Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [ 177 Lu]Lu-PSMA-617 in Healthy Organs.

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [ ¹⁷⁷ Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [ ¹⁷⁷ Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.