Automated Synthesis of 68Ga-Labeled DOTA-MGS8 and Preclinical Characterization of Cholecystokinin-2 Receptor Targeting

The new minigastrin analog DOTA-MGS8 targeting the cholecystokinin-2 receptor (CCK2R) used in this study displays the combination of two site-specific modifications within the C-terminal receptor binding sequence together with an additional N-terminal amino acid substitution preventing fast metabolic degradation. Within this study, the preparation of Ga-68-labeled DOTA-MGS8 was validated using an automated synthesis module, describing the specifications and analytical methods for quality control for possible clinical use. In addition, preclinical studies were carried out to characterize the targeting potential. [Ga-68]Ga-DOTA-MGS8 showed a high receptor-specific cell internalization into AR42J rat pancreatic cells (similar to 40%) with physiological expression of rat CCK2R as well as A431-CCK2R cells transfected to stably express human CCK2R (similar to 47%). A favorable biodistribution profile was observed in BALB/c nude mice xenografted with A431-CCK2R cells and mock-transfected A431 cells as control. The high tumor uptake of similar to 27% IA/g together with low background activity and limited uptake in non-target tissue confirms the potential for high-sensitivity positron emission tomography of stabilized MG analogs in patients with MTC and other CCK2R-related malignancies.

Automated summary

This study presents a new minigastrin analog, DOTA-MGS8, targeting the cholecystokinin-2 receptor (CCK2R). Ga-68-labeled DOTA-MGS8 was successfully synthesized using an automated synthesis module, and preclinical studies demonstrated its high receptor-specific cell internalization and favorable biodistribution profile. This suggests that stabilized MG analogs like DOTA-MGS8 have the potential for high-sensitivity positron emission tomography in patients with CCK2R-related malignancies.