Rational design of NT-PSMA heterobivalent probes for prostate cancer theranostics

Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which acc...

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Published in:RSC medicinal chemistry Vol. 15; no. 12; pp. 4153 - 4158
Main Authors: Previti, Santo, Bodin, Sacha, Rémond, Emmanuelle, Vimont, Delphine, Hindié, Elif, Morgat, Clément, Cavelier, Florine
Format: Journal Article
Language:English
Published: CAMBRIDGE Royal Soc Chemistry 16.09.2024
Royal Society of Chemistry
RSC
Subjects:
Biochemistry & Molecular Biology
Chemistry
Chemistry, Medicinal
Life Sciences
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
ISSN:2632-8682, 2632-8682
Online Access:Get full text
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Summary:Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which account for 15% of cases. The neurotensin receptor-1 (NTS 1 ) has been highlighted as a suitable oncotarget for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS 1 could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe ( JMV 7489 ) designed to target PSMA and/or NTS 1 bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both syntheses in batch and in the solid phase. Saturation binding experiments were next performed on HT-29 and PC3-PIP cells to derive K d and B max values. On the PC3-PIP cells, [ 68 Ga]Ga- JMV 7489 displayed good affinity towards PSMA ( K d = 53 ± 17 nM; B max = 1393 ± 29 fmol/10 6 cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS 1 was depicted ( K d = 157 ± 71 nM; B max = 241 ± 42 fmol/10 6 cells on PC3-PIP cells; K d = 246 ± 1 nM; B max = 151 ± 44 fmol/10 6 cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [ 68 Ga]Ga- JMV 7089 . These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS 1 with high affinity towards NTS 1 . Linker and chelating agents strongly influence the binding affinity of the NTS 1 -PSMA heterobivalent probe towards NTS 1 . Comparable affinities between mono- and heterobivalent ligands towards PSMA were observed.
Bibliography:https://doi.org/10.1039/d4md00491d
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ISSN:2632-8682
2632-8682
DOI:10.1039/d4md00491d