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

Autor: Rahimi MN; Department of Radiopharmaceutical Sciences, Cancer Imaging, The Peter MacCallum Cancer Centre, Victoria 3000, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia., Corlett A; Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia., Van Zuylekom J; Models of Cancer Translational Research Centre, The Peter MacCallum Cancer Centre, Victoria 3000, Australia., Sani MA; The Bio21 Institute, School of Chemistry, The University of Melbourne, Melbourne, Victoria, 3010 Australia., Blyth B; Models of Cancer Translational Research Centre, The Peter MacCallum Cancer Centre, Victoria 3000, Australia., Thompson P; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia., Roselt PD; Department of Radiopharmaceutical Sciences, Cancer Imaging, The Peter MacCallum Cancer Centre, Victoria 3000, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia., Haskali MB; Department of Radiopharmaceutical Sciences, Cancer Imaging, The Peter MacCallum Cancer Centre, Victoria 3000, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia.
Jazyk: angličtina
Zdroj: Theranostics [Theranostics] 2024 Feb 24; Vol. 14 (5), pp. 1815-1828. Date of Electronic Publication: 2024 Feb 24 (Print Publication: 2024).
DOI: 10.7150/thno.89701
Abstrakt: 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- N MeGly-Trp- N MeNle-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.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)
Databáze: MEDLINE
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