Bispecific PSMA/GRPR radioligands for discordant prostate cancer lesions

PSMA and GRPR expression in prostate cancer are complementary rather than fully overlapping: GRPR tends to be higher in earlier, lower-grade disease and PSMA in more advanced disease, and a head-to-head comparison of 68Ga-PSMA-11 and 68Ga-RM2 (a GRPR ligand) PET found broadly similar overall detection rates but each tracer found lesions the other missed. This has motivated development of bispecific 'heterodimer' molecules that carry both a PSMA-binding urea-based inhibitor and a GRPR-binding bombesin-analogue peptide on a single scaffold, so that a lesion expressing either receptor (or both) would be detected or treated.

Several such heterodimers have been synthesised and tested in mouse models. A DUPA-RM26 heterodimer (NOTA-DUPA-RM26) showed high affinity and specific binding to both PSMA-positive and GRPR-positive cell lines with only moderate affinity loss compared with the individual monomers; a related iPSMA-BN heterodimer reached a first-in-human PET imaging study reporting specific uptake in the pancreas (GRPR-expressing) and salivary glands (PSMA-expressing) of healthy volunteers; and a 2024 paper reported a DOTA-conjugated heterodimer combining PSMA-617 and the GRPR antagonist RM2, labelled with both gallium-68 and lutetium-177, which showed dual-receptor tumour targeting, faster pharmacokinetics and lower kidney uptake than either parent compound alone in mouse xenografts.

Despite this preclinical progress, two independent reviews (2020 and 2025) both state that none of the described PSMA/GRPR bispecific radioligands has yet been evaluated in a clinical trial in patients; the concept remains preclinical, distinct from the closely related but separately developed GRPR-only and PSMA-only radioligands already in clinical use or trials.