Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers

Peptide receptor radionuclide therapy(PRRT) is a promising formof systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2receptor (CCK2R) is an important molecular target thatis highly expressed in a range of cancers. This study describes thesynthesis and in vivo characterization of a novelseries of Lu-177-labeled peptides ([Lu-177]Lu-2b-4b) in comparison with the referenceCCK(2)R-targeting peptide CP04 ([Lu-177]Lu-1b). [Lu-177]Lu-1b-4b showed high chemicalpurity (HPLC & GE; 94%), low Log D (7.4) (-4.09 to -4.55) with strong binding affinityto CCK2R (K (D) 0.097-1.61nM), and relatively high protein binding (55.6-80.2%) and internalization(40-67%). Biodistribution studies of the novel Lu-177-labeled peptides in tumors (AR42J and A431-CCK2R) showeduptake one- to eight-fold greater than the reference compound CP04at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retentionwere established for [Lu-177]Lu-2b-4b, making these compounds excellent candidates for theranosticapplications against CCK2R-expressing tumors.

Automated summary

This study synthesized and characterized a series of Lu-177-labeled peptides ([Lu-177]Lu-2b-4b) and compared them with the reference CCK(2)R-targeting peptide CP04 ([Lu-177]Lu-1b). [Lu-177]Lu-1b-4b showed high chemical purity, low Log D, strong binding affinity to CCK2R, and relatively high protein binding and internalization. Biodistribution studies showed that [Lu-177]Lu-2b-4b had higher uptake in tumors compared to CP04 at different time points. These findings suggest that [Lu-177]Lu-2b-4b could be a promising therapy for CCK2R-expressing tumors.