{"entity":{"id":"idea-bispecific-radioligands","kind":"idea","name":"Bispecific PSMA/GRPR radioligands for discordant prostate cancer lesions","aka":[],"tldr":"Not every prostate cancer cell carries the same marker: some show the PSMA protein that most scans target, others show a different marker called GRPR instead. A single tracer molecule built to stick to both markers at once could find and treat tumours that a PSMA-only or GRPR-only scan would miss.","summary":"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.\n\nSeveral 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.\n\nDespite 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.","asOf":"2026-09-22","links":[{"label":"Bispecific Radioligands (BRLs): Two Is Better Than One (PMC review, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12386959/"},{"label":"Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy (MDPI review, 2020)","url":"https://www.mdpi.com/1424-8247/13/8/173"},{"label":"Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer (PMC, 2024)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11571012/"},{"label":"Gastrin Releasing Peptide Receptors-targeted PET imaging in prostate cancer (Erasmus MC review)","url":"https://pure.eur.nl/ws/portalfiles/portal/150811942/1-s2.0-S1556859824000191-main.pdf"}],"tags":["bispecific","prostate","molecular imaging"],"related":["psma","grpr","psma-pet","ga-68","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A single small-molecule radioligand that binds both PSMA and GRPR will detect and, in a therapeutic form, treat more prostate cancer lesions than a PSMA-only or GRPR-only agent, because it captures tumours regardless of which receptor they predominantly express, including cases with discordant single-tracer PET results.","rationale":"PSMA and GRPR expression patterns in prostate cancer are complementary across disease stages, and a head-to-head PET comparison found each single-target tracer detected lesions the other missed, supporting the rationale for a dual-target agent. Multiple PSMA/GRPR heterodimers have shown dual-receptor binding, tumour uptake and favourable biodistribution in mouse xenograft models, including one first-in-human imaging study of a related heterodimer in healthy volunteers, but two independent reviews confirm that no PSMA/GRPR bispecific radioligand has yet been tested in cancer patients.","test":"A first-in-human phase 0/1 imaging study of a PSMA/GRPR bispecific PET tracer in patients with biochemically recurrent prostate cancer and known discordant single-tracer PSMA and GRPR PET results, roughly 20-30 patients, comparing lesion detection rate against same-patient single-target PSMA and GRPR PET scans, as the precursor step before testing a therapeutic bispecific ligand.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":9},"route":"/ideas/idea-bispecific-radioligands/","neighbours":{"target":[{"id":"grpr","kind":"target","name":"GRPR (gastrin-releasing peptide receptor)","route":"/targets/grpr/"},{"id":"psma","kind":"target","name":"PSMA","route":"/targets/psma/"}],"technology":[{"id":"psma-pet","kind":"technology","name":"PSMA PET","route":"/technologies/psma-pet/"}],"isotope":[{"id":"ga-68","kind":"isotope","name":"Gallium-68","route":"/isotopes/ga-68/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}]}}