Department of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
Molecules. 2022 Mar 21;27(6):2034. doi: 10.3390/molecules27062034.
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-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]Ga-DOTA-MGS8 showed a high receptor-specific cell internalization into AR42J rat pancreatic cells (40%) with physiological expression of rat CCK2R as well as A431-CCK2R cells transfected to stably express human CCK2R (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 ~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.
本研究中使用的新型胆囊收缩素 2 受体（CCK2R）靶向迷你胃泌素类似物 DOTA-MGS8 在 C 末端受体结合序列内具有两个特定位置的修饰组合，以及另外一个防止快速代谢降解的 N 末端氨基酸取代。在本研究中，使用自动化合成模块验证了 Ga 标记的 DOTA-MGS8 的制备，描述了可能用于临床用途的质量控制的规格和分析方法。此外，还进行了临床前研究以表征靶向潜力。[Ga]Ga-DOTA-MGS8 显示出高受体特异性细胞内化到 AR42J 大鼠胰腺细胞（约 40%），以及表达大鼠 CCK2R 的生理状态以及稳定表达人 CCK2R 的 A431-CCK2R 细胞（约 47%）。在异种移植 A431-CCK2R 细胞和作为对照的 mock 转染 A431 细胞的 BALB/c 裸鼠中观察到有利的生物分布谱。~27%IA/g 的高肿瘤摄取以及低背景活性和非靶组织摄取有限，证实了在 MTC 和其他 CCK2R 相关恶性肿瘤患者中稳定 MG 类似物的高灵敏度正电子发射断层扫描的潜力。
