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EJNMMI Research
Published in: EJNMMI Research 1/2020

01-12-2020 | Positron Emission Tomography | Original research

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

Authors: Rosalba Mansi, Karim Abid, Guillaume P. Nicolas, Luigi Del Pozzo, Eric Grouzmann, Melpomeni Fani

Published in: EJNMMI Research | Issue 1/2020

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Abstract

Background

Somatostatin receptor (SST) targeting, specifically of the subtype 2 (SST2), with radiolabeled somatostatin analogs, is established for imaging and treatment of neuroendocrine tumors. Owing to the concomitant and heterogeneous expression of several subtypes on the same tumor, analogs targeting more subtypes than SST2 potentially target a broader spectrum of tumors and/or increase the uptake of a given tumor. The analog ST8950 ((4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2), bearing 2 iodo-amino acids, exhibits sub-nanomolar affinity to SST2 and SST5. We report herein the development and preclinical evaluation of DOTA-ST8950 labeled with 68Ga, for imaging SST2- and SST5-expressing tumors. Comparative in vitro and in vivo studies were performed with the de-iodinated DOTA-ST8951 ((4-amino)-d-Phe-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2) and with the reference compounds DOTA-TATE (SST2 selective) and DOTA-NOC (for SST2 and SST5).

Results

Compared with natGa-DOTA-NOC, natGa-DOTA-ST8950 exhibited higher affinity to SST2 and SST5 (IC50 (95%CI), nM = 0.32 (0.20–0.50) and 1.9 (1.1–3.1) vs 0.70 (0.50-0.96) and 3.4 (1.8-6.2), respectively), while natGa-DOTA-ST8951 lost affinity for both subtypes. natGa-DOTA-ST8950 had the same potency for inducing SST2-mediated cAMP accumulation as natGa-DOTA-TATE and slightly better than natGa-DOTA-NOC (EC50, nM = 0.46 (0.23–0.92) vs 0.47 (0.15–1.5) vs 0.59 (0.18–1.9), respectively). [67Ga]Ga-DOTA-ST8950 had a similar internalization rate as [67Ga]Ga-DOTA-NOC in SST2-expressing cells (12.4 ± 1.6% vs 16.6 ± 2.2%, at 4 h, p = 0.0586). In vivo, [68Ga]Ga-DOTA-ST8950 showed high and specific accumulation in SST2- and SST5-expressing tumors, comparable with [68Ga]Ga-DOTA-NOC (26 ± 8 vs 30 ± 8 %IA/g, p = 0.4630 for SST2 and 15 ± 6 vs 12 ± 5 %IA/g, p = 0.3282, for SST5, 1 h p.i.) and accumulation in the SST-positive tissues, the kidneys and the liver. PET/CT images of [68Ga]Ga-DOTA-ST8950, performed in a dual HEK-SST2 and HEK-SST5 tumor xenografted model, clearly visualized both tumors and illustrated high tumor-to-background contrast.

Conclusions

[68Ga]Ga-DOTA-ST8950 reveals its potential for PET imaging SST2- and SST5-expressing tumors. It compares favorably with the clinically used [68Ga]Ga-DOTA-NOC in terms of tumor uptake; however, its uptake in the liver remains a challenge for clinical translation. In addition, this study reveals the essential role of the iodo-substitutions in positions 1 and 3 of [68Ga]Ga-DOTA-ST8950 for maintaining affinity to SST2 and SST5, as the de-iodinated [68Ga]Ga-DOTA-ST8951 lost affinity for both receptor subtypes.
Literature
1.
Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27:273–82.PubMed
2.
Asnacios A, Courbon F, Rochaix P, Bauvin E, Cances-Lauwers V, Susini C, et al. Indium-111-pentetreotide scintigraphy and somatostatin receptor subtype 2 expression: new prognostic factors for malignant well-differentiated endocrine tumors. J Clin Oncol. 2008;26:963–70.PubMed
3.
Buscail L, Esteve JP, Saint-Laurent N, Bertrand V, Reisine T, O'Carroll AM, et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci U S A. 1995;92:1580–4.PubMedPubMedCentral
4.
Kulaksiz H, Eissele R, Rossler D, Schulz S, Hollt V, Cetin Y, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut. 2002;50:52–60.PubMedPubMedCentral
5.
Papotti M, Bongiovanni M, Volante M, Allia E, Landolfi S, Helboe L, et al. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 2002;440:461–75.PubMed
6.
Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. 2003;30:781–93.PubMed
7.
Forssell-Aronsson EB, Nilsson O, Bejegard SA, Kolby L, Bernhardt P, Molne J, et al. 111In-DTPA-D-Phe1-octreotide binding and somatostatin receptor subtypes in thyroid tumors. J Nucl Med. 2000;41:636–42.PubMed
8.
Rivier JE, Hoeger C, Erchegyi J, Gulyas J, DeBoard R, Craig AG, et al. Potent somatostatin undecapeptide agonists selective for somatostatin receptor 1 (sst1). J Med Chem. 2001;44:2238–46.PubMed
9.
Traub T, Petkov V, Ofluoglu S, Pangerl T, Raderer M, Fueger BJ, et al. 111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung. J Nucl Med. 2001;42:1309–15.PubMed
10.
Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34:982–93.PubMed
11.
Wild D, Schmitt JS, Ginj M, Macke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30:1338–47.PubMed
12.
Wild D, Macke HR, Waser B, Reubi JC, Ginj M, Rasch H, et al. 68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5. Eur J Nucl Med Mol Imaging. 2005;32:724.PubMed
13.
Lewis I, Bauer W, Albert R, Chandramouli N, Pless J, Weckbecker G, et al. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J Med Chem. 2003;46:2334–44.PubMed
14.
Schmid HA. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008;286:69–74.PubMed
15.
Fani M, Braun F, Mann A, Kliewer A, Kaufmann J, Weber WA, et al. Development of the 68Ga-labeled pan-somatostatin analog SOM230 (SOMscan). Abstract. J Nucl Med. 2012;53:1686.
16.
Fani M, Gourni E, Braun F, Mann A, Kliewer A, Kaufmann J, et al. Development and Preclinical Evaluation of the New Pan-Somatostatin PET Imaging Probe 68Ga-DOTA-SOM230 (SOMscan®). Abstract. NANETS. 2012;2012:C16.
17.
Liu F, Liu T, Xu X, Guo X, Li N, Xiong C, et al. Design, synthesis, and biological evaluation of (68)Ga-DOTA-PA1 for lung cancer: a novel PET tracer for multiple somatostatin receptor imaging. Mol Pharm. 2018;15:619–28.PubMed
18.
Ginj M, Chen J, Walter MA, Eltschinger V, Reubi JC, Maecke HR. Preclinical evaluation of new and highly potent analogues of octreotide for predictive imaging and targeted radiotherapy. Clin Cancer Res. 2005;11:1136–45.PubMed
19.
Ginj M, Zhang H, Eisenwiener KP, Wild D, Schulz S, Rink H, et al. New pansomatostatin ligands and their chelated versions: affinity profile, agonist activity, internalization, and tumor targeting. Clin Cancer Res. 2008;14:2019–27.PubMed
20.
Tatsi A, Maina T, Cescato R, Waser B, Krenning EP, de Jong M, et al. [111In-DOTA]Somatostatin-14 analogs as potential pansomatostatin-like radiotracers - first results of a preclinical study. EJNMMI Res. 2012;2:25.PubMedPubMedCentral
21.
Tatsi A, Maina T, Cescato R, Waser B, Krenning EP, de Jong M, et al. [DOTA]Somatostatin-14 analogs and their (111)In-radioligands: effects of decreasing ring-size on sst1-5 profile, stability and tumor targeting. Eur J Med Chem. 2014;73:30–7.PubMed
22.
Maina T, Cescato R, Waser B, Tatsi A, Kaloudi A, Krenning EP, et al. [111In-DOTA]LTT-SS28, a first pansomatostatin radioligand for in vivo targeting of somatostatin receptor-positive tumors. J Med Chem. 2014;57:6564–71.PubMed
23.
Cai RZ, Szoke B, Lu R, Fu D, Redding TW, Schally AV. Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Natl Acad Sci U S A. 1986;83:1896–900.PubMedPubMedCentral
24.
Moore SB, van der Hoek J, de Capua A, van Koetsveld PM, Hofland LJ, Lamberts SW, et al. Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from rat pituitary cells. J Med Chem. 2005;48:6643–52.PubMed
25.
Streuli J, Harris AG, Cottiny C, Allagnat F, Daly AF, Grouzmann E, et al. Cellular effects of AP102, a somatostatin analog with balanced affinities for the hSSTR2 and hSSTR5 receptors. Neuropeptides. 2018;68:84–9.PubMed
26.
Tarasco E, Seebeck P, Pfundstein S, Daly AF, Eugster PJ, Harris AG, et al. Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats. Endocrine. 2017;58:124–33.PubMed
27.
Fani M, Del Pozzo L, Abiraj K, Mansi R, Tamma ML, Cescato R, et al. PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med. 2011;52:1110–8.PubMed
28.
Taboada GF, Luque RM, Bastos W, Guimaraes RF, Marcondes JB, Chimelli LM, et al. Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol. 2007;156:65–74.PubMed
29.
Kabasakal L, Demirci E, Ocak M, Decristoforo C, Araman A, Ozsoy Y, et al. Comparison of (6)(8)Ga-DOTATATE and (6)(8)Ga-DOTANOC PET/CT imaging in the same patient group with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012;39:1271–7.PubMed
30.
Wild D, Bomanji JB, Benkert P, Maecke H, Ell PJ, Reubi JC, et al. Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT within patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2013;54:364–72.PubMed
31.
Lamarca A, Pritchard DM, Westwood T, Papaxoinis G, Nonaka D, Vinjamuri S, et al. 68Gallium DOTANOC-PET imaging in lung carcinoids: impact on patients' management. Neuroendocrinology. 2018;106:128–38.PubMed
32.
Woltering EA, O'Dorisio MS, Murphy WA, Chen F, Drouant GJ, Espenan GD, et al. Synthesis and characterization of multiply-tyrosinated, multiply-iodinated somatostatin analogs. J Pept Res. 1999;53:201–13.PubMed
33.
Schottelius M, Simecek J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ. Twins in spirit - episode I: comparative preclinical evaluation of [(68)Ga]DOTATATE and [(68)Ga]HA-DOTATATE. EJNMMI Res. 2015;5:22.PubMedPubMedCentral
34.
Reubi JC, Erchegyi J, Cescato R, Waser B, Rivier JE. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog. Eur J Nucl Med Mol Imaging. 2010;37:1551–8.PubMedPubMedCentral
35.
Cescato R, Schulz S, Waser B, Eltschinger V, Rivier JE, Wester HJ, et al. Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists. J Nucl Med. 2006;47:502–11.PubMed
36.
Stroh T, Jackson AC, Sarret P, Dal Farra C, Vincent JP, Kreienkamp HJ, et al. Intracellular dynamics of sst5 receptors in transfected COS-7 cells: maintenance of cell surface receptors during ligand-induced endocytosis. Endocrinology. 2000;141:354–65.PubMed
37.
Fani M, Braun F, Waser B, Beetschen K, Cescato R, Erchegyi J, et al. Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications. J Nucl Med. 2012;53:1481–9.PubMed
38.
Taelman VF, Radojewski P, Marincek N, Ben-Shlomo A, Grotzky A, Olariu CI, et al. Upregulation of key molecules for targeted imaging and therapy. J Nucl Med. 2016;57:1805–10.PubMed
Metadata
Title
A new 68Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
Authors
Rosalba Mansi
Karim Abid
Guillaume P. Nicolas
Luigi Del Pozzo
Eric Grouzmann
Melpomeni Fani
Publication date
01-12-2020
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-020-00677-3

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