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 In Vivo Biokinetics of 177Lu-OPS201 in Mice and Pigs as a Model for Predicting Human Dosimetry

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Seval Beykan ◽  
Melpomeni Fani ◽  
Svend Borup Jensen ◽  
Guillaume Nicolas ◽  
Damian Wild ◽  
...  
Keyword(s):  
Specific Activity ◽  
Somatostatin Receptor ◽  
Optimal Scaling ◽  
Relative Mass ◽  
Receptor Subtype ◽  
Data Sets ◽  
Mass Scaling ◽  
Time Scaling ◽  
Somatostatin Receptor Subtype 2

Introduction. 177Lu-OPS201 is a high-affinity somatostatin receptor subtype 2 antagonist for PRRT in patients with neuroendocrine tumors. The aim is to find the optimal scaling for dosimetry and to compare the biokinetics of 177Lu-OPS201 in animals and humans. Methods. Data on biokinetics of 177Lu-OPS201 were analyzed in athymic nude Foxn1nu mice (28 F, weight: 26 ± 1 g), Danish Landrace pigs (3 F-1 M, weight: 28 ± 2 kg), and patients (3 F-1 M, weight: 61 ± 17 kg) with administered activities of 0.19–0.27 MBq (mice), 97–113 MBq (pigs), and 850–1086 MBq (patients). After euthanizing mice (up to 168 h), the organ-specific activity contents (including blood) were measured. Multiple planar and SPECT/CT scans were performed until 250 h (pigs) and 72 h (patients) to quantify the uptake in the kidneys and liver. Blood samples were taken up to 23 h (patients) and 300 h (pigs). In pigs and patients, kidney protection was applied. Time-dependent uptake data sets were created for each species and organ/tissue. Biexponential fits were applied to compare the biokinetics in the kidneys, liver, and blood of each species. The time-integrated activity coefficients (TIACs) were calculated by using NUKFIT. To determine the optimal scaling, several methods (relative mass scaling, time scaling, combined mass and time scaling, and allometric scaling) were compared. Results. A fast blood clearance of the compound was observed in the first phase (<56 h) for all species. In comparison with patients, pigs showed higher liver retention. Based on the direct comparison of the TIACs, an underestimation in mice (liver and kidneys) and an overestimation in pigs’ kidneys compared to the patient data (kidney TIAC: mice = 1.4 h, pigs = 7.7 h, and patients = 5.8 h; liver TIAC: mice = 0.7 h, pigs = 4.1 h, and patients = 5.3 h) were observed. Most similar TIACs were obtained by applying time scaling (mice) and combined scaling (pigs) (kidney TIAC: mice = 3.9 h, pigs = 4.8 h, and patients = 5.8 h; liver TIAC: mice = 0.9 h, pigs = 4.7 h, and patients = 5.3 h). Conclusion. If the organ mass ratios between the species are high, the combined mass and time scaling method is optimal to minimize the interspecies differences. The analysis of the fit functions and the TIACs shows that pigs are better mimicking human biokinetics.

Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2

2020 ◽  
Vol 47 (11) ◽  
pp. 2577-2588 ◽  
Author(s):  
Asma Bashir ◽  
Mark Bitsch Vestergaard ◽  
Tina Binderup ◽  
Helle Broholm ◽  
Lisbeth Marner ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Pharmacokinetic Analysis ◽  
Receptor Subtype ◽  
Somatostatin Receptor Subtype 2

Novel insights in somatostatin receptor physiology

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S3-S11 ◽  
Author(s):  
Giovanni Tulipano ◽  
Stefan Schulz
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Ligand Complex ◽  
Endosomal Sorting ◽  
Intracellular Vesicle ◽  
Molecular Events ◽  
Somatostatin Receptor Subtypes

The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential β-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.

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.

scholarly journals Pharmacological Characterization of Veldoreotide as a Somatostatin Receptor 4 Agonist

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1075
Author(s):  
Pooja Dasgupta ◽  
Thomas Gűnther ◽  
Stefan Schulz
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Hek293 Cells ◽  
Somatostatin Analogue ◽  
Protein Signaling ◽  
Pharmacological Characterization ◽  
The Individual ◽  
G Protein Coupled

Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein‒coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (Emax, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (Emax, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5.

scholarly journals 177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition

2019 ◽  
Vol 26 (4) ◽  
pp. 437-449 ◽  
Author(s):  
Tobias Hofving ◽  
Viktor Sandblom ◽  
Yvonne Arvidsson ◽  
Emman Shubbar ◽  
Gülay Altiparmak ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Xenograft Model ◽  
Progression Free Survival ◽  
Tumour Volume ◽  
Tumour Cells ◽  
Hsp90 Inhibition ◽  
Killing Effect

177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2 × 10−11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

scholarly journals Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

2021 ◽  
Author(s):  
Francesca Borgna ◽  
Stephanie Haller ◽  
Josep M. Monné Rodriguez ◽  
Mihaela Ginj ◽  
Pascal V. Grundler ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Paradigm Shift ◽  
Somatostatin Receptor ◽  
Neuroendocrine Neoplasms ◽  
Therapeutic Advantage ◽  
Tumor Bearing ◽  
Single Cancer ◽  
Therapy Studies

Abstract Purpose The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

scholarly journals [18F]FET-βAG-TOCA: The Design, Evaluation and Clinical Translation of a Fluorinated Octreotide

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 865 ◽  
Author(s):  
Louis Allott ◽  
Suraiya Dubash ◽  
Eric O. Aboagye
Keyword(s):  
Somatostatin Receptor ◽  
Peptide Receptor Radionuclide Therapy ◽  
Somatostatin Analogues ◽  
Good Manufacturing Practice ◽  
Biological Evaluation ◽  
Clinical Translation ◽  
Prosthetic Group ◽  
Radiolabelled Peptides ◽  
Gallium 68

The success of Lutathera™ ([177Lu]Lu-DOTA-TATE) in the NETTER-1 clinical trial as a peptide receptor radionuclide therapy (PRRT) for somatostatin receptor expressing (SSTR) neuroendocrine tumours (NET) is likely to increase the demand for patient stratification by positron emission tomography (PET). The current gold standard of gallium-68 radiolabelled somatostatin analogues (e.g., [68Ga]Ga-DOTA-TATE) works effectively, but access is constrained by the limited availability and scalability of gallium-68 radiopharmaceutical production. The aim of this review is three-fold: firstly, we discuss the peptide library design, biological evaluation and clinical translation of [18F]fluoroethyltriazole-βAG-TOCA ([18F]FET-βAG-TOCA), our fluorine-18 radiolabelled octreotide; secondly, to exemplify the potential of the 2-[18F]fluoroethylazide prosthetic group and copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry in accessing good manufacturing practice (GMP) compatible radiopharmaceuticals; thirdly, we aim to illustrate a framework for the translation of similarly radiolabelled peptides, in which in vivo pharmacokinetics drives candidate selection, supported by robust radiochemistry methodology and a route to GMP production. It is hoped that this review will continue to inspire the development and translation of fluorine-18 radiolabelled peptides into clinical studies for the benefit of patients.

scholarly journals Internalized Somatostatin Receptor Subtype 2 in Neuroendocrine Tumors of Octreotide-Treated Patients

2010 ◽  
Vol 95 (5) ◽  
pp. 2343-2350 ◽  
Author(s):  
Jean Claude Reubi ◽  
Beatrice Waser ◽  
Renzo Cescato ◽  
Beat Gloor ◽  
Christoph Stettler ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Somatostatin Receptor ◽  
Receptor Autoradiography ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
High Dose ◽  
Somatostatin Receptor Subtype 2 ◽  
In Vitro Receptor Autoradiography

Abstract Context: Somatostatin receptor subtype 2 (sst2) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst2 tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst2. Patients and Methods: In the present study, we evaluated whether sst2 expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst2 immunohistochemistry was performed in all samples with three different sst2 antibodies (R2-88, UMB-1, and SS-800). Sst2 receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst2, and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst2, whereas untreated patients had exclusively membranous sst2. The internalized sst2 receptor corresponded to a single sst2 band in immunoblots and to sst2 receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst2 receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments. Conclusion: It is the first evidence showing that sst2 receptors can be internalized in sst2-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst2 receptor biology and trafficking dynamics in patients.

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