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Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2

[Image: see text] Neurotensin receptor 2 (NTS(2)) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS(2) overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radio...

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Autores principales: Bodin, Sacha, Previti, Santo, Jestin, Emmanuelle, Vimont, Delphine, Ait-Arsa, Imade, Lamare, Frédéric, Rémond, Emmanuelle, Hindié, Elif, Cavelier, Florine, Morgat, Clément
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9948202/
https://www.ncbi.nlm.nih.gov/pubmed/36844603
http://dx.doi.org/10.1021/acsomega.2c07814
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author Bodin, Sacha
Previti, Santo
Jestin, Emmanuelle
Vimont, Delphine
Ait-Arsa, Imade
Lamare, Frédéric
Rémond, Emmanuelle
Hindié, Elif
Cavelier, Florine
Morgat, Clément
author_facet Bodin, Sacha
Previti, Santo
Jestin, Emmanuelle
Vimont, Delphine
Ait-Arsa, Imade
Lamare, Frédéric
Rémond, Emmanuelle
Hindié, Elif
Cavelier, Florine
Morgat, Clément
author_sort Bodin, Sacha
collection PubMed
description [Image: see text] Neurotensin receptor 2 (NTS(2)) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS(2) overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS(2). JMV 7488 (DOTA-(βAla)(2)-Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with (68)Ga and (111)In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [(68)Ga]Ga-JMV 7488 and [(111)In]In-JMV 7488 were quite hydrophilic (logD(7.4) = −3.1 ± 0.2 and −2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS(2) (K(D) = 38 ± 17 nM for [(68)Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K(D) = 36 ± 4 nM for [(111)In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS(1) binding up to 500 nM). On cell-based evaluation, [(68)Ga]Ga-JMV 7488 and [(111)In]In-JMV 7488 showed high and fast NTS(2)-mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [(111)In]In-JMV 7488, respectively, along with low NTS(2)-membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [(68)Ga]Ga-JMV 7488 on HT-29 and increased for [(111)In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS(2) agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [(68)Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS(2). Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [(68)Ga]Ga-JMV 7488 uptake although the mechanism was not NTS(2)-mediated.
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spelling pubmed-99482022023-02-24 Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2 Bodin, Sacha Previti, Santo Jestin, Emmanuelle Vimont, Delphine Ait-Arsa, Imade Lamare, Frédéric Rémond, Emmanuelle Hindié, Elif Cavelier, Florine Morgat, Clément ACS Omega [Image: see text] Neurotensin receptor 2 (NTS(2)) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS(2) overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS(2). JMV 7488 (DOTA-(βAla)(2)-Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with (68)Ga and (111)In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [(68)Ga]Ga-JMV 7488 and [(111)In]In-JMV 7488 were quite hydrophilic (logD(7.4) = −3.1 ± 0.2 and −2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS(2) (K(D) = 38 ± 17 nM for [(68)Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K(D) = 36 ± 4 nM for [(111)In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS(1) binding up to 500 nM). On cell-based evaluation, [(68)Ga]Ga-JMV 7488 and [(111)In]In-JMV 7488 showed high and fast NTS(2)-mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [(111)In]In-JMV 7488, respectively, along with low NTS(2)-membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [(68)Ga]Ga-JMV 7488 on HT-29 and increased for [(111)In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS(2) agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [(68)Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS(2). Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [(68)Ga]Ga-JMV 7488 uptake although the mechanism was not NTS(2)-mediated. American Chemical Society 2023-02-10 /pmc/articles/PMC9948202/ /pubmed/36844603 http://dx.doi.org/10.1021/acsomega.2c07814 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Bodin, Sacha
Previti, Santo
Jestin, Emmanuelle
Vimont, Delphine
Ait-Arsa, Imade
Lamare, Frédéric
Rémond, Emmanuelle
Hindié, Elif
Cavelier, Florine
Morgat, Clément
Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title_full Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title_fullStr Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title_full_unstemmed Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title_short Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2
title_sort design, synthesis, and biological evaluation of the first radio-metalated neurotensin analogue targeting neurotensin receptor 2
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9948202/
https://www.ncbi.nlm.nih.gov/pubmed/36844603
http://dx.doi.org/10.1021/acsomega.2c07814
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