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

Year: 2024

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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 ( 3 ) combining PSMA-617 ( 1 ) and the GRPR antagonist RM2 ( 2 ) with the radiometal chelator DOTA. 3 was radiolabeled with 68 Ga ([ 68 Ga]Ga- 3 ) and 177 Lu ([ 177 Lu]Lu- 3 ). [ 68 Ga]Ga- 3 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 ( 1 and 2 ), ligand 3 showed specific cell binding, similar receptor affinities, and higher lipophilicity, while its internalization rates and cell-binding were superior. Docking calculations showed that 3 can have binding interactions of PSMA-617 ( 1 ) inside the PSMA receptor funnel and RM2 ( 2 ) inside the GRPR. In vivo biodistribution studies for [ 68 Ga]Ga- 3 showed dual targeting for PSMA(+) and GRPR(+) tumors and higher tumor uptake, faster pharmacokinetic, and lower kidney uptake compared to 1 and 2

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00324