the same in France, and cost savings came to 100% from differences other than drug prices. For Germany and the UK, the proportion of savings due to less clogging and shorter administration time was estimated to be around 32% and 20%, respectively. Based on low and high country-specific patient cohort size estimations of individuals eligible for SRL treatment among the patient population with acromegaly and neuroendocrine tumors, annual savings were estimated to be up to EUR 2,000,000 for France, EUR 6,000,000 for Germany, and EUR 7,000,000 for the UK. This model suggests that increasing usage of the Somatuline device for injection of SRL might lead to substantial savings for health care providers

Clinical Validation of a Pixon-Based Reconstruction Method Allowing a Twofold Reduction in Planar Images Time of 111In-Pentetreotide Somatostatin Receptor Scintigraphy

Directory of Open Access Journals (Sweden)

Philippe Thuillier

2017-08-01

Full Text Available ObjectiveThe objective of this study was to evaluate the diagnostic efficacy of Pixon-based reconstruction method on planar somatostatin receptor scintigraphy (SRS.MethodsAll patients with neuroendocrine tumors (NETs disease who were referred for SRS to our department during 1-year period from January to December 2015 were consecutively included. Three nuclear physicians independently reviewed all the data sets of images which included conventional images (CI; 15 min/view and processed images (PI obtained by reconstructing the first 450 s extracted data using Oncoflash® software package. Image analysis using a 3-point rating scale for abnormal uptake of 111 Indium-DTPA-Phe-octreotide in any lesion or organ was interpreted as positive, uncertain, or negative for the evidence of NET disease. A maximum grade uptake of the radiotracer in the lesion was assessed by the Krenning scale method. The results of image interpretation by the two methods were considered significantly discordant when the difference in organ involvement assessment was negative vs. positive or in lesion uptake was ≥2 grades. Agreement between the results of two methods and by different scan observers was evaluated using Cohen κ coefficients.ResultsThere was no significant (p = 0.403 correlation between data acquisition protocol and quality image. The rates of significant discrepancies for exam interpretation and organs involvement assessment were 2.8 and 2.6%, respectively. Mean κ values revealed a good agreement for concordance between CI and PI interpretation without difference of agreement for inter/intra-observer analysis.ConclusionOur results suggest the feasibility to use a Pixon-based reconstruction method for SRS planar images allowing a twofold reduction of acquisition time and without significant alteration of image quality or on image interpretation.

Long-term Primary Medical Therapy with Somatostatin Analogs in Acromegaly

Directory of Open Access Journals (Sweden)

Deng-Huang Su

2006-01-01

Full Text Available To cure acromegalic patients, transsphenoidal surgery is considered first, especially for microadenoma. However, less than 50% of patients with macroadenoma achieve satisfactory biochemical control. Moreover, surgery may cause hypopituitarism. Medical therapy may offer the prospect of near normalization of growth hormone (GH/insulin-like growth factor-1 levels with substantial tumor shrinkage in a significant number of patients. Here, we report two cases of acromegaly under treatment with somato-statin analogs alone for more than 10 years. Case 1 was a 54-year-old man with a pituitary macro-adenoma. He received 4 years of octreotide treatment followed by 6 years of prolonged-release (PR lanreotide resulting in normal GH level. Case 2 was a 60-year-old woman with a 1.3 cm pituitary tumor. She received 8 years of octreotide treatment followed by 6 years of PR lanreotide resulting in subnormal GH level and gallbladder sludge. She had received bilateral total hip replacement for hip osteoarthritis at the age of 59 years. These cases illustrate that long-term treatment with somatostatin analogs offers an alternative choice in selected acromegalic patients, such as those with pituitary tumor who cannot be cured by surgery, those who have unacceptable anesthetic risk and those who refuse surgery.

Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

Directory of Open Access Journals (Sweden)

Cristina Alvarez-Escola

2016-11-01

Full Text Available In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH and insulin-like growth factor (IGF1 levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status. The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission.

Labelling and quality control of somatostatin analogues with 99mTc

International Nuclear Information System (INIS)

Verdera, S.; Balter, H.; Rodriguez, G.; Robles, A.; Oliver, P.; Laiz, J.; Souto, B.

2001-01-01

Techniques and methodologies for labelling peptides with 99m Tc and methods for their purification, chemical, radiochemical and biological controls were evaluated. With the purpose of gaining experience, labelling with 125 I was also studied. RC-160 was labelled with 125 I using iodogen as well as chloramine-T method. Higher yields were obtained with chloramine-T method (60%), rendering 125 I-peptide with 98% of radiochemical purity, with specific activity of 240 μCi/μg - 274 μCi/μg. The product was stable for five weeks (at -20 deg. C). For somatostatin receptors studies rat brain cortex membrane was prepared. Maximum binding capacity was 24.7% and Kaff for the binding of RC-160 to receptor was estimated as 2.0x10 10 M -1 . Other peptides as β-(2-Naphthyl)- D Ala-Cys-Tyr- D Trp-Lys-Val-Cys-Thr amide (N-9642, Σ) and mouse epidermal growth factor (mEGF) were also labelled by means of limiting chloramine-T method. In case of mEGF the availability of membrane receptors allowed us to experiment in mice as well as in vitro. The reaction yields were up to 60% and 70% respectively. Biodistribution of 125 I-mEGF in a mouse with adenoma demonstrated preferential uptake in tumour (21,7% injected dose). The radioimmunoassay system gave 39% maximum binding (MB) and 50% displacement (ED 50 ) for 10 ng/mL unlabelled mEGF. Direct method and BFC's for labelling peptides with 99m Tc were investigated and purification and quality controls studies were performed by TLC, HPLC (UV and gamma detection). RC-160 was labelled by a direct method using sodium dithionite as reducing agent with radiochemical purity >95%. The product was stable up to six hours (at RT). Considerable adsorption problems were observed. Biological behavior was in accordance with the compounds' lipophilicity. The synthesis of TOC conjugates with HYNIC as BFC was done with 45%±5% (n=3) yield. Labelling of HYNIC-TOC with tricine as co-ligand was conducted with up to 90% yield. Studies of RC-160 labelling using

Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR)

DEFF Research Database (Denmark)

Christensen, Anders; Kiss, Katalin; Lelkaitis, Giedrius

2017-01-01

Background: Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhib...... with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer....

The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization.

Science.gov (United States)

Teichmann, Anke; Rutz, Claudia; Kreuchwig, Annika; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

2012-08-03

N-terminal signal peptides mediate the interaction of native proteins with the translocon complex of the endoplasmic reticulum membrane and are cleaved off during early protein biogenesis. The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) possesses an N-terminal pseudo signal peptide, which represents a so far unique domain within the large protein family of G protein-coupled receptors (GPCRs). In contrast to a conventional signal peptide, the pseudo signal peptide remains uncleaved and consequently forms a hydrophobic extension at the N terminus of the receptor. The functional consequence of the presence of the pseudo signal peptide is not understood. Here, we have analyzed the significance of this domain for receptor dimerization/oligomerization in detail. To this end, we took the CRF(2(a))R and the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R) possessing a conventional cleaved signal peptide and conducted signal peptide exchange experiments. Using single cell and single molecule imaging methods (fluorescence resonance energy transfer and fluorescence cross-correlation spectroscopy, respectively) as well as biochemical experiments, we obtained two novel findings; we could show that (i) the CRF(2(a))R is expressed exclusively as a monomer, and (ii) the presence of the pseudo signal peptide prevents its oligomerization. Thus, we have identified a novel functional domain within the GPCR protein family, which plays a role in receptor oligomerization and which may be useful to study the functional significance of this process in general.

Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

Science.gov (United States)

Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

2016-09-01

The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

Somatostatin analogues labelled with 99mTc

International Nuclear Information System (INIS)

Obenaus, Esteban R.; Crudo, Jose L.; Edreira, Martin M.; Castiglia, Silvia G.

1999-01-01

Biological and radiochemical studies have been carried out on two labelled somatostatin analogues, the peptide RC-150 and the Tyr 3 -Octreotide. Both analogues have been labelled with 99m Tc using the direct and the indirect method and MAG-3 and HYNIC as chelating agents. By the direct method RC-150 was labelled using sodium ascorbate and dithionite as reducing agents. The radiochemical purity was 70%. By the indirect method, in the case of RC-160 with MAG-3 a radiochemical purity higher than 70% was attained while a purity of 100% was reached in the case of Tyr 3 -Octreotide with HYNIC. The biological distribution of HYNIC-Tyr 3 -Octreotide has been studied in rats. (author)

Somatostatin in the rat periventricular nucleus: sex differences and effect of gonadal steroids

NARCIS (Netherlands)

Vugt, van H.H.; Heijning, van de B.J.M.; Beek, van der E.M.

2008-01-01

In the rat, the sexual dimorphism in growth hormone release is driven by sex steroids, and is suggested to result mainly from differences in somatostatin (SOM) release patterns from the median eminence. We studied the effect of gonadal steroids on SOM peptide-containing cells in the periventricular

DMPD: Toll-like receptors and Type I interferons. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available m. 2007 May 25;282(21):15319-23. Epub 2007 Mar 29. (.png) (.svg) (.html) (.csml) Show Toll-like receptors and Type I interferons. Pub...medID 17395581 Title Toll-like receptors and Type I interferons. Authors Uematsu S,

Pegvisomant treatment in a 4-year-old girl with neurofibromatosis type 1

DEFF Research Database (Denmark)

Main, Katharina M; Sehested, Astrid; Feldt-Rasmussen, Ulla

2006-01-01

with acromegaly. We wanted to investigate whether pegvisomant was effective in a child with octreotide-resistant GH excess. CASE: A 4-year-old girl with neurofibromatosis type 1 and GH excess associated with optic glioma received pegvisomant injections (10 mg subcutaneously) with increasing intervals from daily....... Intracranial tumours remained unchanged in size and visual impairment did not deteriorate. CONCLUSION: Pegvisomant normalized IGF-I and IGFBP-3 levels. Growth velocity was normalized after initial catch-down growth, and it remains to be seen whether this result can be maintained during long-term treatment.......BACKGROUND/AIMS: Growth hormone (GH) excess in childhood is a rare disorder. Current treatment options such as somatostatin analogues, pituitary surgery or irradiation can have serious side effects. Recently, a GH receptor antagonist, pegvisomant, was introduced for the treatment of adults...

An evaluation of the effects of somatostatin analogue therapy in non-functioning pituitary adenomas in comparison to acromegaly.

Science.gov (United States)

Zawada, Natalia Bożena; Kunert-Radek, Jolanta; Pawlikowski, Marek; Pisarek, Hanna; Radek, Maciej

2016-01-01

Non-functioning pituitary adenomas (NFPA) are often diagnosed late as invasive macroadenomas. The surgical resection is usually incomplete and about 50% of patients require additional surgery. Recent data suggest that somatostatin analogues (SSA), so important in the pharmacotherapy of acromegaly, can also be effective in the management of NFPA. We analysed data of patients who had been treated up to 10 years previously with SSA: 40 with acromegaly (23 - primary, 17 - recurrent tumours) and 22 with NFPA (4 - primary, 18 - recurrent tumours). Hormonal profile, dynamics of tumour size change, ophthalmic syndromes, somatostatin receptor (SSTR) scintigraphy, and immunohistochemistry of SSTR subtypes of operated tumours as well as side effects were investigated. Biochemical cure of acromegaly was achieved in 57.5% of patients, while reduction of tumour size was observed in 37% of patients and it was more frequent in not-operated cases. Regarding NFPA, stabilisation of tumour size was noticed in 68% of patients. Tumour shrinkage was reported in 9% of cases, but in 23% of the study group the adenoma size increased with indication for reoperation. The efficacy of SSA in NFPA is much lower in comparison to their well-established effects in the treatment of acromegaly. Stabilisation of tumour size, which is observed in the majority of NFPA, is significantly more frequent in comparison to the natural history of untreated NFPA and our previous studies as well. Analysis of SSTR subtypes is an argument in favour of introduction of novel broad-spectrum SSA that may be more effective in the treatment of NFPA. Referring to acromegaly, adenoma size decrease was reported more frequently in primary therapy. Considering recurrent tumours better outcomes were achieved in patients who were pre-treated with SSA before planned surgery. (Endokrynol Pol 2016; 67 (3): 292-298).

Synthesis and evaluation in vitro in cancer cells AR42J of the radiopharmaceutical {sup 99m}Tc-Tyr{sup 3}-Octreotide-dendrimer similar of somatostatin; Sintesis y evaluacion in vitro en celulas de cancer AR42J del radiofarmaco {sup 99m}Tc-Tyr{sup 3}-Octreotido-dendrimero analogo de la somatostatina

Energy Technology Data Exchange (ETDEWEB)

Orocio R, E.

2013-07-01

The objective of this project was preparing a multimeric system through the conjugation of several molecules of the peptide Tyr{sup 3}-Octreotide to a dendrimer molecule based on Poly-amidoamine (PAMAM), as well as radiolabeled with {sup 99m}Tc and evaluating its behavior like new radiopharmaceutical similar of somatostatin. The dendrimer PAMAM generation 3.5 that possesses terminal groups of sodium carboxylate, was functionalized to peptide Tyr{sup 3}-Octreotide through a reaction of peptide coupling with HATU (hexafluorophosphate (V) of 1-oxide-3-(bis(dimethylamino)methylene)-3H-[1,2,3]triazole[4,5-b]pyridine) as activating agent of carboxylate groups using the Size Exclusion Chromatography (Sec) as purification method. The product was characterized by Ultraviolet visible spectrophotometry, Mid-infrared and Far-infrared, Elemental analysis, Energy dispersive X-ray spectroscopy, Scanning electron microscopy, Thermogravimetry and Differential scanning calorimetry. The radiolabeled with {sup 99m}Tc was carried out using a direct method that involves the reduction of the anion TcO{sub 4}{sup -} with stannous chloride, so that the dendrimer is capable of coordinating to the technetium forming a chelate compound. The radiochemical purity of the radiolabeled compound was determined by thin layer chromatography using a sodium chloride solution to 20% (m/v) as mobile phase and was verified by molecular exclusion chromatography. The radiolabeled compound was possible to obtain it with a radiochemical purity superior to 90%. Also, the specific and not specific union was evaluated of the synthesized compound in mouse pancreas cancer cells AR42J, positive to somatostatin receptors, showing specific recognition for this receptors type with high cellular internalization. The biodistribution studies were carried out in BALB/c mice at different post injection times and in nude mice with induced tumors AR42J. The results showed that the {sup 99m}Tc-PAMAM-Tyr{sup 3}-Octreotide is

In-vivo-receptor scintigraphy with [sup 111]In-octreotid in patients with breast tumors. In-vivo-Rezeptorszintigraphie mit [sup 111]In-Octreotid bei Patientinnen mit palpablen Mammatumoren

Energy Technology Data Exchange (ETDEWEB)

Goehring, U.J. (Frauenklinik, Koeln Univ. (Germany)); Scheidhauer, K. (Klinik fuer Nuklearmedizin, Koeln Univ. (Germany)); Schomaecker, K. (Klinik fuer Nuklearmedizin, Koeln Univ. (Germany)); Scharl, A. (Frauenklinik, Koeln Univ. (Germany))

1993-12-01

Somatostatin is a ligand for a transmembrane peptid receptor protein, which is frequently expressed in breast cancer. We injected the radiolabeled somatostatin analogon In-111-pentatreotid in 19 patients suspicious for breast carcinoma. Planar imaging of the thorax was performed up to 15 minutes p.i. and 3-5 hours p.i. Single photon emission computed tomography (SPECT) was additionaly performed 3-5 hours p.i. Radioactivity was rapidly cleared from blood; concentration in serum decreased by 75% within 1 h. 78% of activity was excreted in urine within 8 h. Positive imaging was seen in 2 of 5 patients with benign breast tumors (fibroadenoma). 11 of 14 carcinomas yielded concentration of 111-In-pentatreotid. 4 of 8 patients with axillary node metastases displayed axillar activity, which was not seen in any patient without node involvement (n=6). These date demonstrate, that radiolabeled pentatreotide binds to certain breast tumors. There is evidence, that in-vivo-imaging of peptid receptors in breast carcinomas is feasible. (orig.)

Peripheral-type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands

International Nuclear Information System (INIS)

Snyder, S.H.; Verma, A.; Trifiletti, R.R.

1987-01-01

The peripheral-type benzodiazepine receptor is a site identified by its nanomolar affinity for [ 3 H]diazepam, similar to the affinity of diazepam for the central-type benzodiazepine receptor in the brain. The peripheral type benzodiazepine receptor occurs in many peripheral tissues but has discrete localizations as indicated by autoradiographic studies showing uniquely high densities of the receptors in the adrenal cortex and in Leydig cells of the testes. Subcellular localization studies reveal a selective association of the receptors with the outer membrane of mitochondria. Photoaffinity labeling of the mitochondrial receptor with [ 3 H]flunitrazepam reveals two discrete labeled protein bands of 30 and 35 kDa, respectively. The 35-kDa band appears to be identical with the voltage-dependent anion channel protein porin. Fractionation of numerous peripheral tissues reveals a single principal endogenous ligand for the receptor, consisting of porphyrins, which display nanomolar affinity. Interactions of porphyrins with the mitochondrial receptor may clarify its physiological role and account for many pharmacological actions of benzodiazepines

Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods.

Science.gov (United States)

Collin, Caitlin; Hauser, Frank; Gonzalez de Valdivia, Ernesto; de Valdivia, Ernesto Gonzalez; Li, Shizhong; Reisenberger, Julia; Carlsen, Eva M M; Khan, Zaid; Hansen, Niels O; Puhm, Florian; Søndergaard, Leif; Niemiec, Justyna; Heninger, Magdalena; Ren, Guilin R; Grimmelikhuijzen, Cornelis J P

2013-09-01

Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1-m5). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC50, 5 × 10(-8) M) and muscarine (EC50, 6 × 10(-8) M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked by the antagonists. A- and B-type mAChRs were also cloned and functionally characterized from the red flour beetle Tribolium castaneum. Recently, Haga et al. (Nature 2012, 482: 547-551) published the crystal structure of the human m2 mAChR, revealing 14 amino acid residues forming the binding pocket for QNB. These residues are identical between the human m2 and the D. melanogaster and T. castaneum A-type mAChRs, while many of them are different between the human m2 and the B-type receptors. Using bioinformatics, one orthologue of the A-type and one of the B-type mAChRs could also be found in all other arthropods with a sequenced genome. Protostomes, such as arthropods, and deuterostomes, such as mammals and other vertebrates, belong to two evolutionarily distinct lineages of animal evolution that split about 700 million years ago. We found that animals that originated before this split, such as cnidarians (Hydra), had two A-type mAChRs. From these data we propose a model for the evolution of mAChRs.

Direct stimulation of angiotensin II type 2 receptor enhances spatial memory

DEFF Research Database (Denmark)

Jing, Fei; Mogi, Masaki; Sakata, Akiko

2012-01-01

We examined the possibility that direct stimulation of the angiotensin II type 2 (AT(2)) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function...

Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant.

Science.gov (United States)

Goldenberg, Naila; Racine, Michael S; Thomas, Pamela; Degnan, Bernard; Chandler, William; Barkan, Ariel

2008-08-01

Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. This was a descriptive case series of up to 3.5 yr duration. The study was conducted at a university hospital. Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. The intervention was administration of pegvisomant. Plasma IGF-I and growth velocity were measured. In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory.

Study of somatostatin in simple obesity

Energy Technology Data Exchange (ETDEWEB)

Abdel-Hafez, M A; El-Ghazaly, S; El-Feky, N A; Sayed, S N [Cairo Univ. (Egypt)

1990-02-01

C-peptide, as a marker for pancreatic beta cells function, and somatostatin (SS) in plasma of obese males (n = 15) and a corresponding normal weight control subjects (n = 10) are studied. Fasting plasma SS and serum C-peptide are significantly higher in obese vs lean group. This can be explained by hypertrophy of both D- and B-cells of the pancreatic islets reported by other investigators. Post-prandial plasma SS is insignificantly increased in obese vs the control group whereas the increase in C-peptide levels is significant suggesting unequal response of B- and D-cells to meal in the obese group. It is concluded that circulating SS may play an important role in the development if obesity. Hyperinsulinaemia documented in obesity may be due to hypersecretion of insulin. That may contribute to increased somatomedin-C in obesity. (author).

Study of somatostatin in simple obesity

International Nuclear Information System (INIS)

Abdel-Hafez, M.A.; El-Ghazaly, S.; El-Feky, N.A.; Sayed, S.N.

1990-01-01

C-peptide, as a marker for pancreatic beta cells function, and somatostatin (SS) in plasma of obese males (n = 15) and a corresponding normal weight control subjects (n = 10) are studied. Fasting plasma SS and serum C-peptide are significantly higher in obese vs lean group. This can be explained by hypertrophy of both D- and B-cells of the pancreatic islets reported by other investigators. Post-prandial plasma SS is insignificantly increased in obese vs the control group whereas the increase in C-peptide levels is significant suggesting unequal response of B- and D-cells to meal in the obese group. It is concluded that circulating SS may play an important role in the development if obesity. Hyperinsulinaemia documented in obesity may be due to hypersecretion of insulin. That may contribute to increased somatomedin-C in obesity. (author)

Cannabinoid receptor type-1: breaking the dogmas [version 1; referees: 3 approved

Directory of Open Access Journals (Sweden)

Arnau Busquets Garcia

2016-05-01

Full Text Available The endocannabinoid system (ECS is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids, and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1. In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells and intracellular compartments (e.g., mitochondria. Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons. Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

Somatostatin Negatively Regulates Parasite Burden and Granulomatous Responses in Cysticercosis

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Mitra Khumbatta

2014-01-01

Full Text Available Cysticercosis is an infection of tissues with the larval cysts of the cestode, Taenia  solium. While live parasites elicit little or no inflammation, dying parasites initiate a granulomatous reaction presenting as painful muscle nodules or seizures when cysts are located in the brain. We previously showed in the T. crassiceps murine model of cysticercosis that substance P (SP, a neuropeptide, was detected in early granulomas and was responsible for promoting granuloma formation, while somatostatin (SOM, another neuropeptide and immunomodulatory hormone, was detected in late granulomas; SOM’s contribution to granuloma formation was not examined. In the current studies, we used somatostatin knockout (SOM−/− mice to examine the hypothesis that SOM downmodulates granulomatous inflammation in cysticercosis, thereby promoting parasite growth. Our results demonstrated that parasite burden was reduced 5.9-fold in SOM−/− mice compared to WT mice (P<0.05. This reduction in parasite burden in SOM−/− mice was accompanied by a 95% increase in size of their granulomas (P<0.05, which contained a 1.5-fold increase in levels of IFN-γ and a 26-fold decrease in levels of IL-1β (P<0.05 for both compared to granulomas from WT mice. Thus, SOM regulates both parasite burden and granulomatous inflammation perhaps through modulating granuloma production of IFN-γ and IL-1β.

Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods

DEFF Research Database (Denmark)

Collin, Caitlin Alexis; Hauser, Frank; Gonzalez de Valdivia, Ernesto I

2013-01-01

Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1-m5......). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC50, 5 × 10(-8) M......) and muscarine (EC50, 6 × 10(-8) M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked...

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

Directory of Open Access Journals (Sweden)

Igor P. Dmitriev

2014-10-01

Full Text Available A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.

PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma

International Nuclear Information System (INIS)

Haenscheid, Heribert; Buck, Andreas K.; Samnick, Samuel; Kreissl, Michael; Sweeney, Reinhart A.; Flentje, Michael; Loehr, Mario; Verburg, Frederik A.

2012-01-01

To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with 68 Ga-labelled somatostatin analogue. In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq 177 Lu-DOTATOC or 177 Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV max ) in the meningiomas from the PET scans before and after therapy. The median SUV max in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm 3 was a median of 23.4 x 10 -6 (range 0.4 x 10 -6 to 68.3 x 10 -6 ). A strong correlation was observed between SUV max and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P max and the therapeutic uptake (r = 0.95) and between SUV max and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 x 10 -6 (maximum 9.3 x 10 -6 ) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) 177 Lu for the voxel dose from PRRT. PET with 68 Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose. (orig.)

Pharmaceutical design and pharmacological characterization of Tc99m [99mTc] labelled somatostatin and gastrin analogues

International Nuclear Information System (INIS)

Guggenberg, E. von

2004-10-01

The development of regulatory peptide analogues radiolabelled with 99m Tc is of great interest for nuclear medicine applications, as 99m Tc shows very favourable imaging characteristics, such as low radiation burden to the patient, optimal image quality in SPECT, one-day-acquisition-protocol, availability on demand and cost effectiveness. In this work the principles of pharmaceutical design and preclinical pharmacological characterization of regulatory peptide analogues labelled with 99m Tc with possible application in tumour diagnosis are described. [ 99m Tc-EDDA-HYNIC0,Tyr3]octreotide ( 99m Tc-EDDA-HYNIC-TOC) is a promising new radiopharmaceutical with the potential to replace [ 111 In-DTPA0]octreotide in receptor scintigraphy of somatostatin receptor-positive tumours. Radiolabelling at high labelling yields and high specific activities could be obtained applying a coligand exchange labelling approach from tricine for EDDA under optimized conditions of pH, EDDA and stannous ion concentration. The resulting complex was characterized via HPLC, receptor binding and LC-MS. For the development of a freeze-dried kit formulation with long shelf-life, high stability of the final preparation and retained biological activity, the addition of bulking agent, the pH of the freeze-drying solution and the content of stannous chloride were of major importance. Different methods of radiochemical purity testing were evaluated to guarantee high quality of the preparation in a clinical setting, forming the basis for a further clinical evaluation of this promising new radiopharmaceutical. Radiolabelling of [D-Glu1]minigastrin (MG) with 99m Tc was studied applying two different labelling approaches. HYNIC-MG could be labelled using tricine and EDDA as coligands; and (Nalpha-His)Ac-MG was used as tridentate ligand for the 99m Tc carbonyl core. Stability experiments by HPLC analysis in PBS, serum, histidine- and cysteine-solutions as well as rat liver and kidney homogenates, receptor

Uptake kinetics of the somatostatin receptor ligand [{sup 86}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide ([{sup 86}Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the {sup 90}Y-labelled analogue

Energy Technology Data Exchange (ETDEWEB)

Roesch, F.; Brockmann, J. [Forschungszentrum Juelich GmbH (Germany). Inst. fuer Nuklearchemie; Herzog, H.; Muehlensiepen, H.; Mueller-Gaertner, H.W. [Forschungszentrum Juelich GmbH (Germany). Inst. fuer Medizin; Stolz, B.; Marbach, P. [Novartis Pharma AG, Basel (Switzerland); Koehle, M. [Klinikum der Freien Universitaet Berlin (Germany)

1999-04-29

[{sup 90}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide ([{sup 90}Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [{sup 86}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [{sup 86}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide was administered at two different peptide concentrations, namely 2 and 100 {mu}g peptide per m{sup 2} body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [{sup 86}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [{sup 90}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [{sup 90}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide injected. For the 100 {mu}g/m{sup 2} SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [{sup 90}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide, respectively. The average effective dose equivalent amounted to 0.23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [{sup 90}Y]DOTA-dPhe{sup 1}-Tyr{sup 3}-octreotide in patients with somatostatin receptor-expressing tumours. (orig

Peptides for radiotherapy of neuroendocrine cancers

International Nuclear Information System (INIS)

Melendez A, L.

2002-01-01

During the last decade there has been a resurgence of interest in therapeutic nuclear medicine, due to the limitation of conventional or external beam radiotherapy in the treatment of secondary or metastatic cancer sites outside of the primary treatment area. Some of the human tumours that produce metastases express high levels of somatostatin receptors. In order to make possible the diagnostic and radiotherapeutic treatment of these kind of tumours, various somatostatin analogue peptides have been developed in recent years. Peptides have become an important class of radiopharmaceuticals,due to its unique ability to detect specific sites as receptors or enzymes. This paper describes the work with 99m Tc to establish the labelling and analytical conditions for a somatostatin analogue as a precursor, to undertake a therapeutic radiopharmaceutical labelled with 188 Re for treatment of somatostatin receptor positive tumours. (Author)

Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

DEFF Research Database (Denmark)

Xu, Cang-Bao; Zheng, Jian-Pu; Zhang, Wei

2014-01-01

Vasoconstrictive endothelin type B (ET(B)) receptors promote vasospasm and ischemic cerebro- and cardiovascular diseases. The present study was designed to examine if low density lipoprotein (LDL) induces upregulation of vasoconstrictive ET(B) receptor expression and if extracellular signal...

Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines

DEFF Research Database (Denmark)

Hougaard, S; Nørgaard, P; Abrahamsen, N

1999-01-01

Transforming growth factor beta (TGF-beta) exerts a growth inhibitory effect on many cell types through binding to two types of receptors, the type I and II receptors. Resistance to TGF-beta due to lack of type II receptor (RII) has been described in some cancer types including small cell lung...

Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

DEFF Research Database (Denmark)

Klein, H H; Müller, R; Vestergaard, H

1999-01-01

We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in sit...

Characterization of human endothelial cell urokinase-type plasminogen activator receptor protein and messenger RNA

DEFF Research Database (Denmark)

Barnathan, E S; Kuo, A; Karikó, K

1990-01-01

Human umbilical vein endothelial cells in culture (HUVEC) express receptors for urokinase-type plasminogen activators (u-PA). The immunochemical nature of this receptor and its relationship to u-PA receptors expressed by other cell types is unknown. Cross-linking active site-blocked u-PA to HUVEC...... an endothelial cell cDNA library using the polymerase chain reaction (PCR) and oligonucleotide primers corresponding to the DNA sequence of the receptor cloned from transformed human fibroblasts (Roldan et al, EMBO J 9:467, 1990). The size of the cDNA (approximately 1,054 base pairs, bp) and the presence...

Collagen Type I as a Ligand for Receptor-Mediated Signaling

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Iris Boraschi-Diaz

2017-05-01

Full Text Available Collagens form the fibrous component of the extracellular matrix in all multi-cellular animals. Collagen type I is the most abundant collagen present in skin, tendons, vasculature, as well as the organic portion of the calcified tissue of bone and teeth. This review focuses on numerous receptors for which collagen acts as a ligand, including integrins, discoidin domain receptors DDR1 and 2, OSCAR, GPVI, G6b-B, and LAIR-1 of the leukocyte receptor complex (LRC and mannose family receptor uPARAP/Endo180. We explore the process of collagen production and self-assembly, as well as its degradation by collagenases and gelatinases in order to predict potential temporal and spatial sites of action of different collagen receptors. While the interactions of the mature collagen matrix with integrins and DDR are well-appreciated, potential signals from immature matrix as well as collagen degradation products are possible but not yet described. The role of multiple collagen receptors in physiological processes and their contribution to pathophysiology of diseases affecting collagen homeostasis require further studies.

Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

Science.gov (United States)

Basu, Sandip; Ranade, Rohit

2016-06-01

This report illustrates an excellent partial response of Merkel cell carcinoma with multiple bilobar hepatic metastases to a single cycle of peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE. This response, coupled with minimal side effects, warrants consideration of this therapy early in the disease course (rather than at an advanced stage after failure of other therapies) if the metastatic lesions exhibit adequate tracer avidity on somatostatin receptor-based imaging. Our patient showed progression of systemic disease after having undergone a second surgery and adjuvant radiotherapy to the head and neck, as well as chemotherapy, and hence was considered a candidate for PRRT. In a pretreatment study, the metastatic lesions demonstrated avidity to both somatostatin receptors and (18)F-FDG. Three months after the first cycle of treatment, when the patient was being evaluated for a second cycle, both imaging parameters showed evidence of a partial response that included nearly complete resolution of the two previously seen lesions. In view of the relatively good tolerability, minimal side effects, and targeted nature of the treatment, PRRT may evolve to become the first-line therapy for metastatic Merkel cell carcinoma and should be examined further in a larger number of patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.

Science.gov (United States)

Gan, Zhenji; Rumsey, John; Hazen, Bethany C; Lai, Ling; Leone, Teresa C; Vega, Rick B; Xie, Hui; Conley, Kevin E; Auwerx, Johan; Smith, Steven R; Olson, Eric N; Kralli, Anastasia; Kelly, Daniel P

2013-06-01

The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

Concordance between results of somatostatin receptor scintigraphy with 111In-DOTA-DPhe 1-Tyr 3-octreotide and chromogranin A assay in patients with neuroendocrine tumours.

Science.gov (United States)

Rodrigues, Margarida; Gabriel, Michael; Heute, Dirk; Putzer, Daniel; Griesmacher, Andrea; Virgolini, Irene

2008-10-01

Somatostatin receptor scintigraphy (SRS) and chromogranin A (CgA) assay have successfully been implemented in the clinical work-up and management of neuroendocrine tumour (NET) patients. However, there is still a lack of studies comparing results in these patients. Our aim was to compare directly in NET patients SRS and CgA assay results with special regard to tumour features such as grade of malignancy, primary origin, disease extent and function. One hundred twenty consecutive patients with histological confirmed NETs were investigated with (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide ((111)In-DOTA-TOC) SRS and CgA immunoradiometric assay. Tumours were classified by cell characteristics [well-differentiated NETs, well-differentiated neuroendocrine carcinomas, poorly differentiated neuroendocrine carcinomas (PDNECs)], primary origin (foregut, midgut, hindgut, undetermined), disease extent (limited disease, metastases, primary tumour and metastases) and functionality (secretory, nonsecretory). SRS was positive in 107 (89%) patients; CgA levels were increased in 95 (79%) patients. Overall, concordance between SRS and CgA results was found in 84 patients. Positive SRS but normal CgA level were found in 24 patients, with higher prevalence (p<0.05) in patients with nonsecretory tumours. Conversely, negative SRS but CgA level increased were seen in 12 patients, with higher proportion (p<0.05) in patients with PDNECs and tumours of hindgut origin. Overall, (111)In-DOTA-TOC SRS proved to be more sensitive than CgA in NETs patients. Tumour differentiation, disease extent and presence of liver metastases impact both SRS and CgA results, whereas nonsecretory activity is a negative predictor of only CgA increase. PDNECs and hindgut origin of tumours predispose to discrepancies with negative SRS but increased CgA levels.

68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax

International Nuclear Information System (INIS)

Boy, Christian; Poeppel, Thorsten D.; Jentzen, Walter; Brandau, Wolfgang; Bockisch, Andreas; Heusner, Till A.; Antoch, Gerald; Redmann-Bischofs, Anja; Unger, Nicole; Mann, Klaus; Petersenn, Stephan

2011-01-01

By targeting somatostatin receptors (sst) radiopeptides have been established for both diagnosis and therapy. For physiologically normal human tissues the study provides a normative database of maximum standardized uptake value (SUV max ) and sst mRNA. A total of 120 patients were subjected to diagnostic 68 Ga-DOTATOC positron emission tomography (PET)/CT (age range 19-83 years). SUV max values were measured in physiologically normal tissues defined by normal morphology, absence of surgical intervention and absence of metastatic spread during clinical follow-up. Expression of sst subtypes (sst1-sst5) was measured independently in pooled adult normal human tissue by real-time reverse transcriptase polymerase chain reaction (RT-PCR). SUV max revealed a region-specific pattern (e.g., mean ± SD, spleen 31.1 ± 10.9, kidney 16.9 ± 5.3, liver 12.8 ± 3.6, stomach 7.0 ± 3.1, head of pancreas 6.2 ± 2.3, small bowel 4.8 ± 1.8, thyroid 4.7 ± 2.2, bone 3.9 ± 1.3, large bowel 2.9 ± 0.8, muscle 2.1 ± 0.5, parotid gland 1.9 ± 0.6, axillary lymph node 0.8 ± 0.3 and lung 0.7 ± 0.3). SUV max was age independent. Gender differences were evident within the thyroid (female/male: 3.7 ± 1.6/5.5 ± 2.4, p max values exclusively correlated with sst2 expression (r = 0.846, p max with the expression of the other four subtypes. In normal human tissues 68 Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis. (orig.)

Interleukin-1-receptor antagonist in type 2 diabetes mellitus

DEFF Research Database (Denmark)

Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

2007-01-01

BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...... placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary...

Three mutations switch H7N9 influenza to human-type receptor specificity

Energy Technology Data Exchange (ETDEWEB)

de Vries, Robert P.; Peng, Wenjie; Grant, Oliver C.; Thompson, Andrew J.; Zhu, Xueyong; Bouwman, Kim M.; de la Pena, Alba T. Torrents; van Breemen, Marielle J.; Ambepitiya Wickramasinghe, Iresha N.; de Haan, Cornelis A. M.; Yu, Wenli; McBride, Ryan; Sanders, Rogier W.; Woods, Robert J.; Verheije, Monique H.; Wilson, Ian A.; Paulson, James C.; Fernandez-Sesma, Ana

2017-06-15

The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal) to human-type (NeuAcα2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells.

Three mutations switch H7N9 influenza to human-type receptor specificity.

Directory of Open Access Journals (Sweden)

Robert P de Vries

2017-06-01

Full Text Available The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA mutation (Q226L that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal to human-type (NeuAcα2-6Gal, as documented for the avian progenitors of the 1957 (H2N2 and 1968 (H3N2 human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells.

Circadian modulation of anxiety: a role for somatostatin in the amygdala.

Directory of Open Access Journals (Sweden)

Anne Albrecht

Full Text Available Pharmacological evidence suggests that the neuropeptide somatostatin (SST exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST⁻/⁻ mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST⁻/⁻ mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates. Behavioral differences occurred independently of changes of intrinsically motivated activity in the home cage. A circadian regulation of SST mRNA and protein expression that was evident in the basolateral complex of the amygdala of wild type mice may provide a neuronal substrate for the observed behavior. However, fear memory towards auditory cue or the conditioning context displayed neither a time- nor genotype-dependent modulation. Together this indicates that SST, in a circadian manner and putatively via its regulation of expression in the amygdala, modulates behavior responding to mildly aversive conditions in mice.

Radio-peptides targeting g-protein coupled receptors in cancer: from bench to bed

International Nuclear Information System (INIS)

Maecke, H.R.

2015-01-01

Full text of publication follows. In the development of targeted imaging and therapy agents the most important challenge and prerequisite is to identify and validate the molecular targets of any disease. The targets should be specific, relevant, easily accessible and highly expressed. In addition they should have no or at least very low expression in normal tissue. Among the many drug targets is the large family of G-protein coupled receptors (GPCRs). It is the most important family of marketed drugs and the basic accomplishments in the field were recognised by the award of the recent Nobel price in chemistry. GPCRs also play a role in cancer. Several of these receptors are massively over-expressed in different human tumors such as neuroendocrine tumors (over-expression of the somatostatin receptor family), prostate and breast tumors (bombesin receptor family), brain tumors (NK1 receptor) etc.. This allows to develop (nuclear, MRI, optical) probes for imaging and potentially targeted therapy (theragnostics). Natural ligands targeting GPCRs are often peptides. They need to be modified for metabolic stability, modified for labeling with radio-metals (conjugation of bifunctional chelators) or radio-halogens (prosthetic groups). Preserved biological integrity after modification and labeling needs to be assured, long retention times in the tumor is important, conferred by internalisation. Radio-metal labeling in particular needs to be reasonably fast and the radio metal complexes have to show high stability with regard to radio-metal release. These prerequisites will be discussed for somatostatin receptor based radio-peptides in particular. For a successful clinical application preclinical imaging and biodistribution in adequate animal models are mandatory. New tracers for positron emission tomography (PET) and single photon emission computed tomography (SPECT) will be presented for neuroendocrine tumors and prostate cancer. In particular radiolabeled antagonists will

Receptors for sensory neuropeptides in human inflammatory diseases: Implications for the effector role of sensory neurons

International Nuclear Information System (INIS)

Mantyh, P.W.; Catton, M.D.; Boehmer, C.G.; Welton, M.L.; Passaro, E.P. Jr.; Maggio, J.E.; Vigna, S.R.

1989-01-01

Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. Using quantitative receptor autoradiography we have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in the colon in two human inflammatory diseases, ulcerative colitis and Crohn's disease. The sensory neurotransmitter receptors examined included bombesin, calcitonin gene related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only substance P binding sites associated with arterioles, venules and lymph nodules were dramatically up-regulated in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues

Signalling through C-type lectin receptors: shaping immune responses

NARCIS (Netherlands)

Geijtenbeek, Teunis B. H.; Gringhuis, Sonja I.

2009-01-01

C-type lectin receptors (CLRs) expressed by dendritic cells are crucial for tailoring immune responses to pathogens. Following pathogen binding, CLRs trigger distinct signalling pathways that induce the expression of specific cytokines which determine T cell polarization fates. Some CLRs can induce

Animal experiment of 111In-DTPA-D-Phe1-octreotide

International Nuclear Information System (INIS)

Wang Fan; Xiao Lun; Fan Hongqiang; Jin Xiaohai; Wang Yishan; Chen Daming; Bai Hongsheng; Chen Fang; Li Jiaxiu; Liu Lin

1998-01-01

The animal experiments of a novel somatostatin receptor-positive tumors imaging agent, 111 In-DTPA-D-Phe 1 -octreotide, has been described. Biological properties were evaluated by dynamic and static γ images of somatostatin receptor-positive tumors in nude mice bearing pancreatic carcinoma. The radiocomponent of 111 In-DTPA, which came from 111 In-DTPA-D-Phe 1 -octreotide decomposition, showed 50% of radioactivity in blood and 40% in urine at 3h postinjection. Rapid blood and urine clearance, and high T/B ratio (7.92 up to 24 h postinjection) were observed. The images of somatostatin receptor-positive tumors could be obtained during 0.5-24 h after administration but the best one would be at 24 h

Angiotensin type 2 receptors

DEFF Research Database (Denmark)

Sumners, Colin; de Kloet, Annette D; Krause, Eric G

2015-01-01

In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas

Science.gov (United States)

Wang, Ji-wen; Li, Ying; Mao, Zhi-gang; Hu, Bin; Jiang, Xiao-bing; Song, Bing-bing; Wang, Xin; Zhu, Yong-hong; Wang, Hai-jun

2014-01-01

Excessive growth hormone (GH) is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults. The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly. Control of serum GH and insulin-like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity. Current pharmacotherapy includes somatostatin analogs (SAs) and GH receptor antagonist; the former consists of lanreotide Autogel (ATG) and octreotide long-acting release (LAR), and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4–6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits. PMID:24421637

Application of gamma-aminobutyric acid type A-benzodiazepine receptor imaging for study of neuropsychiatric disorders

International Nuclear Information System (INIS)

Bao Weiqi; Qiu Chun; Guan Yihui

2012-01-01

Gamma-aminobutyric acid type A-benzodiazepine receptors are heterogeneous polypeptide pentamers widely spread in the central nervous system on the neuron membrane. Different subunit combinations educe various neuro-inhibitory pharmacological effects such as sedative, hypnosis, anticonvulsion and anxiolysis. PET can be utilized to study the binding of the receptors in vivo. PET radioligands of gamma-aminobutyric acid type A-benzodiazepine receptors can be classified into 3 types: antagonists,agonists and reverse agonists, of which antagonist radiotracer 11 C-flumazenil is the most commonly applied in epilepsy, anxiety disorders, depression, vegetative state,addiction and other neuro-psychiatric disorders. (authors)

The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor

DEFF Research Database (Denmark)

Atfi, Azeddine; Dumont, Emmanuelle; Colland, Frédéric

2007-01-01

Transforming growth factor-beta (TGF-beta) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-beta type I receptor and the TGF-beta type II receptor (TbetaRII). Upon ligand binding, TGF-beta type I receptor activated by TbetaRII propagat......RII protein presumably by suppressing the association of TbetaRII with Smad7. These results define ADAM12 as a new partner of TbetaRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated....

Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

Science.gov (United States)

Robertson, Chelsea L; Ishibashi, Kenji; Mandelkern, Mark A; Brown, Amira K; Ghahremani, Dara G; Sabb, Fred; Bilder, Robert; Cannon, Tyrone; Borg, Jacqueline; London, Edythe D

2015-04-15

Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition. Copyright © 2015 the authors 0270-6474/15/355990-08$15.00/0.

Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS.

Science.gov (United States)

Leonhardt, Julia; Villela, Daniel C; Teichmann, Anke; Münter, Lisa-Marie; Mayer, Magnus C; Mardahl, Maibritt; Kirsch, Sebastian; Namsolleck, Pawel; Lucht, Kristin; Benz, Verena; Alenina, Natalia; Daniell, Nicholas; Horiuchi, Masatsugu; Iwai, Masaru; Multhaup, Gerhard; Schülein, Ralf; Bader, Michael; Santos, Robson A; Unger, Thomas; Steckelings, Ulrike Muscha

2017-06-01

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other. © 2017 American Heart Association, Inc.

Age-related changes in Serum Growth Hormone, Insulin-like Growth Factor-1 and Somatostatin in System Lupus Erythematosus

Directory of Open Access Journals (Sweden)

Malemud Charles J

2004-10-01

Full Text Available Abstract Background Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus patients to a group of normal female subjects. Methods Basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels were measured by standard radioimmunoassay. Results Serum growth hormone levels failed to correlate with age (r2 = 3.03 in the entire group of normal subjects (i.e. 20 – 80 years. In contrast, serum insulin-like growth factor-1 levels were inversely correlated with age (adjusted r2 = 0.092. Of note, serum growth hormone was positively correlated with age (adjusted r2 = 0.269 in the 20 – 46 year range which overlapped with the age range of patients in the systemic lupus erythematosus group. In that regard, serum growth hormone levels were not significantly higher compared to either the entire group of normal subjects (20 – 80 yrs or to normal subjects age-matched to the systemic lupus erythematosus patients. Serum insulin-like growth factor-1 levels were significantly elevated (p 55 yrs systemic lupus erythematosus patients. Conclusions These results indicated that systemic lupus erythematosus was not characterized by a modulation of the growth hormone/insulin-like growth factor-1 paracrine axis when serum samples from systemic lupus erythematosus patients were compared to age- matched normal female subjects. These results in systemic lupus erythematosus differ from those previously reported in other musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, fibromyalgia, diffuse idiopathic skeletal

Structure and organization of heteromeric AMPA-type glutamate receptors.

Science.gov (United States)

Herguedas, Beatriz; García-Nafría, Javier; Cais, Ondrej; Fernández-Leiro, Rafael; Krieger, James; Ho, Hinze; Greger, Ingo H

2016-04-29

AMPA-type glutamate receptors (AMPARs), which are central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the subunits GluA1 to GluA4. Here we report the first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomer structures. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine cross-linking in full-length receptors, and it permitted us to determine the structure of an intact GluA2/3 receptor by cryogenic electron microscopy. Two models in the ligand-free state, at resolutions of 8.25 and 10.3 angstroms, exhibit substantial vertical compression and close associations between domain layers, reminiscent of N-methyl-D-aspartate receptors. Model 1 resembles a resting state and model 2 a desensitized state, thus providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling. Copyright © 2016, American Association for the Advancement of Science.

Expression of Dihydropyridine and Ryanodine Receptors in Type IIA Fibers of Rat Skeletal Muscle

International Nuclear Information System (INIS)

Anttila, Katja; Mänttäri, Satu; Järvilehto, Matti

2007-01-01

In this study, the fiber type specificity of dihydropyridine receptors (DHPRs) and ryanodine receptors (RyRs) in different rat limb muscles was investigated. Western blot and histochemical analyses provided for the first time evidence that the expression of both receptors correlates to a specific myosin heavy chain (MHC) composition. We observed a significant (p=0.01) correlation between DHP as well as Ry receptor density and the expression of MHC IIa (correlation factor r=0.674 and r=0.645, respectively) in one slow-twitch, postural muscle (m. soleus), one mixed, fast-twitch muscle (m. gastrocnemius) and two fast-twitch muscles (m. rectus femoris, m. extensor digitorum longus). The highest DHP and Ry receptor density was found in the white part of m. rectus femoris (0.058±0.0060 and 0.057±0.0158 ODu, respectively). As expected, the highest relative percentage of MHC IIa was also found in the white part of m. rectus femoris (70.0±7.77%). Furthermore, histochemical experiments revealed that the IIA fibers stained most strongly for the fluorophore-conjugated receptor blockers. Our data clearly suggest that the expression of DHPRs and RyRs follows a fiber type-specific pattern, indicating an important role for these proteins in the maintenance of an effective Ca 2+ cycle in the fast contracting fiber type IIA

PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma

Energy Technology Data Exchange (ETDEWEB)

Haenscheid, Heribert; Buck, Andreas K.; Samnick, Samuel; Kreissl, Michael [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Sweeney, Reinhart A.; Flentje, Michael [University Hospital Wuerzburg, Department of Radiation Oncology, Wuerzburg (Germany); Loehr, Mario [University Hospital Wuerzburg, Department of Neurosurgery, Wuerzburg (Germany); Verburg, Frederik A. [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); RWTH University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany)

2012-08-15

To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with {sup 68}Ga-labelled somatostatin analogue. In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq {sup 177}Lu-DOTATOC or {sup 177}Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV{sub max}) in the meningiomas from the PET scans before and after therapy. The median SUV{sub max} in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm{sup 3} was a median of 23.4 x 10{sup -6} (range 0.4 x 10{sup -6} to 68.3 x 10{sup -6}). A strong correlation was observed between SUV{sub max} and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV{sub max} and the therapeutic uptake (r = 0.95) and between SUV{sub max} and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 x 10{sup -6} (maximum 9.3 x 10{sup -6}) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) {sup 177}Lu for the voxel dose from PRRT. PET with {sup 68}Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour

Radiolabelled peptides for tumour therapy: current status and future directions. Plenary lecture at the EANM 2002

International Nuclear Information System (INIS)

Jong, Marion de; Kwekkeboom, Dik; Valkema, Roelf; Krenning, Eric P.

2003-01-01

On their plasma membranes, cells express receptor proteins with high affinity for regulatory peptides, such as somatostatin. Changes in the density of these receptors during disease, e.g. overexpression in many tumours, provide the basis for new imaging methods. The first peptide analogues successfully applied for visualisation of receptor-positive tumours were radiolabelled somatostatin analogues. The next step was to label these analogues with therapeutic radionuclides for peptide receptor radionuclide therapy (PRRT). Results from preclinical and clinical multicentre studies have already shown an effective therapeutic response when using radiolabelled somatostatin analogues to treat receptor-positive tumours. Infusion of positively charged amino acids reduces kidney uptake, enlarging the therapeutic window. For PRRT of CCK-B receptor-positive tumours, such as medullary thyroid carcinoma, radiolabelled minigastrin analogues are currently being successfully applied. The combination of different therapy modalities holds interest as a means of improving the clinical therapeutic effects of radiolabelled peptides. The combination of different radionuclides, such as 177 Lu- and 90 Y-labelled somatostatin analogues, to reach a wider tumour region of high curability, has been described. A variety of other peptide-based radioligands, such as bombesin and NPY(Y 1 ) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation. Multi-receptor tumour targeting using the combination of bombesin and NPY(Y 1 ) analogues is promising for scintigraphy and PRRT of breast carcinomas and their lymph node metastases. (orig.)

Limitations and pitfalls of 99mTc-EDDA/HYNIC-TOC (Tektrotyd) scintigraphy.

Science.gov (United States)

Garai, Ildikó; Barna, Sandor; Nagy, Gabor; Forgacs, Attila

2016-01-01

Tektrotyd kit was developed by Polatom company for 99mTc labeling to make an alternative tracer of somatostatin receptor scintigraphy available. Since 2005, 99mTc-EDDA/HYNIC-Tyr3-Octreotide has been used in clinical imaging and achieved high impact in management of patients with neuroendocrine tumors. Knowing the limitations and pitfalls is essential to provide ac-curate diagnosis. Therefore, the potential pitfalls associated with the use of 99mTc-EDDA/HYNIC-TOC are reviewed on the basis of own experience. Data were analyzed of 310 patients who underwent somatostatin receptor scintigraphy with 99mTc-Tektrotyd. Pitfalls during radiolabeling process or acquisition can worsen the sensitivity of SRS (somatostatin receptor scintigraphy). Recognizing physi-ological and clinical pitfalls, the diagnostic accuracy will improve.

Autoradiography after incubation of tissue slices in 111 In-pentetreotide. Demonstration of the feasibility of the technique on rat brain slices. Application in two cases of human renal cell carcinoma

International Nuclear Information System (INIS)

Montravers, F.; Allard, S.; Fouret, P.; Daty, N.; Talbot, J.N.; Bernaudin, J.F.

1996-01-01

We report on a macroscopic autoradiographic technique using 111 In-pentetreotide after in vitro incubation of the slices. The feasibility of this technique has been demonstrated by the actual labeling of the deeper layers of the rat cerebral cortex, corresponding to the known cerebral distribution of somatostatin subtype 2 receptor. This technique has subsequently been applied in two of human renal cell carcinoma and has proven the presence of somatostatin receptors in both tumours. In one of these cases, a preoperative scintigraphy using 111 In-pentetreotide showed the absence of tumour visualization. The mechanism proposed to explain this discrepancy between scintigraphic and autoradiographic results is a lack of accessibility of the somatostatin analog to the receptor in case of voluminous renal tumour. (authors). 19 refs., 2 figs

The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

DEFF Research Database (Denmark)

Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

2011-01-01

The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

DEFF Research Database (Denmark)

Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

2007-01-01

Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p...

Effect of somatostatin on repair of ionizing radiation-induced DNA damage in pituitary adenoma cells GH3

Czech Academy of Sciences Publication Activity Database

Řezáčová, M.; Čáp, J.; Vokurková, D.; Lukášová, Emilie; Vávrová, J.; Cerman, J.; Mašín, V.; Mazánková, N.

2008-01-01

Roč. 57, č. 2 (2008), s. 225-235 ISSN 0862-8408 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : acromegaly * somatostatin * ionizing radiation Subject RIV: BO - Biophysics Impact factor: 1.653, year: 2008

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human-type receptors

Energy Technology Data Exchange (ETDEWEB)

de Vries, Robert P.; Tzarum, Netanel; Peng, Wenjie; Thompson, Andrew J.; Ambepitiya Wickramasinghe, Iresha N.; de la Pena, Alba T. Torrents; van Breemen, Marielle J.; Bouwman, Kim M.; Zhu, Xueyong; McBride, Ryan; Yu, Wenli; Sanders, Rogier W.; Verheije, Monique H.; Wilson, Ian A.; Paulson, James C.

2017-07-10

In June 2013, the first case of human infection with an avian H6N1 virus was reported in a Taiwanese woman. Although this was a single non-fatal case, the virus continues to circulate in Taiwanese poultry. As with any emerging avian virus that infects humans, there is concern that acquisition of human-type receptor specificity could enable transmission in the human population. Despite mutations in the receptor-binding pocket of the human H6N1 isolate, it has retained avian-type (NeuAcα2-3Gal) receptor specificity. However, we show here that a single nucleotide substitution, resulting in a change from Gly to Asp at position 225 (G225D), completely switches specificity to human-type (NeuAcα2-6Gal) receptors. Significantly, G225D H6 loses binding to chicken trachea epithelium and is now able to bind to human tracheal tissue. Structural analysis reveals that Asp225 directly interacts with the penultimate Gal of the human-type receptor, stabilizing human receptor binding.

Chimeric Feline Coronaviruses That Encode Type II Spike Protein on Type I Genetic Background Display Accelerated Viral Growth and Altered Receptor Usage▿

Science.gov (United States)

Tekes, Gergely; Hofmann-Lehmann, Regina; Bank-Wolf, Barbara; Maier, Reinhard; Thiel, Heinz-Jürgen; Thiel, Volker

2010-01-01

Persistent infection of domestic cats with feline coronaviruses (FCoVs) can lead to a highly lethal, immunopathological disease termed feline infectious peritonitis (FIP). Interestingly, there are two serotypes, type I and type II FCoVs, that can cause both persistent infection and FIP, even though their main determinant of host cell tropism, the spike (S) protein, is of different phylogeny and displays limited sequence identity. In cell culture, however, there are apparent differences. Type II FCoVs can be propagated to high titers by employing feline aminopeptidase N (fAPN) as a cellular receptor, whereas the propagation of type I FCoVs is usually difficult, and the involvement of fAPN as a receptor is controversial. In this study we have analyzed the phenotypes of recombinant FCoVs that are based on the genetic background of type I FCoV strain Black but encode the type II FCoV strain 79-1146 S protein. Our data demonstrate that recombinant FCoVs expressing a type II FCoV S protein acquire the ability to efficiently use fAPN for host cell entry and corroborate the notion that type I FCoVs use another main host cell receptor. We also observed that recombinant FCoVs display a large-plaque phenotype and, unexpectedly, accelerated growth kinetics indistinguishable from that of type II FCoV strain 79-1146. Thus, the main phenotypic differences for type I and type II FCoVs in cell culture, namely, the growth kinetics and the efficient usage of fAPN as a cellular receptor, can be attributed solely to the FCoV S protein. PMID:19906918

Attenuated purinergic receptor function in patients with type 2 diabetes

DEFF Research Database (Denmark)

Thaning, Pia; Bune, Laurids T.; Hellsten, Ylva

2010-01-01

Objective: Extra cellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation but the extent to which the vasodilatatory capacity of nucleotides and nucleosides are affected in type 2 diabetes is unknown. The present...... study investigated: 1) the vasodilatatory effect of ATP, UTP, and adenosine (ADO) and 2) the expression and distribution of P2Y(2) and P2X(1) receptors in skeletal muscles of diabetic subjects. Research Design and Methods: In 10 diabetic patients and 10 age-matched controls, leg blood flow (LBF......-DM (1.5). The distribution and mRNA-expression of receptors were similar in the two groups. Conclusions: The vasodilatatory effect of the purinergic system is severely reduced in type 2 diabetic patients. The potency of nucleotides varies with the following rank order: UTP>ATP>>>ADO. This is not due...

[Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

Science.gov (United States)

Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

2015-01-01

Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

The future of type 1 cannabinoid receptor allosteric ligands.

Science.gov (United States)

Alaverdashvili, Mariam; Laprairie, Robert B

2018-02-01

Allosteric modulation of the type 1 cannabinoid receptor (CB1R) holds great therapeutic potential. This is because allosteric modulators do not possess intrinsic efficacy, but instead augment (positive allosteric modulation) or diminish (negative allosteric modulation) the receptor's response to endogenous ligand. Consequently, CB1R allosteric modulators have an effect ceiling which allows for the tempering of CB1R signaling without the desensitization, tolerance, dependence, and psychoactivity associated with orthosteric compounds. Pain, movement disorders, epilepsy, obesity are all potential therapeutic targets for CB1R allosteric modulation. Several challenges exist for the development of CB1R allosteric modulators, such as receptor subtype specificity, translation to in vivo systems, and mixed allosteric/agonist/inverse agonist activity. Despite these challenges, elucidation of crystal structures of CB1R and compound design based on structure-activity relationships will advance the field. In this review, we will cover recent progress for CB1R allosteric modulators and discuss the future promise of this research.

Fluorescent ligands for studying neuropeptide receptors by confocal microscopy

Directory of Open Access Journals (Sweden)

A. Beaudet

1998-11-01

Full Text Available This paper reviews the use of confocal microscopy as it pertains to the identification of G-protein coupled receptors and the study of their dynamic properties in cell cultures and in mammalian brain following their tagging with specific fluorescent ligands. Principles that should guide the choice of suitable ligands and fluorophores are discussed. Examples are provided from the work carried out in the authors' laboratory using custom synthetized fluoresceinylated or BODIPY-tagged bioactive peptides. The results show that confocal microscopic detection of specifically bound fluorescent ligands permits high resolution appraisal of neuropeptide receptor distribution both in cell culture and in brain sections. Within the framework of time course experiments, it also allows for a dynamic assessment of the internalization and subsequent intracellular trafficking of bound fluorescent molecules. Thus, it was found that neurotensin, somatostatin and mu- and delta-selective opioid peptides are internalized in a receptor-dependent fashion and according to receptor-specific patterns into their target cells. In the case of neurotensin, this internalization process was found to be clathrin-mediated, to proceed through classical endosomal pathways and, in neurons, to result in a mobilization of newly formed endosomes from neural processes to nerve cell bodies and from the periphery of cell bodies towards the perinuclear zone. These mechanisms are likely to play an important role for ligand inactivation, receptor regulation and perhaps also transmembrane signaling.

Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas

DEFF Research Database (Denmark)

Qader, S.S.; Hakanson, R.; Lundquist, I.

2008-01-01

ghrelin, and to the 23-amino acid peptide obestatin, claimed to be a physiological opponent of acyl ghrelin. This study examines the effects of the proghrelin products, alone and in combinations, on the secretion of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin from isolated islets...... times higher concentration than acyl ghrelin (corresponding to the ratio of the two peptides in circulation), desacyl ghrelin abolished the effects of acyl ghrelin but not those of obestatin. Acyl ghrelin and obestatin affected the secretion of glucagon, PP and somatostatin at physiologically relevant...

Dynamic determination of kinetic parameters for the interaction between polypeptide hormones and cell-surface receptors in the perfused rat liver by the multiple-indicator dilution method

International Nuclear Information System (INIS)

Sato, H.; Sugiyama, Y.; Sawada, Y.; Iga, T.; Sakamoto, S.; Fuwa, T.; Hanano, M.

1988-01-01

Hepatic elimination of epidermal growth factor (EGF) via receptor-mediated endocytosis was studied by a multiple-indicator dilution method in the isolated perfused rat liver, in which cell polarity and spatial organization are maintained. In this method EGF was given with inulin, an extracellular reference, as a bolus into the portal vein, and dilution curves of both compounds in the hepatic vein effluent were analyzed. Analysis of the dilution curve for EGF, compared with that for somatostatin, which showed no specific binding to isolated liver plasma membranes, resulted as follows: (i) both extraction ratio and distribution volume of 125 I-labeled EGF decreased as the injected amount of unlabeled EGF increased; (ii) the ratio plot of the dilution curve for EGF exhibited an upward straight line initially for a short period of time, whereas the ratio plot of somatostatin gradually decreased. The multiple-indicator dilution method was used for other peptides also. Insulin and glucagon, known to have hepatocyte receptors, behaved similarly to EGF in shape of their ratio plots. The kinetic parameters calculated by this analysis were comparable with reported values obtained by in vitro direct binding measurements at equilibrium using liver homogenates. They conclude that the multiple-indicator dilution method is a good tool for analyzing the dynamics of peptide hormones-cell-surface receptor interaction under a condition in which spatial architecture of the liver is maintained

Study on the changes of serum levels of polypeptide growth factors (EGF, TGF-α) and related hormones (gastrin, somatostatin) in patients with peptic ulcer

International Nuclear Information System (INIS)

Cao Jianfan; Ma Yunbao; Zhang Xiaoyi

2005-01-01

Objective: To study the possible roles of EGF, TGF-α, gastrin and somatostatin in the pathogenesis of peptic ulcer by measuring the changes of serum levels of those four parameters in the patients with peptic ulcer. Methods: Serum levels of epidermal growth factor (EGF), transforming growth factor-α (TGF-α), gastrin (Gas) and somatostatin (SS) were measured with RIA in 30 patients with gastric ulcer, 32 patients with duodenal ulcer and 30 controls. Results: Serum levels of gastrin and EGF were significantly higher in the patients with peptic ulcer than those in the controls (both P 0.05). However, serum TGF-α levels were significantly lower in the ulcer patients than those in the controls (P<0.01). Conclusion: Changes of serum levels of gastrin, EGF and TGF-α were quite significant in the ulcer patients and determining of which might be of clinical meanings. Determination of somatostatin changes seemed to be of less importance. (authors)

PeaTAR1B: Characterization of a Second Type 1 Tyramine Receptor of the American Cockroach, Periplaneta americana.

Science.gov (United States)

Blenau, Wolfgang; Balfanz, Sabine; Baumann, Arnd

2017-10-30

The catecholamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. In insects; these neuroactive substances are functionally replaced by the phenolamines octopamine and tyramine. Phenolamines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Type 1 tyramine receptors are better activated by tyramine than by octopamine. In contrast; type 2 tyramine receptors are almost exclusively activated by tyramine. Functionally; activation of type 1 tyramine receptors leads to a decrease in the intracellular concentration of cAMP ([cAMP] i ) whereas type 2 tyramine receptors can mediate Ca 2+ signals or both Ca 2+ signals and effects on [cAMP] i . Here; we report that the American cockroach ( Periplaneta americana ) expresses a second type 1 tyramine receptor (PeaTAR1B) in addition to PeaTAR1A (previously called PeaTYR1). When heterologously expressed in flpTM cells; activation of PeaTAR1B by tyramine leads to a concentration-dependent decrease in [cAMP] i . Its activity can be blocked by a series of established antagonists. The functional characterization of two type 1 tyramine receptors from P. americana ; PeaTAR1A and PeaTAR1B; which respond to tyramine by changing cAMP levels; is a major step towards understanding the actions of tyramine in cockroach physiology and behavior; particularly in comparison to the effects of octopamine.

PeaTAR1B: Characterization of a Second Type 1 Tyramine Receptor of the American Cockroach, Periplaneta americana

Directory of Open Access Journals (Sweden)

Wolfgang Blenau

2017-10-01

Full Text Available The catecholamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. In insects; these neuroactive substances are functionally replaced by the phenolamines octopamine and tyramine. Phenolamines activate specific guanine nucleotide-binding (G protein-coupled receptors (GPCRs. Type 1 tyramine receptors are better activated by tyramine than by octopamine. In contrast; type 2 tyramine receptors are almost exclusively activated by tyramine. Functionally; activation of type 1 tyramine receptors leads to a decrease in the intracellular concentration of cAMP ([cAMP]i whereas type 2 tyramine receptors can mediate Ca2+ signals or both Ca2+ signals and effects on [cAMP]i. Here; we report that the American cockroach (Periplaneta americana expresses a second type 1 tyramine receptor (PeaTAR1B in addition to PeaTAR1A (previously called PeaTYR1. When heterologously expressed in flpTM cells; activation of PeaTAR1B by tyramine leads to a concentration-dependent decrease in [cAMP]i. Its activity can be blocked by a series of established antagonists. The functional characterization of two type 1 tyramine receptors from P. americana; PeaTAR1A and PeaTAR1B; which respond to tyramine by changing cAMP levels; is a major step towards understanding the actions of tyramine in cockroach physiology and behavior; particularly in comparison to the effects of octopamine.

Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation.

Science.gov (United States)

Peng, Wenjie; Bouwman, Kim M; McBride, Ryan; Grant, Oliver C; Woods, Robert J; Verheije, Monique H; Paulson, James C; de Vries, Robert P

2018-05-15

All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human-type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet-transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6-sialylated N-linked glycans recognized by human influenza viruses. IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret

Dual specificity of activin type II receptor ActRIIb in dorso-ventral patterning during zebrafish embryogenesis.

Science.gov (United States)

Nagaso, H; Suzuki, A; Tada, M; Ueno, N

1999-04-01

Members of the transforming growth factor-beta (TGF-beta) superfamily are thought to regulate specification of a variety of tissue types in early embryogenesis. These effects are mediated through a cell surface receptor complex, consisting of two classes of ser/thr kinase receptor, type I and type II. In the present study, cDNA encoding zebrafish activin type II receptors, ActRIIa and ActRIIb was cloned and characterized. Overexpression of ActRIIb in zebrafish embryos caused dorsalization of embryos, as observed in activin-overexpressing embryos. However, in blastula stage embryos, ActRIIb induced formation of both dorsal and ventro-lateral mesoderm. It has been suggested that these inducing signals from ActRIIb are mediated through each specific type I receptor, TARAM-A and BMPRIA, depending on activin and bone morphogenetic protein (BMP), respectively. In addition, it was shown that a kinase-deleted form of ActRIIb (dnActRIIb) suppressed both activin- and BMP-like signaling pathways. These results suggest that ActRIIb at least has dual roles in both activin and BMP signaling pathways during zebrafish embryogenesis.

Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

Directory of Open Access Journals (Sweden)

Alessandro Silvani

Full Text Available Cannabinoid type 1 (CB1 receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD. We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD and HFD. CB1 cannabinoid receptor knock-out (KO and wild-type (WT mice were fed SD or HFD for 4 months (n = 9-10 per group. Mice were instrumented with electroencephalographic (EEG and electromyographic electrodes. Recordings were performed during baseline (48 hours, sleep deprivation (gentle handling, 6 hours, sleep recovery (18 hours, and after cage switch (insomnia model paradigm, 6 hours. We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS and rapid-eye-movement sleep (REMS than WT during the dark (active period but not during the light (rest period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

Physiology and physiopathology of central type Benzodiazepine receptors: Study in the monkey and in human brain using positron emission tomography

International Nuclear Information System (INIS)

Hantraye, P.

1987-01-01

A new non-invasive technique that allows to study in a living subject central type benzodiazepine receptors is developed. A combined approach is applied using a specific positron-emitting radiotracer for the in vivo labelling of the receptors and positron emission tomography allowing, by external detection, a quantitative determination of tissue radioactivity. The radioligand used for the in vivo labelling of benzodiazepine receptors is the antagonist RO 15-1788 labelled with carbon 11. The various stages of the study are described: in vivo characterization in the monkey of central type benzodiazepine receptors; characterization of central type benzodiazepine receptors in human brain using selective molecules for the BZ1 benzodiazepine subclass; demonstration of the heterogeneity of central type benzodiazepine receptors in the brain; study of pathological alteration of benzodiazepine receptors in experimental epilepsy [fr

The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu.

Science.gov (United States)

Volková, Marie; Mandíková, Jana; Bárta, Pavel; Navrátilová, Lucie; Lázníčková, Alice; Trejtnar, František

2015-01-01

In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite. Copyright © 2015 John Wiley & Sons, Ltd.

Agonist-dependent effects of mutations in the sphingosine-1-phosphate type 1 receptor

NARCIS (Netherlands)

van Loenen, Pieter B.; de Graaf, Chris; Verzijl, Dennis; Leurs, Rob; Rognan, Didier; Peters, Stephan L. M.; Alewijnse, Astrid E.

2011-01-01

The sphingosine-1-phosphate type 1 (S1P(1)) receptor is a new target in the treatment of auto-immune diseases as evidenced by the recent approval of FTY720 (Fingolimod). The ligand-binding pocket of the S1P(1) receptor has been generally characterised but detailed insight into ligand-specific

Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

Science.gov (United States)

Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

1998-01-01

OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression

Science.gov (United States)

Nugent, Allison C.; Bain, Earle E.; Carlson, Paul J.; Neumeister, Alexander; Bonne, Omer; Carson, Richard E.; Eckelman, William; Herscovitch, Peter; Zarate, Carlos A.; Charney, Dennis S.; Drevets, Wayne C.

2013-01-01

Multiple lines of evidence suggest that serotonin type 1A (5-HT1A) receptor dysfunction is involved in the pathophysiology of mood disorders, and that alterations in 5-HT1A receptor function play a role in the mechanisms of antidepressant and mood stabilizer treatment. The literature is in disagreement, however, as to whether 5-HT1A receptor binding abnormalities exist in bipolar disorder (BD). We acquired PET images of 5-HT1A receptor binding in 26 unmedicated BD subjects and 37 healthy controls using [18F]FCWAY, a highly selective 5-HT1A receptor radio-ligand. The mean 5-HT1A receptor binding potential (BPP) was significantly lower in BD subjects compared to controls in cortical regions where 5-HT1A receptors are expressed post-synaptically, most prominently in the mesiotemporal cortex. Post-hoc assessments involving other receptor specific binding parameters suggested that this difference particularly affected the females with BD. The mean BPP did not differ between groups in the raphe nucleus, however, where 5-HT1A receptors are predominantly expressed pre-synaptically. Across subjects the BPP in the mesiotemporal cortex was inversely correlated with trough plasma cortisol levels, consistent with preclinical literature indicating that hippocampal 5-HT1A receptor expression is inhibited by glucocorticoid receptor stimulation. These findings suggest that 5-HT1A receptor binding is abnormally reduced in BD, and this abnormality may particularly involve the postsynaptic 5-HT1A receptor system of individuals with a tendency toward cortisol hypersecretion. PMID:23434290

Current knowledge on the sensitivity of the 68Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours

International Nuclear Information System (INIS)

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; Guggenberg, Elisabeth von; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Ilanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-01-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three 68 Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these 68 Ga-sstr-binding peptides in the imaging setting. On 68 Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUV max ) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUV max -values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUV max -data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with 68 Ga

Current knowledge on the sensitivity of the (68)Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours.

Science.gov (United States)

Virgolini, Irene; Gabriel, Michael; Kroiss, Alexander; von Guggenberg, Elisabeth; Prommegger, Rupert; Warwitz, Boris; Nilica, Bernhard; Roig, Llanos Geraldo; Rodrigues, Margarida; Uprimny, Christian

2016-10-01

Physiologically increased pancreatic uptake at the head/uncinate process is observed in more than one-third of patients after injection of one of the three (68)Ga-labelled octreotide-based peptides used for somatostatin (sst) receptor (r) imaging. There are minor differences between these (68)Ga-sstr-binding peptides in the imaging setting. On (68)Ga-sstr-imaging the physiological uptake can be diffuse or focal and usually remains stable over time. Differences in the maximal standardised uptake values (SUVmax) reported for the normal pancreas as well as for pancreatic neuroendocrine tumour (PNET) lesions may be related to several factors, including (a) differences in the peptide binding affinities as well as differences in sstr subtype expression of pancreatic α- and β-cells, and heterogeneity / density of tumour cells, (b) differences in scanner resolution, image reconstruction techniques and acquisition protocols, (c) mostly retrospective study designs, (d) mixed patient populations, or (e) interference with medications such as treatment with long-acting sst analogues. The major limitation in most of the studies lies in the lack of histopathological confirmation of abnormal findings. There is a significant overlap between the calculated SUVmax-values for physiological pancreas and PNET-lesions of the head/uncinate process that do not favour the use of quantitative parameters in the clinical setting. Anecdotal long-term follow-up studies have even indicated that increased uptake in the head/uncinate process still can turn out to be malignant over years of follow up. SUVmax-data for the pancreatic body and tail are limited. Therefore, any visible focal tracer uptake in the pancreas must be considered as suspicious for malignancy irrespective of quantitative parameters. In general, sstr-PET/CT has significant implications for the management of NET patients leading to a change in treatment decision in about one-third of patients. Therefore, follow-up with (68)Ga

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels.

Science.gov (United States)

Pedraza-Arévalo, S; Córdoba-Chacón, J; Pozo-Salas, A I; L-López, F; de Lecea, L; Gahete, M D; Castaño, J P; Luque, R M

2015-06-01

Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis.

The mechanisms behind decreased internalization of angiotensin II type 1 receptor.

Science.gov (United States)

Bian, Jingwei; Zhang, Suli; Yi, Ming; Yue, Mingming; Liu, Huirong

2018-04-01

The internalization of angiotensin II type 1 receptor (AT 1 R) plays an important role in maintaining cardiovascular homeostasis. Decreased receptor internalization is closely related to cardiovascular diseases induced by the abnormal activation of AT 1 R, such as hypertension. However, the mechanism behind reduced AT 1 R internalization is not fully understood. This review focuses on four parts of the receptor internalization process (the combination of agonists and receptors, receptor phosphorylation, endocytosis, and recycling) and summarizes the possible mechanisms by which AT 1 R internalization is reduced based on these four parts of the process. (1) The agonist has a large molecular weight or a stronger ability to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5) P 2 ), which can increase the consumption of PtdIns (4,5) P 2 . (2) AT 1 R phosphorylation is weakened because of an abnormal function of phosphorylated kinase or changes in phospho-barcoding and GPCR-β-arrestin complex conformation. (3) The abnormal formation of vesicles or AT 1 R heterodimers with fewer endocytic receptors results in less AT 1 R endocytosis. (4) The enhanced activity and upregulated expression of small GTP-binding protein 4 (Rab4) and 11 (Rab11), which regulate receptor recycling, and phosphatidylinositol 3-kinase increase AT 1 R recycling. In addition, lower expression of AT 1 R-associated protein (ATRAP) or higher expression of AT 1 R-associated protein 1 (ARAP1) can reduce receptor internalization. Copyright © 2018 Elsevier Inc. All rights reserved.

Some aspects of the endocrine tumours of the digestive tract

International Nuclear Information System (INIS)

Sassolas, G.

1996-01-01

Endocrine tumours of digestive tract (GEP) synthesize many hormonal products which are responsible for clinical expression in relation with their nature, amount and biological activity, some of these tumours being non-functioning or silent. Moreover these tumours have some characteristics related to neuroendocrine differentiation, which provide tumour markers in addition to hormonal markers, such as chromogranin. A which is of special interest in non-functioning tumours. Pancreatic tumours are the most frequently recognized tumours in systematic screening procedures performed in MEN 1 patients. They are multi-secreting and multifocal, and they exhibit a loss of heterozygosity in the 11q13 locus. Growth factors such as IGF-1 and PDGF and their specific receptors are expressed in GEP tumours but their role in tumour growth remains to be determined. Somatostatin receptors are present on most endocrine digestive tumours, conditioning the therapeutic effects of somatostatin analogues that reduce hormonal tumoral production and alleviate the related symptoms. In addition, in vivo visualization of somatostatin receptor positive tumours by scintigraphy using radiolabelled somatostatin analogues is of clinical interest. (author)

Treatment of acromegaly patients at the Federal University of Triângulo Mineiro (UFTM: Experience Report

Directory of Open Access Journals (Sweden)

Maria de Fátima Borges

Full Text Available OBJECTIVE: To evaluate the effectiveness of the treatment of acromegaly patients at the Federal University of Triangulo Mineiro. METHODS: Cross-sectional and retrospective study of thirty cases treated over a period of two decades. RESULTS: 17 men (56.7% aged 14-67 years and 13 women aged 14-86 years were analyzed. Twenty-one patients underwent transphenoidal surgery, whichwas associated with somatostatin receptor ligands in 11 patients (39.3%, somatostatin receptor ligands + radiotherapyin 5 patients (17.8%, radiotherapy in 3 patients (10.7%, and radiotherapy + somatostatin receptorligands + cabergoline in 1 patient (3.6%. Additionally, 2 patients underwent radiotherapy and surgeryalone. Six patients received somatostatin receptor ligands before surgery, and 2 were not treated due to refusal and death. Nine patients have died, and 20 are being followed; 13 (65% have growth hormonelevels o1 ng/mL, and 11 have normal insulin-like growth factor 1 levels. CONCLUSION: The current treatment options enable patients seen in regional reference centers to achieve strict control parameters, which allows them to be treated close to their homes.

Treatment of acromegaly patients at the Federal University of Triângulo Mineiro (UFTM): Experience Report

Science.gov (United States)

de Fátima Borges, Maria; Lara, Beatriz Hallal Jorge; Tomé, Janaíne Machado; de Araújo, Leopoldo Prezia; Bugiga, Flávio Cesar Lucas; Sousa, Júlio Cláudio; Soares, Jacqueline Mendes Fonseca; Dezena, Roberto Alexandre; Ferreira, Beatriz Pires

2017-01-01

OBJECTIVE: To evaluate the effectiveness of the treatment of acromegaly patients at the Federal University of Triangulo Mineiro. METHODS: Cross-sectional and retrospective study of thirty cases treated over a period of two decades. RESULTS: 17 men (56.7%) aged 14-67 years and 13 women aged 14-86 years were analyzed. Twenty-one patients underwent transphenoidal surgery, whichwas associated with somatostatin receptor ligands in 11 patients (39.3%), somatostatin receptor ligands + radiotherapyin 5 patients (17.8%), radiotherapy in 3 patients (10.7%), and radiotherapy + somatostatin receptorligands + cabergoline in 1 patient (3.6%). Additionally, 2 patients underwent radiotherapy and surgeryalone. Six patients received somatostatin receptor ligands before surgery, and 2 were not treated due to refusal and death. Nine patients have died, and 20 are being followed; 13 (65%) have growth hormonelevels o1 ng/mL, and 11 have normal insulin-like growth factor 1 levels. CONCLUSION: The current treatment options enable patients seen in regional reference centers to achieve strict control parameters, which allows them to be treated close to their homes. PMID:28492721

PET Study with false positive {sup 68}Ga-Dotatate caused by the presence of an accessory spleen; Estudio PET con {sup 68}Ga-Dotatate falso positivo causado por la presencia de un bazo accesorio

Energy Technology Data Exchange (ETDEWEB)

Massardo, Teresa [Centro PET de Imagenes Moleculares, Hospital Militar de Santiago / Seccion Medicina Nuclear, Departamento Medicina, Hospital Clinico Universidad de Chile. Santiago (Chile); Jofre, Josefina; Sierralta, M. Paulina; Canessa, Jose [Centro PET de Imagenes Moleculares, Hospital Militar de Santiago. Santiago (Chile)

2013-05-31

Neuroendocrine tumors with somatostatin receptor expression are suitable for imaging with somatostatin analogues. {sup 68}Ga-labeled peptides are useful for the diagnosis, staging and assessment of therapeutic response of these tumors. However, for a correct interpretation it is necessary to know the normal biodistribution of somatostatin receptors in the body. Asymmetric adrenal uptake may be a normal variant to cause confusion, or an accessory or ectopic spleen can lead to a false positive result. We report a case of asymmetric adrenal uptake which was correctly considered as a normal variant, but an accessory spleen caused the false impression of being a metastasis from a previously resected primary carcinoid tumor.

Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

NARCIS (Netherlands)

Gaykema, R.P.A.; Compaan, J.C.; Nyakas, C.; Horvath, E.; Luiten, P.G.M.

1989-01-01

The effect of cholinergic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16-18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the

Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients

NARCIS (Netherlands)

S.J.C.M.M. Neggers (Bas); W.W. de Herder (Wouter); R.A. Feelders (Richard); A-J. van der Lely (Aart-Jan)

2011-01-01

textabstractThe efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the

Somatostatin receptor PET in neuroendocrine tumours: {sup 68}Ga-DOTA{sup 0},Tyr{sup 3}-octreotide versus {sup 68}Ga-DOTA{sup 0}-lanreotide

Energy Technology Data Exchange (ETDEWEB)

Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [Vienna Medical University, Department of Nuclear Medicine, Vienna (Austria); Widmann, Gerlig [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria)

2013-03-15

The aim of this study was to evaluate the impact of {sup 68}Ga-labelled DOTA{sup 0}-lanreotide ({sup 68}Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or {sup 68}Ga-labelled DOTA{sup 0},Tyr{sup 3}-octreotide ({sup 68}Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or {sup 68}Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent {sup 68}Ga-DOTA-LAN PET to evaluate a treatment option with {sup 90}Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 {+-} 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. {sup 68}Ga-DOTA-LAN and {sup 68}Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of {sup 68}Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for {sup 68}Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. {sup 68}Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV{sub max}) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to {sup 68}Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. {sup 68}Ga

Modulation of type II TGF-β receptor degradation by integrin-linked kinase.

Science.gov (United States)

Vi, Linda; Boo, Stellar; Sayedyahossein, Samar; Singh, Randeep K; McLean, Sarah; Di Guglielmo, Gianni M; Dagnino, Lina

2015-03-01

Cutaneous responses to injury, infection, and tumor formation involve the activation of resident dermal fibroblasts and subsequent transition to myofibroblasts. The key for induction of myofibroblast differentiation is the activation of transforming growth factor-β (TGF-β) receptors and stimulation of integrins and their associated proteins, including integrin-linked kinase (ILK). Cross-talk processes between TGF-β and ILK are crucial for myofibroblast formation, as ILK-deficient dermal fibroblasts exhibit impaired responses to TGF-β receptor stimulation. We now show that ILK associates with type II TGF-β receptors (TβRII) in ligand- and receptor kinase activity-independent manners. In cells with targeted Ilk gene inactivation, cellular levels of TβRII are decreased, through mechanisms that involve enhanced ubiquitination and proteasomal degradation. Partitioning of TGF-β receptors into membrane has been linked to proteasome-dependent receptor degradation. We found that interfering with membrane raft formation in ILK-deficient cells restored TβRII levels and signaling. These observations support a model whereby ILK functions in fibroblasts to direct TβRII away from degradative pathways during their differentiation into myofibroblasts.

Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

Science.gov (United States)

Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

2014-09-01

This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

Concordance between results of somatostatin receptor scintigraphy with {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide and chromogranin A assay in patients with neuroendocrine tumours

Energy Technology Data Exchange (ETDEWEB)

Rodrigues, Margarida [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Hietzing Hospital, Institute of Nuclear Medicine, Vienna (Austria); Gabriel, Michael; Heute, Dirk; Putzer, Daniel; Virgolini, Irene [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Griesmacher, Andrea [Medical University of Innsbruck, Central Institute of Medical and Chemical Laboratory Diagnostics, Innsbruck (Austria)

2008-10-15

Somatostatin receptor scintigraphy (SRS) and chromogranin A (CgA) assay have successfully been implemented in the clinical work-up and management of neuroendocrine tumour (NET) patients. However, there is still a lack of studies comparing results in these patients. Our aim was to compare directly in NET patients SRS and CgA assay results with special regard to tumour features such as grade of malignancy, primary origin, disease extent and function. One hundred twenty consecutive patients with histological confirmed NETs were investigated with {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide ({sup 111}In-DOTA-TOC) SRS and CgA immunoradiometric assay. Tumours were classified by cell characteristics [well-differentiated NETs, well-differentiated neuroendocrine carcinomas, poorly differentiated neuroendocrine carcinomas (PDNECs)], primary origin (foregut, midgut, hindgut, undetermined), disease extent (limited disease, metastases, primary tumour and metastases) and functionality (secretory, nonsecretory). SRS was positive in 107 (89%) patients; CgA levels were increased in 95 (79%) patients. Overall, concordance between SRS and CgA results was found in 84 patients. Positive SRS but normal CgA level were found in 24 patients, with higher prevalence (p<0.05) in patients with nonsecretory tumours. Conversely, negative SRS but CgA level increased were seen in 12 patients, with higher proportion (p < 0.05) in patients with PDNECs and tumours of hindgut origin. Overall, {sup 111}In-DOTA-TOC SRS proved to be more sensitive than CgA in NETs patients. Tumour differentiation, disease extent and presence of liver metastases impact both SRS and CgA results, whereas nonsecretory activity is a negative predictor of only CgA increase. PDNECs and hindgut origin of tumours predispose to discrepancies with negative SRS but increased CgA levels. (orig.)

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

Science.gov (United States)

Naik, Chinna; Basu, Sandip

2017-01-01

Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177 Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region ( n = 1), duodenum ( n = 1), and pancreas ( n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25-75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [ 99m Tc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/ 68 Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177 Lu-DOTA-octreotate (DOTATATE) PRRT was

Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor

Directory of Open Access Journals (Sweden)

Veronika Y. Sysoeva

2017-12-01

Full Text Available Obesity is often associated with high systemic and local activity of renin-angiotensin system (RAS. Mesenchymal stem cells of adipose tissue are the main source of adipocytes. The aim of this study was to clarify how local RAS could control adipose differentiation of human adipose tissue derived mesenchymal stem cells (ADSCs. We examined the distribution of angiotensin receptor expressing cells in human adipose tissue and found that type 1 and type 2 receptors are co-expressed in its stromal compartment, which is known to contain mesenchymal stem cells. To study the expression of receptors specifically in ADSCs we have isolated them from adipose tissue. Up to 99% of cultured ADSCs expressed angiotensin II (AngII receptor type 1 (AT1. Using the analysis of Ca2+ mobilization in single cells we found that only 5.2 ± 2.7% of ADSCs specifically respond to serial Ang II applications via AT1 receptor and expressed this receptor constantly. This AT1const ADSCs subpopulation exhibited increased adipose competency, which was triggered by endogenous AngII. Inhibitory and expression analyses showed that AT1const ADSCs highly co-express AngII type 2 receptor (AT2, which was responsible for increased adipose competency of this ADSC subpopulation.

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2

DEFF Research Database (Denmark)

Seemann, Petra; Schwappacher, Raphaela; Kjær, Klaus Wilbrandt

2005-01-01

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b...

N-(2-methoxyphenyl) benzenesulfonamide, a novel regulator of neuronal G protein-gated inward rectifier K+ channels.

Science.gov (United States)

Walsh, Kenneth B; Gay, Elaine A; Blough, Bruce E; Geurkink, David W

2017-11-15

G protein-gated inward rectifier K + (GIRK) channels are members of the super-family of proteins known as inward rectifier K + (Kir) channels and are expressed throughout the peripheral and central nervous systems. Neuronal GIRK channels are the downstream targets of a number of neuromodulators including opioids, somatostatin, dopamine and cannabinoids. Previous studies have demonstrated that the ATP-sensitive K + channel, another member of the Kir channel family, is regulated by sulfonamide drugs. Therefore, to determine if sulfonamides also modulate GIRK channels, we screened a library of arylsulfonamide compounds using a GIRK channel fluorescent assay that utilized pituitary AtT20 cells expressing GIRK channels along with the somatostatin type-2 and -5 receptors. Enhancement of the GIRK channel fluorescent signal by one compound, N-(2-methoxyphenyl) benzenesulfonamide (MPBS), was dependent on the activation of the channel by somatostatin. In whole-cell patch clamp experiments, application of MPBS both shifted the somatostatin concentration-response curve (EC 50 = 3.5nM [control] vs.1.0nM [MPBS]) for GIRK channel activation and increased the maximum GIRK current measured with 100nM somatostatin. However, GIRK channel activation was not observed when MPBS was applied to the cells in the absence of somatostatin. While the MPBS structural analog 4-fluoro-N-(2-methoxyphenyl) benzenesulfonamide also augmented the somatostatin-induced GIRK fluorescent signal, no increase in the signal was observed with the sulfonamides tolbutamide, sulfapyridine and celecoxib. In conclusion, MPBS represents a novel prototypic GPCR-dependent regulator of neuronal GIRK channels. Copyright © 2017 Elsevier B.V. All rights reserved.

Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

Science.gov (United States)

Low, Malcolm J.; Otero-Corchon, Veronica; Parlow, Albert F.; Ramirez, Jose L.; Kumar, Ujendra; Patel, Yogesh C.; Rubinstein, Marcelo

2001-01-01

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst–/–) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst–/– compared with Smst+/+ mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst–/– mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst-/- mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth. PMID:11413165

beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations

DEFF Research Database (Denmark)

Sanni, S J; Hansen, J T; Bonde, M M

2010-01-01

The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often...

Development and clinical applications of a small peptide as a radiolabeled in vivo diagnostic probe

International Nuclear Information System (INIS)

Reubi, J.C.; Lamberts, S.W.; Krenning, E.

1995-01-01

Several dozens of small peptides, widely distributed in the human body, highly potent and important regulators of biological processes in numerous tissues, have been identified in the past several years. One of those, somatostatin, the first of such peptides used in the nuclear medicine field, has been developed as an in vivo labeled diagnostic probe for a variety of pathologies. Basic knowledge on somatostatin, somatostatin receptors and somatostatin target tissues as well as on the clinical implications of this diagnostic tool are briefly reviewed. (authors). 9 refs., 3 figs

Translational Advancement of Somatostatin Gene Delivery for Disease Modification and Cognitive Sparing in Intractable Epilepsy

Science.gov (United States)

2015-09-01

seizures. A thoroughly characterized rodent epilepsy model will be used as a platform to test the hypotheses. In this model temporal lobe electrical...expression in the hippocampus resected from a young temporal lobe epilepsy patient. Post-baccalaureate student Andrew Moss has since expanded this project...somatostatin gene delivery persistently reduces seizure severity in a rat model of temporal lobe epilepsy , Gowri Natarajan, Jessica Anne McElroy

Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.

Science.gov (United States)

Lewis, David A; Hashimoto, Takanori; Morris, Harvey M

2008-10-01

Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.

The development of radioimmunoassay for somatostatin, its use in the measurement of this peptide in tissues and biological fluids, and an assessment of its physiological role in health and disease

International Nuclear Information System (INIS)

Pimstone, B.; Sheppard, M.

1979-06-01

Somatostatin peptide initially isolated from ovine hypothalamus has inhibitory effect on secretion growth hormone and on other pituitary hormones like TSH, ACTH. The assay sensitivity sensitivity was approximately 6 pg/tube. The authors did not observe any significant crossreactivity with 19 different hormones and biological substances. High concentration of somatostatin was found in central nervous system, but not only in median eminence of hypothalamus but also in other areas including spine cord. High level of somatostatin was also observed in pancreas, gastric antrum and distal colon. The determinations of somatostatin-like in sera of 22 men and 26 women allowed to establish the normal values which are 0.274+-0.009 ng/ml. MCR in normal subjects was 1949+-250 ml/min, in cases with chronic liver disease the values were similar, and in subjects with chronic renal failure highly significant lowering of MCR equal 501+-32.7 ml/min was observed. Tsub(1/2) varied from 1.1 to 3.0 min in normal subjects, in patients with liver diseases was in ranges 1.2 - 4.8 min and in chronic renal failure from 2.6 - 4.9 min

Somatostatine analogs marked with 99m-TC

International Nuclear Information System (INIS)

Obenaus, E; Crudo, J; Edreira, M; Castiglia, S.G. de

2003-01-01

The aim of the present work was to study the biological and radiochemical behaviour of two somatostatin analogues, the RC-160 and Tyr 3 Octreotide(TOC) peptides when labeling with 99m Tc by an indirect method using S-Benzoyl- mercaptoacetyl triglycine (MAG3) and hydrazino nicotinamide (HYNIC) as chelating agents. The synthesis of RC160 with S-Benzoyl MAG3 and TOC with HYNIC, for labeling with 99m Tc are also described. The conjugates were prepared on a small scale and labeled with the radionuclide using tricine as coligands for HYNIC conjugates. Chromatographic studies were performed using an HPLC system and radiochemical purities higher than 75% and 95% were obtained respectively. Biodistributions studies in normal Wistar rats were performed and results were correlated with chromatographic and protein binding properties. Lower lipophilicity of the labeled conjugates resulted in a higher renal excretion. HYNIC-TOC complex showed promising results when labeling with 99m Tc using tricine as coligand although higher stability should be found for ternary coligands compared to tricine (Au)

Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.

Science.gov (United States)

Schöffmann, Angela; Wimmer, Laurin; Goldmann, Daria; Khom, Sophia; Hintersteiner, Juliane; Baburin, Igor; Schwarz, Thomas; Hintersteininger, Michael; Pakfeifer, Peter; Oufir, Mouhssin; Hamburger, Matthias; Erker, Thomas; Ecker, Gerhard F; Mihovilovic, Marko D; Hering, Steffen

2014-07-10

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators.

Radiolabelled peptides: New radiopharmaceuticals for targeted therapy

International Nuclear Information System (INIS)

Chinol, M.

2001-01-01

Radiolabelled peptides have been the focus of an increasing interest by the nuclear medicine community within the last few years. This has mainly been due to successful development of one of these peptides, somatostatin, as a tool to visualise various pathologic conditions known to express a high number of somatostatin receptors. Somatostatin receptors have been identified in different tumours such as neuroendocrine tumours, tumours of the central nervous system, breast, lung and lymphatic tissue. These observations served as the biomolecular basis for the clinical use of radiolabelled somatostatin analogs, which are at present of great interest for diagnostic and therapeutic applications. A promising somatostatin analogue, DOTA-D-Phe 1 -Ty 3 -octreotide, named DOTATOC, has shown favourable biodistribution and high affinity binding to SSTR2 and SSTR5, high hydrophilicity and ease of labelling and stability with 111 In and 90 Y. A clinical trial aimed at evaluating the biodistribution and dosimetry of DOTATOC radiolabelled with 111 In, in anticipation of therapy trials with 90 Y-DOTATOC in patients was undertaken. 111 In-DOTATOC showed favourable pharmacokinetics (fast blood clearance and urinary excretion) and biodistribution, and high affinity to tumours expressing somatostatin receptors (thus, a high residence time in tumour). These results are promising for therapy trials with 90 Y-DOTAOC, for which radiation dosimetry appears acceptable for normal organs (including the red marrow). Moreover, labelling conditions of DOTATOC with 90 Y has been optimised in order to achieve labelling yields of more than 98% and specific activities of greater than 60 GBq (1.6 Ci)/μmol. (author)

Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor

DEFF Research Database (Denmark)

Jensen, Anders A.; Madsen, Bo E.; Krogsgaard-Larsen, P

2001-01-01

homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant...... rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies...

Endoglin-mediated suppression of prostate cancer invasion is regulated by activin and bone morphogenetic protein type II receptors.

Directory of Open Access Journals (Sweden)

Michael J Breen

Full Text Available Mortality from prostate cancer (PCa is due to the formation of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor β (TGFβ superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion was also shown by us to be dependent upon the type I TGFβ receptor, activin receptor-like kinase 2 (ALK2, and the downstream effector, Smad1. In this study we demonstrate for the first time that two type II TGFβ receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA and bone morphogenetic protein receptor type II (BMPRII. Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. In contrast BMPRII regulates Smad1 in a biphasic manner, promoting Smad1 signaling through its kinase domain but suppressing it through its cytoplasmic tail. BMPRII's Smad1-regulatory effects are dependent upon its expression level. Further, its ability to suppress invasion is independent of either kinase function or tail domain. We demonstrate that ActRIIA and BMPRII physically interact, and that each also interacts with endoglin. The current findings demonstrate that both BMPRII and ActRIIA are necessary for endoglin-mediated suppression of human PCa cell invasion, that they have differential effects on Smad1 signaling, that they make separate contributions to regulation of invasion, and that they functionally and physically interact.

Splenosis Mimicking Relapse of a Neuroendocrine Tumor at Gallium-68-DOTATOC PET/CT

International Nuclear Information System (INIS)

Treglia, Giorgio; Luca, Giovanella; Barbara, Muoio; Carmelo, Caldarella

2014-01-01

A 48-year-old female patient underwent splenopancreasectomy for a 4-cm pancreatic neuroendocrine tumor (pNET), grade G2, located in the pancreatic tail. One year after surgery, the patient presented an increased serum level of the tumor marker chromogranin A (value: 160 U/l). Therefore, she underwent somatostatin receptor PET/CT using gallium-68-DOTATOC for restaging. This imaging method showed a focal area of increased radiopharmaceutical uptake corresponding to a 2.5-cm nodule located in the left superior abdomen near a clip from the previous surgery, suggesting a possible relapse of pNET. Based on this PET/CT finding, the patient underwent ultrasonography-guided core biopsy of this nodule. Histology did not reveal findings suggestive of pNET but identified spleen tissue most likely caused by splenosis accidentally seeded at the previous operation. It is likely that the increased serum level of the tumor marker chromogranin A was due to the chronic proton-pump inhibitors use. Somatostatin receptor PET/CT is an accurate imaging method for staging and restaging pNET, presenting high sensitivity and specificity in this setting. Nevertheless, possible sources of false-negative and -positive findings with this method should be taken into account. Inflammatory lesions represent the most frequent causes of false-positive findings for pNET at somatostatin receptor imaging because inflammatory cellsmay overexpress somatostatin receptors on their cell surface. In our case, we showed that splenosis may represent a possible cause of false-positive findings for pNET relapse due to the physiological uptake of somatostatin analogs by the spleen tissue

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

DEFF Research Database (Denmark)

Dimitrijevic, Ivan; Edvinsson, Lars; Chen, Qingwen

2009-01-01

expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina...... pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro...

Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

International Nuclear Information System (INIS)

Waser, Beatrice; Reubi, Jean Claude

2011-01-01

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist 125 I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic β-cells and mouse insulinomas, but it does not label human pancreatic β-cells and insulinomas. High affinity displacement (IC 50 approximately 2 nM) is observed in mouse β-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist 125 I-GLP-1(7-36)amide intensively labels mouse pancreatic β-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

International Nuclear Information System (INIS)

Bodei, L.; Kidd, M.; Modlin, I.M.; Drozdov, I.; Prasad, V.; Severi, S.; Paganelli, G.; Ambrosini, V.; Kwekkeboom, D.J.; Krenning, E.P.; Baum, R.P.

2015-01-01

Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between 68 Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive 68 Ga-SSA PET: data set 1 ( 68 Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ( 68 Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUV max ), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUV max measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ 2 = 20.1, p < 2.5 x 10 -6 ). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUV max (R 2 = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUV max . Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUV max [ROC-derived AUC (R 2 = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters

Up-Regulation of Endothelin Type A Receptor in Human and Rat Radiation Proctitis: Preclinical Therapeutic Approach With Endothelin Receptor Blockade

International Nuclear Information System (INIS)

Jullien, Nicolash; Blirando, Karl; Milliat, Fabien; Sabourin, Jean-Christophe; Benderitter, Marc; Francois, Agnes

2009-01-01

Purpose: Rectum radiation damage and fibrosis are often associated with radiation therapy of pelvic tumors. The endothelin (ET) system has been implicated in several fibrotic diseases but never studied in the context of gastrointestinal radiation damage. This study assessed modifications in ET type 1 (ET-1), ET type A receptor (ET A ), and ET type B receptor (ET B ) localization and/or expression in irradiated human rectal tissue and in a rat model of delayed colorectal injury. We also evaluated the therapeutic potential of long-term ET receptor blockade. Methods and Materials: Routine histological studies of sections of healthy and radiation-injured human rectum tissue were done; the sections were also immunostained for ET A and ET B receptors. The rat model involved the delivery of 27 Gy in a single dose to the colons and rectums of the animals. The ET-1/ET A /ET B expression and ET A /ET B localization were studied at 10 weeks postexposure. The abilities of bosentan and atrasentan to protect against delayed rectal injury were also investigated. Results: The immunolocalization of ET A and ET B in healthy human rectums was similar to that in rat rectums. However, strong ET A immunostaining was seen in the presence of human radiation proctitis, and increased ET A mRNA levels were seen in the rat following colorectal irradiation. Immunostaining for ET A was also strongly positive in rats in areas of radiation-induced mucosal ulceration, atypia, and fibroproliferation. However, neither bosentan nor atrasentan prevented radiation damage to the rectum when given long term. The only effect seen for atrasentan was an increased number of sclerotic vessel sections in injured tissues. Conclusions: As the result of the overexpression of ET A , radiation exposure deregulates the endothelin system through an 'ET A profile' in the human and rodent rectum. However, therapeutic interventions involving mixed or specific ET A receptor blockade do not prevent radiation damage

The Vasopressin Type-2 Receptor and Prostaglandin Receptors EP2 and EP4 can Increase Aquaporin-2 Plasma Membrane Targeting Through a cAMP Independent Pathway

DEFF Research Database (Denmark)

Olesen, Emma Tina Bisgaard; Moeller, Hanne Bjerregaard; Assentoft, Mette

2016-01-01

Apical membrane targeting of the collecting duct water channel aquaporin-2 (AQP2) is essential for body water balance. As this event is regulated by Gs coupled 7-transmembrane receptors such as the vasopressin type 2 receptor (V2R) and the prostanoid receptors EP2 and EP4, it is believed to be c...

Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor

Energy Technology Data Exchange (ETDEWEB)

Cubellis, M.V.; Andreasen, P.; Ragno, P.; Mayer, M.; Dano, K.; Blasi, F. (Univ. of Copenhagen (Denmark))

1989-07-01

Urokinase plasminogen activator (uPA) interacts with a surface receptor and with specific inhibitors, such as plasminogen activator inhibitor type 1 (PAI-1). These interactions are mediated by two functionally independent domains of the molecule: the catalytic domain (at the carboxyl terminus) and the growth factor domain (at the amino terminus). The authors have now investigated whether PAI-1 can bind and inhibit receptor-bound uPA. Binding of {sup 125}I-labeled ATF (amino-terminal fragment of uPA) to human U937 monocyte-like cells can be competed for by uPA-PAI-1 complexes, but not by PAI-1 alone. Preformed {sup 125}I-labeled uPA-PAI-1 complexes can bind to uPA receptor with the same binding specificity as uPA. PAI-1 also binds to, and inhibits the activity of, receptor-bound uPA in U937 cells, as shown in U937 cells by a caseinolytic plaque assay. Plasminogen activator activity of these cells is dependent on exogenous uPA, is competed for by receptor-binding diisopropyl fluorophosphate-treated uPA, and is inhibited by the addition of PAI-1. In conclusion, in U937 cells the binding to the receptor does not shield uPA from the action of PAI-1. The possibility that in adherent cells a different localization of PAI-1 and uPA leads to protection of uPA from PAI-1 is to be considered.

THE EFFECT OF THE SOMATOSTATIN ANALOGUE OCTREOTIDE ON EXPERIMENTAL INTESTINAL OBSTRUCTION IN RATS

Directory of Open Access Journals (Sweden)

Paran Haim

1998-01-01

Full Text Available Background: Somatostatin has an inhibitory effect on the endocrine and exocrine secretions of the gut. It may have a beneficial effect in the conservative treatment of intestinal obstruction. The aim of the present study is to investigate the effect of octreotide in mechanical intestinal obstruction in rats. Method: Intestinal obstruction was induced in rats by ligation of a segment of the distal ileum. Animals were treated with the somatostatin analogue octreotide (n=16, or saline (n=16. Eight rats were operated but their intestine was not ligated (n=8 serving as sham controls. Forty eight hours after the operation, the animals were operated upon again and blood samples from the femoral vein were tested for electrolytes, urea, glucose, lactic acid, amylase, ph and bicarbonate. Portal vein blood samples were also obtained and tested for lactic acid and amylase. Results: Intestinal obstruction resulted, after 48 hours, in severe dilatation of bowel loops. A significant increase in plasma levels of urea, amylase and lactic acid was observed. Plasma pH decreased. In blood samples from the portal vein, a significant increase in lactic acid was observed, indicating metabolic acidosis, probably secondary to bowel ischemia. Octreotide treatment, resulted in less acidosis, with concomitant lower urea and lactic acid levels in the plasma and especially in the portal vein. Conclusion: Octreotide treatment may have a beneficial effect in the conservative treatment of selected cases of intestinal obstruction.

Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

Energy Technology Data Exchange (ETDEWEB)

Kojima, Hiroyuki, E-mail: kojima@iph.pref.hokkaido.jp [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Muromoto, Ryuta; Takahashi, Miki [Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan); Takeuchi, Shinji [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Takeda, Yukimasa; Jetten, Anton M. [National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709 (United States); Matsuda, Tadashi [Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)

2012-03-15

The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10{sup −6} M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. -- Highlights: ► Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. ► Five azole-type fungicides act as RORα/γ inverse agonists. ► These fungicides

Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

International Nuclear Information System (INIS)

Kojima, Hiroyuki; Muromoto, Ryuta; Takahashi, Miki; Takeuchi, Shinji; Takeda, Yukimasa; Jetten, Anton M.; Matsuda, Tadashi

2012-01-01

The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10 −6 M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. -- Highlights: ► Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. ► Five azole-type fungicides act as RORα/γ inverse agonists. ► These fungicides suppress

Erratum Aldosterone synthase C-344T, angiotensin II type 1 receptor ...

Indian Academy of Sciences (India)

Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. Manisha Patnaik, Pallabi Pati, Surendra N. Swain, Manoj K. Mohapatra, Bhagirathi Dwibedi, Shantanu K. Kar.

Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

DEFF Research Database (Denmark)

Steckelings, U Muscha; Kloet, Annette de; Sumners, Colin

2017-01-01

Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent...

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

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Marta Perez-Rando

2017-06-01

Full Text Available N-methyl-D-aspartate receptors (NMDARs are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB. We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney

DEFF Research Database (Denmark)

Patel, Sanket N; Ali, Quaisar; Samuel, Preethi

2017-01-01

The actions of angiotensin II type 2 receptor (AT2R) and the receptor Mas (MasR) are complex but show similar pronatriuretic function; particularly, AT2R expression and natriuretic function are enhanced in obese/diabetic rat kidney. In light of some reports suggesting a potential positive...... interaction between these receptors, we tested hypothesis that renal AT2R and MasR physically interact and are interdependent to stimulate cell signaling and promote natriuresis in obese rats. We found that infusion of AT2R agonist C21 in obese Zucker rats (OZR) increased urine flow and urinary Na excretion...... coimmunoprecipitated with MasR in cortical homogenate of OZR. Immunoblotting of cortical homogenate cross-linked with zero-length oxidative (sulfhydryl groups) cross-linker cupric-phenanthroline revealed a shift of AT2R and MasR bands upward with overlapping migration for their complexes which were sensitive...

Receptor type I and type II binding regions and the peptidyl-prolyl isomerase site of cyclophilin B are required for enhancement of T-lymphocyte adhesion to fibronectin.

Science.gov (United States)

Carpentier, Mathieu; Allain, Fabrice; Slomianny, Marie-Christine; Durieux, Sandrine; Vanpouille, Christophe; Haendler, Bernard; Spik, Geneviève

2002-04-23

Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes. The type I sites correspond to functional receptors involved in endocytosis and the type II sites to sulfated glycosaminoglycans (GAGs). Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs. The peptidyl-prolyl isomerase activity of CyPB is not required for receptor binding. We have recently demonstrated that CyPB enhances adhesion of peripheral blood T-lymphocytes to fibronectin, a component of the extracellular matrix. We intended to identify additional amino acids involved in the binding of CyPB to its functional type I receptor and to determine regions responsible for the stimulation of peripheral blood T-lymphocyte adhesion. We determined that residues R76, G77, K132, D155, and D158 of the calcineurin (CN) interacting region were implicated in the recognition of type I receptor but not of GAGs. We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect. On the other hand, the adhesion of peripheral blood T-lymphocytes to coated fibronectin was not stimulated by CyPB mutants devoid of either type I receptor or GAGs binding activity or by mutants of the PPIase site. Altogether, the results demonstrate that different regions of CyPB are involved in peripheral blood T-lymphocyte activation and imply a novel important physiological function for peptidyl-prolyl isomerase activity.

Vasoactive intestinal peptide and somatostatin in the plasma and sigmoid mucosa in irritable bowel syndrome

International Nuclear Information System (INIS)

Zhang Ru; Wang Fuxian

2004-01-01

To investigate the possible role and clinical significance of vasoactive intestinal peptide (VIP) and somatostatin(SS) in the irritable bowel syndrome (IBS), the VIP and SS in the plasma and sigmoid mucosa were measured by radioimmunoassay in the control group and the IBS group. The VIP concentration in the plasma and sigmoid mucosa of the IBS patients with constipation was significantly higher than that of the control group (P<0.01), while that of the IBS patients with diarrhea was significantly lower than that of the control group (P<0.05). The SS concentration in two sites was significantly elevated in IBS patients of both types and was significantly higher in IBS with constipation than in IBS with diarrhea (P<0.05). Conclusion: The VIP and SS in IBS are abnormal, which might play a role in the pathogenesis of IBS. The plasma and mucosa concenration of VIP and SS in two kinds of IBS patients are significantly different, which indicates that there might be different pathophysiological basis involved in the pathogenesis of the two kinds of IBS patients. (authors)

Genotoxic evaluation of [DOTA,Tyr3]octreotate labeled with 131I and 177Lu in human peripheral lymphocytes in vitro by micronucleus assay

International Nuclear Information System (INIS)

Suzauki, Miriam Fussae; Silva, Marcia Augusta da; Caldeira Filho, Jose de Souza; Colturato, Maria Tereza; Araujo, Elaine Bortoleti de; Bartolini, Paolo; Okazaki, Kayo

2005-01-01

The radiolabeled receptor-binding peptides have being used for cancer diagnosis and therapy. The octreotate, a somatostatin analogue peptide, bound to various tumors expressing sst receptors (thyroid, pancreas, prostrate, melanoma and lymphomas). The amount and the type of receptors for somatostatin influence the tissue uptake. The [DOTA, Tyr 3 ]octreotate has been used because of its high affinity to somatostatin subtype receptors sstr 2 and sstr 5 . The pharmacokinetic study showed that the blood clearance is rapid and only 9% of the intravenous injected activity remains in human blood after one hour. The aim of this study was to evaluate the cytogenetic effect of radiolabeled [DOTA, Tyr 3 ]octreotate in blood cells in vitro, using the cytokinesis-block micronucleus (MN) assay. This technique allows evaluating the mutagenic effects of both endogenous and exogenous agents at chromosome level. Blood samples of healthy donors were collected in heparinized syringes and exposed to different activities of [DOTA, Tyr 3 ]octreotate labeled with with 131 I (n=3) and 177 Lu (n=3), where radioactive concentration ranged from 600 to 5600 kBq/mL, corresponding to an injected activity of 3.1 to 28.9 GBq in a reference man of 70 kg weight. 131 I and 177 Lu are beta- and gamma-emitters. After one-hour exposition to radiopharmaceuticals at 37 deg C, the cells were washed with culture medium for removing the non internalised octreotate and cultivated for 72 hours, according to criteria adopted by the IAEA. The results showed a positive correlation between radioactive concentrations (X) and the frequency of binucleated cells with micronuclei (Y) (P 131 I-DOTA, Tyr 3 ]octreotate was Y = (1.634 ± 0.236) + (0.912 ± 0.137) 10 -3 X and for [ 177 Lu-DOTA, Tyr 3 ]octreotate was Y = (1.715 ± 0.342) + (0.743 ± 0.135) 10 -3 X. The non labeled molecule, [DOTA, Tyr 3 ]octreotate, has no influence in the induction of cytogenetic damage. The micronucleus assay with rat pancreatic tumor cells