Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017-12-05 , DOI: 10.1016/j.bmc.2017.12.007 Hiroyuki Kimura , Yu Ogawa , Hiroyuki Fujimoto , Eri Mukai , Hidekazu Kawashima , Kenji Arimitsu , Kentaro Toyoda , Naotaka Fujita , Yusuke Yagi , Keita Hamamatsu , Takaaki Murakami , Atsushi Murakami , Masahiro Ono , Yuji Nakamoto , Kaori Togashi , Nobuya Inagaki , Hideo Saji
β-cell mass (BCM) is known to be decreased in subjects with type-2 diabetes (T2D). Quantitative analysis for BCM would be useful for understanding how T2D progresses and how BCM affects treatment efficacy and for earlier diagnosis of T2D and development of new therapeutic strategies. However, a noninvasive method to measure BCM has not yet been developed.
We developed four 18F-labeled exendin(9-39) derivatives for β-cell imaging by PET: [18F]FB9-Ex(9-39), [18F]FB12-Ex(9-39), [18F]FB27-Ex(9-39), and [18F]FB40-Ex(9-39). Affinity to the glucagon-like peptide-1 receptor (GLP-1R) was evaluated with dispersed islet cells of ddY mice. Uptake of exendin(9-39) derivatives in the pancreas as well as in other organs was evaluated by a biodistribution study. Small-animal PET study was performed after injecting [18F]FB40-Ex(9-39).
FB40-Ex(9-39) showed moderate affinity to the GLP-1R. Among all of the derivatives, [18F]FB40-Ex(9-39) resulted in the highest uptake of radioactivity in the pancreas 30 min after injection. Moreover, it showed significantly less radioactivity accumulated in the liver and kidney, resulting in an overall increase in the pancreas-to-organ ratio. In the PET imaging study, pancreas was visualized at 30 min after injection of [18F]FB40-Ex(9-39).
[18F]FB40-Ex(9-39) met the basic requirements for an imaging probe for GLP-1R in pancreatic β-cells. Further enhancement of pancreatic uptake and specific binding to GLP-1R will lead to a clear visualization of pancreatic β-cells.
中文翻译：
评估18种F标记的胰高血糖素样肽-1受体的exendin（9-39）衍生物用于胰腺β细胞成像的评估
已知患有2型糖尿病（T2D）的受试者的β细胞质量（BCM）降低。BCM的定量分析将有助于理解T2D的进展情况以及BCM如何影响治疗效果，以及对T2D的早期诊断和新治疗策略的开发。但是，尚未开发出用于测量BCM的非侵入性方法。
我们开发了四种18 F标记的exendin（9-39）衍生物用于PET的β细胞成像：[ 18 F] FB9-Ex（9-39），[ 18 F] FB12-Ex（9-39），[ 18 F] FB27-Ex（9-39）和[ 18 F] FB40-Ex（9-39）。用ddY小鼠的胰岛细胞评估对胰高血糖素样肽-1受体（GLP-1R）的亲和力。通过生物分布研究评估了胰腺以及其他器官中exendin（9-39）衍生物的摄取。注射[ 18 F] FB40-Ex（9-39）后进行小动物PET研究。
FB40-Ex（9-39）对GLP-1R具有中等亲和力。在所有衍生物中，[ 18 F] FB40-Ex（9-39）注射后30分钟导致胰腺中放射性的最高吸收。而且，它显示出在肝脏和肾脏中积累的放射性明显较少，从而导致胰腺与器官的比率总体增加。在PET成像研究中，在注射[ 18 F] FB40-Ex（9-39）后30分钟时可以看到胰腺。
[ 18 F] FB40-Ex（9-39）满足胰腺β细胞中GLP-1R成像探针的基本要求。胰腺摄取的进一步增强和与GLP-1R的特异性结合将导致胰腺β细胞的清晰可视化。
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