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

Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK₂R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of ¹⁷⁷Lu-labeled peptides ([¹⁷⁷Lu]Lu-2b-4b) in comparison with the reference CCK₂R-targeting peptide CP04 ([¹⁷⁷Lu]Lu-1b). [¹⁷⁷Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D_7.4 (−4.09 to −4.55) with strong binding affinity to CCK₂R (K_D 0.097-1.61 nM), and relatively high protein binding (55.6-80.2%) and internalization (40-67%). Biodistribution studies of the novel ¹⁷⁷Lu-labeled peptides in tumors (AR42J and A431-CCK₂R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [¹⁷⁷Lu]Lu-2b-4b, making these compounds excellent candidates for theranostic applications against CCK₂R-expressing tumors.