Résumé
An estimated 375,304 people worldwide died from prostate cancer in 2020. Despite the achievements in terms of diagnosis and treatment, the 5-year survival rate is equal to 31% at the late stage.Radiopharmaceuticals targeting the Prostate-Specific Membrane Antigen (PSMA) led to significant improvements both for imaging and therapy.[1] However, the use of PSMA-targeting radioligands is unproductive in prostate cancer with low expression of PSMA which accounts for 15% of cases.The development of heterodimers targeting two distinct onco-receptors could be a valid strategy to bypass the prostate cancer heterogeneity. In this context, neurotensin receptor 1 (NTS1) was found to be over-expressed in prostate cancer not expressing PSMA.[2]Herein we describe the synthesis and biological characterization of JMV 7489, a branched heterodimer carrying both PSMA and NT pharmacophores, appropriate linkers, and DOTA as the chelating agent suitable for theranostic purpose.JMV 7489 was obtained with a hybrid synthetic approach, which involved both synthesis in batch and Solid-Phase Peptide Synthesis (SPPS). This strategy was applied since both pharmacophores harbour a C-terminal moiety.JMV 7489 was then radiolabelled with 68 Ga. On the PC3-pip cells (PSMA+/NTS1+), [68 Ga]Ga-JMV 7489 exhibited good affinity towards PMSA (Kd = 53 nM), whereas lower affinity at the NTS1 was observed (Kd = 157 nM). Comparable Kd values towards NTS1 on HT-29 cells (PSMA-/NTS1+) were obtained.The Kd value shown by [68Ga]Ga-JMV 7489 towards PSMA is 3-fold higher than other NT-PSMA heterodimers and is comparable to PSMA monomers.[3] On the other hand, the affinity towards NTS1 is lower with respect to the NT monomers. In order to investigate the loss of affinity, the corresponding monomers JMV 7089 was developed. Surprisingly, the affinity value was also decreased (Kd = 154.7 nM) compare to the monomers, suggesting that the linker and DOTA-pharmacophore distance negatively influence the affinity. The integration of the NT-pharmacophore into the NT-PSMA heterodimer was therefore well tolerated although the resulting affinity was still moderate.References1. Roberts M.J. et al Using PSMA imaging for prognostication in localized and advanced prostate cancer. Nat Rev Urol 2023, 20, 23–47.2. Schollhammer R. et al Theranostics of primary prostate cancer: beyond PSMA and GRP-R. Cancers (Basel) 2023, 15, 2,345.3. Ma X. et al Development of Bispecific NT-PSMA heterodimer for prostate cancer imaging: a potential approach to address tumor heterogeneity. Bioconjug Chem 2019, 30, 1314–1322.