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 (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.