Albumin-Binding Moieties Tune the Pharmacokinetics and Tumor Uptake of 177Lu-Labeled GRPR Radioligands

Abstract Although the gastrin-releasing peptide receptor (GRPR) is an established theranostic target across multiple cancers, many GRPR-targeting peptides undergo rapid renal clearance, limiting tumor uptake and therapeutic exposure. Albumin-binding moieties (ABMs) reversibly interact with serum albumin, prolonging systemic exposure and increasing the opportunity for tumor uptake. To examine how ABM structure and placement affect this behavior, we prepared four DOTA-functionalized GRPR-targeting conjugates, varying both ABM lipophilicity and position relative to the DOTA chelator. The conjugates were radiolabeled with lutetium-177 in radiochemical yields and purities of >98%. All radioconjugates retained GRPR-mediated uptake in PC-3 cells, exhibited subnanomolar receptor affinity and enhanced blood retention. [177Lu]Lu-CA6356, bearing a 4-(p-iodophenyl)butyric acid-derived ABM, achieved the highest tumor uptake in PC-3 xenografts at 4 h pi (12 ± 2% IA/g), which increased by approximately 30% 24 h pi. These findings show that ABM identity and placement can modulate systemic exposure and tumor uptake in GRPR-targeting radioligands.