AI Summary
The content discusses the rational design of heterobivalent probes targeting both the Prostate-Specific Membrane Antigen (PSMA) and the neurotensin receptor-1 (NTS1) for prostate cancer theranostics. The development of a hybrid probe, JMV 7489, was reported, showing good affinity towards PSMA and lower affinity towards NTS1. The study highlights the importance of the DOTA macrocycle and the linker in designing probes targeting both receptors effectively.
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 cancer with low expression of PSMA which accounts for 15% of cases. The neurotensin receptor-1 (NTS1) has been highlighted as a suitable onco-target for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS1 could improve prostate cancer management. Herein, we report the development of a branched hybrid probe (JMV 7489) designed to target PSMA and/or NTS1 bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both synthesis in batch and solid phase. Saturation binding experiments were next performed on HT-29 and PC3-pip cells to derive Kd and Bmax values. On the PC3-pip cells, [68Ga]Ga-JMV 7489 displayed good affinity towards PSMA (Kd = 53 ± 17 nM; Bmax = 1393 ± 29 fmol/106 cells) in the same range as the corresponding reference monomer. Lower affinity value at the NTS1 was depicted (Kd = 157 ± 71 nM; Bmax = 241 ± 42 fmol/106 cells on PC3-pip cells; Kd = 246 ± 1 nM; Bmax = 151 ± 44 fmol/106 cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [68Ga]Ga-JMV 7089. These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent targeting PSMA and NTS1 with high affinity towards NTS1.