Previti Santo, Bodin Sacha, Rémond Emmanuelle, Vimont Delphine, Hindié Elif, Morgat Clément, Cavelier Florine
Pôle Chime Balard, IBMM, UMR 5247 CNRS, Université Montpellier ENSCM F-34000 Montpellier France
Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina Viale Stagno d'Alcontres 31 98166 Messina Italy
RSC Med Chem. 2024 Sep 16;15(12):4153-8. doi: 10.1039/d4md00491d.
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) 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 could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe () designed to target PSMA and/or NTS 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 and values. On the PC3-PIP cells, [Ga]Ga- displayed good affinity towards PSMA ( = 53 ± 17 nM; = 1393 ± 29 fmol/10 cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS was depicted ( = 157 ± 71 nM; = 241 ± 42 fmol/10 cells on PC3-PIP cells; = 246 ± 1 nM; = 151 ± 44 fmol/10 cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [Ga]Ga-. These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS with high affinity towards NTS.
用放射性药物靶向前列腺特异性膜抗原(PSMA)进行成像和/或治疗,已在前列腺癌患者的管理方面取得了显著进展。然而,PSMA靶向在PSMA低表达的前列腺癌中仍然不成功,这类病例占15%。神经降压素受体-1(NTS)已被视为PSMA阴性前列腺癌病变成像和治疗的合适肿瘤靶点。因此,同时靶向PSMA和NTS的异二价探针可改善前列腺癌的管理。在此,我们报告了一种分支杂交探针()的研发情况,该探针设计用于靶向带有相关药效基团的PSMA和/或NTS,并以DOTA作为螯合剂。新配体采用混合方法合成,包括分批合成和固相合成。接下来在HT-29和PC3-PIP细胞上进行饱和结合实验,以得出和值。在PC3-PIP细胞上,[Ga]Ga-对PSMA显示出良好的亲和力(= 53 ± 17 nM;= 1393 ± 29 fmol/10个细胞),与相应的参考单体处于同一范围。对NTS的亲和力值较低(在PC3-PIP细胞上= 157 ± 71 nM;= 241 ± 42 fmol/10个细胞;在HT-29细胞上= 246 ± 1 nM;= 151 ± 44 fmol/10个细胞),令人惊讶的是,相应的单体[Ga]Ga-也是如此。这些结果表明,DOTA大环和连接体是设计对NTS具有高亲和力的靶向PSMA和NTS的异二价探针的关键要素。