Somatostatin Receptors in Pituitary and Development of Somatostatin Receptor Subtype-Selective Analogs

Endocrine ◽  
2003 ◽  
Vol 20 (3) ◽  
pp. 265-270 ◽  
Author(s):  
Ilan Shimon
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Subtype ◽  
Subtype Selective

scholarly journals Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

2020 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Melpomeni Fani ◽  
Viktoria Weingaertner ◽  
Petra Kolenc Peitl ◽  
Rosalba Mansi ◽  
Raghuvir H. Gaonkar ◽  
...  
Keyword(s):  
Protein Binding ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Preclinical Study ◽  
Clinical Translation ◽  
Hek293 Cells ◽  
Neuroendocrine Neoplasms ◽  
Receptor Subtype ◽  
Selection Of

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

scholarly journals Immunohistochemical Localization of Somatostatin Receptor sst2A in Human Pancreatic Islets

1998 ◽  
Vol 83 (10) ◽  
pp. 3746-3749 ◽  
Author(s):  
J. C. Reubi ◽  
A. Kappeler ◽  
B. Waser ◽  
A. Schonbrunn ◽  
J. Laissue
Keyword(s):  
Pancreatic Islets ◽  
Islet Cells ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Exocrine Secretion ◽  
Pancreatic Tissue ◽  
Receptor Subtype ◽  
Human Pancreas ◽  
Specific Staining ◽  
Acinar Tissue

Somatostatin and octreotide inhibit endocrine pancreatic functions in man, via specific somatostatin receptors. However, the cellular distribution of the different somatostatin receptor subtype proteins has not been determined in the human pancreas. Here, the immunohistochemical distribution of the sst2A receptor was investigated using the sst2A receptor specific anti-peptide antibody R2-88 in cryostat as well as in formalin-fixed paraffin-embedded sections of human pancreatic tissue, and compared with insulin, glucagon and somatostatin immunostaining of adjacent sections. All pancreatic islets were immunostained with R2-88. Most islet cells were labeled: the sst2A receptors were present in insulin as well as glucagon producing cells, but were not detected in intra-islet vessels nor in adjacent acinar tissue. Absorption of the sst2A antibody with 100 nM of the antigen peptide abolished specific staining in tissue sections. Immunohistochemical staining with 125I-Tyr3-octreotide. Therefore, the clinical efficacy of octreotide on glucagon and insulin release can be explained by the presence of sst2A receptors in human A and B pancreatic islet cells. Moreover, absence of sst2A receptors in human acinar tissue suggests that the action of somatostatin on pancreatic exocrine secretion is mediated either indirectly or through a different somatostatin receptor subtype on acinar cells.

Somatostatin receptors

1995 ◽  
Vol 269 (6) ◽  
pp. G813-G820 ◽  
Author(s):  
T. Reisine
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
Receptor Subtypes ◽  
Binding Domains ◽  
Somatostatin Receptor Subtypes ◽  
Selective Agonists ◽  
The Individual ◽  
Subtype Selective ◽  
Biological Actions

Somatostatin induces its biological actions by activating a family of receptor subtypes. The recent cloning of five somatostatin receptor subtypes has led to the development of subtype-selective agonists. These compounds are revealing distinct functions of the individual receptor subtypes. Mutagenesis studies have revealed domains of several of the receptors involved in specific recognition of somatostatin analogues. Molecular modeling of both of these ligand-binding domains and the constrained somatostatin analogues that they interact with may lead to the development of nonpeptide somatostatin drugs that could be useful in the treatment of tumors and various metabolic, gastrointestinal, and central nervous system disorders.

Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures

2002 ◽  
Vol 283 (2) ◽  
pp. E311-E317 ◽  
Author(s):  
Connie Chisholm ◽  
Gordon R. Greenberg
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
High Specificity ◽  
Intestinal Cell ◽  
Receptor Subtype ◽  
Fetal Rat ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Somatostatin 14

Five somatostatin receptors (SSTRs) bind somatostatin-14 (S-14) and somatostatin-28 (S-28), but SSTR5 has the highest affinity for S-28. To determine whether S-28 acting through SSTR5 mediates inhibition of glucagon-like peptide-1 (GLP-1), fetal rat intestinal cell cultures were treated with somatostatin analogs with relatively high specificity for SSTRs 2–5. S-28 dose-dependently inhibited GLP-1 secretion stimulated by gastrin-releasing peptide more potently than S-14 (EC50 0.01 vs. 5.8 nM). GLP-1 secretion was inhibited by an SSTR5 analog, BIM-23268, more potently than S-14 and nearly as effectively as S-28. The SSTR5 analog L-372,588 also suppressed GLP-1 secretion equivalent to S-28, but a structurally similar peptide, L-362,855 (Tyr to Phe at position 7), was ineffective. An SSTR2-selective analog was less effective than S-28, and an SSTR3 analog was inactive. Separate treatment with GLP-1-(7–36)-NH2 increased S-28 and S-14 secretion by three- and fivefold; BIM-23268 abolished S-28 without altering S-14, whereas the SSTR2 analog was inactive. The results indicate that somatostatin regulation of GLP-1 secretion occurs via S-28 through activation of SSTR5. GLP-1-stimulated S-28 secretion is also autoregulated by SSTR5 activation, suggesting a feedback loop between GLP-1 and S-28 modulated by SSTR5.

scholarly journals Octreotide and Pasireotide Combination Treatment in Somatotroph Tumor Cells: Predominant Role of SST2 in Mediating Ligand Effects

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1816
Author(s):  
Jessica Amarù ◽  
Federica Barbieri ◽  
Marica Arvigo ◽  
Agnese Solari ◽  
Adriana Bajetto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cells ◽  
Intracellular Signaling ◽  
Somatostatin Receptor ◽  
Combined Treatment ◽  
Primary Cultures ◽  
Receptor Subtype ◽  
Camp Accumulation ◽  
Gh Secretion ◽  
Somatostatin Receptor Ligands

First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

scholarly journals A new 68Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Rosalba Mansi ◽  
Karim Abid ◽  
Guillaume P. Nicolas ◽  
Luigi Del Pozzo ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Amino Acids ◽  
Somatostatin Receptor ◽  
Somatostatin Analog ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

scholarly journals Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 232
Author(s):  
Rashmi G. Shah ◽  
Marine A. Merlin ◽  
Samuel Adant ◽  
Fayçal Zine-Eddine ◽  
Jean-Mathieu Beauregard ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Objective Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Normal Cells ◽  
Radiation Delivery ◽  
Different Types ◽  
Pre Treatment ◽  
High Doses ◽  
Low Dose Chemotherapy

The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.

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