Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCKR Cancer Theranostic Agents: A Preclinical Study.

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCKR)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCKR-radioligands instead, we herein present three analogs of the nonpeptidic CCKR-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCKR cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCKR cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCKR and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCKR-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCKR, but not the CCKR-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCKR-targeted theranostics of human cancer.