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% <i>vs.</i> 94% for CP04) and demonstrated three-fold improved metabolic stability <i>in vivo</i>, 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 <i>versus</i> 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.