Abstract：
Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.
摘要：
使用正电子发射断层扫描（PET）的分子成像可以作为可视化大脑中生物目标的有前途的工具。对G蛋白偶联的食欲素受体OX1R和OX2R的表达模式和体内成像的见解将进一步了解食欲素系统及其在各种生理和病理生理过程中的作用。根据我们的先导化合物JH112和已批准的与OX1R和OX2R结合的催眠药物suvorexant的晶体结构，分别,我们在此描述了两种新型放射性配体的设计和合成，[18F]KD23和[18F]KD10。我们结构修饰成功的关键是用氟苯基取代三唑部分的生物等排。19F取代的类似物KD23显示出对OX1R的高亲和力和对OX2R的选择性，而高亲和力配体KD10对两种亚型显示相似的Ki值。从各自的频哪醇酯前体开始的放射性标记分别导致[18F]KD23和[18F]KD10的93％和88％的优异的放射化学产率。20分钟内。新化合物将用于旨在对脑组织中食欲素受体进行亚型选择性成像的PET研究。
