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

Abstract

Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK 2 R) 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 177 Lu-labeled peptides ([ 177 Lu]Lu-2b−4b) in comparison with the reference CCK 2 R-targeting peptide CP04 ([ 177 Lu]Lu-1b).[ 177 Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D 7.4 (−4.09 to −4.55) with strong binding affinity to CCK 2 R (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 177 Lu-labeled peptides in tumors (AR42J and A431-CCK 2 R) 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 [ 177 Lu]Lu-2b−4b, making these compounds excellent candidates for theranostic applications against CCK 2 R-expressing tumors.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…They describe lutetium-177-labeled peptides designed by constraining the peptidic backbone to induce the formation of a possible β-hairpin structure that binds to cholecystokinin-2 receptors (CCK-2R) with picomolar to subnanomolar affinities. Rapid clearance and high tumor uptake and retention were found for these foldamers, making these compounds candidates for theranostic applications against CCK2R-expressing tumors …”