Precision peptide theranostics: developing - to -terminus optimized theranostics targeting cholecystokinin-2 receptor.

Peptides are ideal for theranostic development as they afford rapid target accumulation, fast clearance from background tissue, and exhibit good tissue penetration. Previously, we developed a novel series of peptides that presented discreet folding propensity leading to an optimal candidate [Ga]Ga-DOTA- ([D-Glu]-Ala-Tyr-MeGly-Trp-MeNle-Asp-Nal-NH) with 50 pM binding affinity against cholecystokinin-2 receptors (CCKR). However, we were confronted with challenges of unfavorably high renal uptake. A structure activity relationship study was undertaken of the lead theranostic candidate. Prudent structural modifications were made to the peptide scaffold to evaluate the contributions of specific -terminal residues to the overall biological activity. Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK tumors, and their biodistribution was quantitated . We identified and confirmed that D-Glu to D-Ala substitution produced 2 optimal candidates, [Ga]Ga-DOTA- and [Ga]Ga-DOTA-. These radiopeptides presented with high target/background ratios, enhanced tumor retention, excellent metabolic stability in plasma and mice organ homogenates, and a 4-fold reduction in renal uptake, significantly outperforming their non-alanine counterparts. Our study identified novel radiopharmaceutical candidates that target the CCKR. Their high tumor uptake and reduced renal accumulation warrant clinical translation.