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 D7.4 (−4.09 to −4.55) with strong binding affinity
to CCK2R (KD 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.