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

Area of Science:

• Radiopharmaceutical development
• Molecular imaging and therapy
• Peptide-based theranostics

Background:

• Peptides offer advantages for theranostic applications, including rapid target accumulation and clearance.
• The initial candidate, [68Ga]Ga-DOTA-GA1, showed high binding affinity for cholecystokinin-2 receptors (CCK2R) but suffered from high renal uptake.

Purpose of the Study:

• To optimize the lead theranostic peptide candidate by addressing high renal uptake.
• To identify novel radiopharmaceutical candidates with improved biodistribution profiles for CCK2R-targeted theranostics.

Main Methods:

• Structure-activity relationship study involving modifications to the N-terminal residues of the peptide scaffold.
• Evaluation of modified peptides in nude mice bearing CCK2R-transfected tumors.
• Ex vivo biodistribution studies to quantify tissue uptake and retention.

Main Results:

• Substitution of D-Glu3 with D-Ala3 yielded two optimal candidates, [68Ga]Ga-DOTA-GA12 and [68Ga]Ga-DOTA-GA13.
• These new radiopeptides demonstrated high target-to-background ratios and enhanced tumor retention.
• A significant four-fold reduction in renal uptake was observed compared to the original peptide, alongside excellent metabolic stability.

Conclusions:

• Novel radiopharmaceutical candidates targeting CCK2R were identified.
• The improved biodistribution, characterized by high tumor uptake and reduced renal accumulation, supports their clinical translation.
• These findings represent a significant advancement in CCK2R-targeted theranostic agents.