Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer Targeting Prostate Cancer.

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have been used for diagnostic molecular imaging/therapy of prostate cancer (PCa). To address tumor heterogeneity, we synthesized and evaluated a bispecific PSMA/GRPR ligand () combining PSMA-617 () and the GRPR antagonist RM2 () with the radiometal chelator DOTA. was radiolabeled with Ga ([Ga]Ga-) and Lu ([Lu]Lu-). [Ga]Ga- was tested in the following PCa cell lines for receptor affinity, time kinetic cell-binding/specificity, and cell-internalization: PC-3 and LNCaP. Compared to the monomers ( and ), ligand showed specific cell binding, similar receptor affinities, and higher lipophilicity, while its internalization rates and cell-binding were superior. Docking calculations showed that can have binding interactions of PSMA-617 () inside the PSMA receptor funnel and RM2 () inside the GRPR. biodistribution studies for [Ga]Ga- showed dual targeting for PSMA(+) and GRPR(+) tumors and higher tumor uptake, faster pharmacokinetic, and lower kidney uptake compared to and .