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

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 tar...

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Autores principales: Mansi, Rosalba, Abid, Karim, Nicolas, Guillaume P., Del Pozzo, Luigi, Grouzmann, Eric, Fani, Melpomeni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406630/
https://www.ncbi.nlm.nih.gov/pubmed/32757150
http://dx.doi.org/10.1186/s13550-020-00677-3
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author Mansi, Rosalba
Abid, Karim
Nicolas, Guillaume P.
Del Pozzo, Luigi
Grouzmann, Eric
Fani, Melpomeni
author_facet Mansi, Rosalba
Abid, Karim
Nicolas, Guillaume P.
Del Pozzo, Luigi
Grouzmann, Eric
Fani, Melpomeni
author_sort Mansi, Rosalba
collection PubMed
description 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-NH(2)), 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 (68)Ga, 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-NH(2)) and with the reference compounds DOTA-TATE (SST2 selective) and DOTA-NOC (for SST2 and SST5). RESULTS: Compared with (nat)Ga-DOTA-NOC, (nat)Ga-DOTA-ST8950 exhibited higher affinity to SST2 and SST5 (IC(50) (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 (nat)Ga-DOTA-ST8951 lost affinity for both subtypes. (nat)Ga-DOTA-ST8950 had the same potency for inducing SST2-mediated cAMP accumulation as (nat)Ga-DOTA-TATE and slightly better than (nat)Ga-DOTA-NOC (EC(50), nM = 0.46 (0.23–0.92) vs 0.47 (0.15–1.5) vs 0.59 (0.18–1.9), respectively). [(67)Ga]Ga-DOTA-ST8950 had a similar internalization rate as [(67)Ga]Ga-DOTA-NOC in SST2-expressing cells (12.4 ± 1.6% vs 16.6 ± 2.2%, at 4 h, p = 0.0586). In vivo, [(68)Ga]Ga-DOTA-ST8950 showed high and specific accumulation in SST2- and SST5-expressing tumors, comparable with [(68)Ga]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 [(68)Ga]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: [(68)Ga]Ga-DOTA-ST8950 reveals its potential for PET imaging SST2- and SST5-expressing tumors. It compares favorably with the clinically used [(68)Ga]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 [(68)Ga]Ga-DOTA-ST8950 for maintaining affinity to SST2 and SST5, as the de-iodinated [(68)Ga]Ga-DOTA-ST8951 lost affinity for both receptor subtypes.
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spelling pubmed-74066302020-08-13 A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting Mansi, Rosalba Abid, Karim Nicolas, Guillaume P. Del Pozzo, Luigi Grouzmann, Eric Fani, Melpomeni EJNMMI Res Original Research 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-NH(2)), 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 (68)Ga, 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-NH(2)) and with the reference compounds DOTA-TATE (SST2 selective) and DOTA-NOC (for SST2 and SST5). RESULTS: Compared with (nat)Ga-DOTA-NOC, (nat)Ga-DOTA-ST8950 exhibited higher affinity to SST2 and SST5 (IC(50) (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 (nat)Ga-DOTA-ST8951 lost affinity for both subtypes. (nat)Ga-DOTA-ST8950 had the same potency for inducing SST2-mediated cAMP accumulation as (nat)Ga-DOTA-TATE and slightly better than (nat)Ga-DOTA-NOC (EC(50), nM = 0.46 (0.23–0.92) vs 0.47 (0.15–1.5) vs 0.59 (0.18–1.9), respectively). [(67)Ga]Ga-DOTA-ST8950 had a similar internalization rate as [(67)Ga]Ga-DOTA-NOC in SST2-expressing cells (12.4 ± 1.6% vs 16.6 ± 2.2%, at 4 h, p = 0.0586). In vivo, [(68)Ga]Ga-DOTA-ST8950 showed high and specific accumulation in SST2- and SST5-expressing tumors, comparable with [(68)Ga]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 [(68)Ga]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: [(68)Ga]Ga-DOTA-ST8950 reveals its potential for PET imaging SST2- and SST5-expressing tumors. It compares favorably with the clinically used [(68)Ga]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 [(68)Ga]Ga-DOTA-ST8950 for maintaining affinity to SST2 and SST5, as the de-iodinated [(68)Ga]Ga-DOTA-ST8951 lost affinity for both receptor subtypes. Springer Berlin Heidelberg 2020-08-05 /pmc/articles/PMC7406630/ /pubmed/32757150 http://dx.doi.org/10.1186/s13550-020-00677-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Research
Mansi, Rosalba
Abid, Karim
Nicolas, Guillaume P.
Del Pozzo, Luigi
Grouzmann, Eric
Fani, Melpomeni
A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title_full A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title_fullStr A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title_full_unstemmed A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title_short A new (68)Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
title_sort new (68)ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406630/
https://www.ncbi.nlm.nih.gov/pubmed/32757150
http://dx.doi.org/10.1186/s13550-020-00677-3
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