Bispecific PSMA-617 / RM2 Heterodimer for Theranostics Applications in Prostate Cancer

11 January 2024, Version 1


PSMA and GRPR protein receptors are upregulated during prostate cancer (PCa) progression, and thus they have both been used for diagnostic molecular imaging and therapy of the disease. To address tumor heterogeneity, we synthesized and evaluated the bispecific PSMA/GRPR ligand (3) with a 10 atom spacer between PSMA-617 (1) and the GRPR antagonist RM2 (2) generated with click chemistry and coupled with chelator DOTA, to enable radiolabelling. Ligand 3 was radiolabelled with 68Ga, [68Ga]Ga-3 and 177Lu, [177Lu]Lu-3. [68Ga]Ga-3 was tested with PCa cell lines PC-3 and LNCaP for its affinity for GRPR and PSMA receptors, lipophilicity, for its cell-binding specificity, time kinetic binding affinities and cell-internalization. Heterodimer 3 showed specific cell binding, similar affinities for PSMA receptor and GRPR and higher lipophilicity compared to monomers PSMA-617 (1) and RM2 (2), while total internalization rates and cell-binding were superior over monomers. Docking calculations showed that the PSMA-617 (1) /RM2 (2) heterodimer 3 can have binding interactions of PSMA-617 (1) inside the PSMA receptor funnel and of RM2 (2) inside the GRPR. In vivo biodistribution studies for [68Ga]Ga-3 showed dual targeting of PSMA-positive tumors and GRPR-positive tumors and fast pharmacokinetic properties, higher cancer cell-uptake and lower kidney uptake in comparison to the monomers.


Prostate cancer
molecular dynamics simulations
homology modelling
induced-fit docking
cell-binding specificity
PET imaging

Supplementary materials

Supporting information
Supporting information containing docking studies for the heterodimeric ligand described in the MS


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