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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Nov 20

PMID 39563828

Authors

Christos Liolios

Danai Bouziotis

Wiebke Sihver

Martin Schafer

George Lambrinidis

Evangelia-Alexandra Salvanou

Ulrike Bauder-Wust

Martina Benesova

Klaus Kopka

Antonios Kolocouris

Penelope Bouziotis

Affiliations

Soon will be listed here.

Abstract

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 .

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