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用于前列腺癌诊疗的NT-PSMA异二价探针的合理设计。

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

作者信息

Previti Santo, Bodin Sacha, Rémond Emmanuelle, Vimont Delphine, Hindié Elif, Morgat Clément, Cavelier Florine

机构信息

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

出版信息

RSC Med Chem. 2024 Sep 16;15(12):4153-8. doi: 10.1039/d4md00491d.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53c7/11636609/0154d33047e5/d4md00491d-c1.jpg

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