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

Rahimi, MN; Corlett, A; Van Zuylekom, J; Sani, MA; Blyth, B; Thompson, P; Roselt, PD; Haskali, MB

Author(s): Rahimi, MN; Corlett, A; Van Zuylekom, J; Sani, MA; Blyth, B; Thompson, P; Roselt, PD; Haskali, MB;
Details: Publication Year 2024,Volume 14,Issue #5,Page 1815-1828
Journal Title: Theranostics
Publication Type: Research article
Abstract: 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 [(68)Ga]Ga-DOTA-GA1 ([D-Glu](6)-Ala-Tyr-NMeGly-Trp-NMeNle-Asp-Nal-NH(2)) with 50 pM binding affinity against cholecystokinin-2 receptors (CCK(2)R). However, we were confronted with challenges of unfavorably high renal uptake. Methods: 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 N-terminal residues to the overall biological activity. Optimal candidates were then evaluated in nude mice bearing transfected A431-CCK(2) tumors, and their biodistribution was quantitated ex vivo. Results: We identified and confirmed that D-Glu(3) to D-Ala(3) substitution produced 2 optimal candidates, [(68)Ga]Ga-DOTA-GA12 and [(68)Ga]Ga-DOTA-GA13. 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. Conclusions: Our study identified novel radiopharmaceutical candidates that target the CCK(2)R. Their high tumor uptake and reduced renal accumulation warrant clinical translation.
Publisher: Ivyspring International Publisher
Keywords: Mice; Animals; *Receptor, Cholecystokinin B/metabolism; *Gallium Radioisotopes/chemistry; Precision Medicine; Mice, Nude; Tissue Distribution; Cell Line, Tumor; Peptides/chemistry
Department(s): Cancer Imaging; Laboratory Research
Publisher's Version: https://doi.org/10.7150/thno.89701
Open Access at Publisher's Site: https://doi.org/10.7150/thno.89701
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-04-18 04:53:22

Last Modified: 2024-04-18 05:10:25