Evaluating the therapeutic efficacy of gastramide theranostics targeting cholecystokinin-2 receptors in a preclinical setting.

Cholecystokinin-2 receptors (CCK2R) are overexpressed in neuroendocrine tumors, making them attractive targets for radiopharmaceutical therapy. However, clinical CCK2R-targeting agents demonstrate limited therapeutic efficacy, with only a small fraction of patients achieving sufficient tumor uptake for effective treatment. This study presents the evaluation of novel gastramide theranostic compounds GA4 and GA13, designed with enhanced structural properties for superior CCK2R targeting. DOTA-GA4, DOTA-GA13, and the clinical standard CP04 were synthesized and radiolabeled with lutetium-177 (177Lu) for comprehensive evaluation. The gastramide analogues achieved superior radiochemical stability (≥99% vs. 94% for CP04) and demonstrated three-fold improved metabolic stability in vivo, with 87% intact peptides remaining compared to only 29% for CP04. [177Lu]Lu-DOTA-GA4 and [177Lu]Lu-DOTA-GA13 translated these stability advantages and increased binding affinity into exceptional therapeutic performance, reducing AR42J cell viability to 30% and 19% respectively compared to 50% for CP04. In xenograft studies, 20 MBq doses of gastramide compounds extended median survival by 22-23.5 days versus only 6 days for CP04. These results establish gastramide theranostics as an effective approach to CCK2R-targeted therapy, addressing current limitations and providing an improved treatment option for neuroendocrine tumors with substantially enhanced therapeutic outcomes.