We designed four novel acetamidobenzoxazolone compounds 7a–d as candidates for positron emission tomography (PET) radiotracers for imaging the translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (K_i = 13.4 nM) with the TSPO and moderate lipophilicity (log D = 1.92). [¹⁸F]7d was radiosynthesized by [¹⁸F]fluorination of the bromopyridine precursor 7h with [¹⁸F]F^– in 12 ± 5% radiochemical yield (n = 6, decay-corrected). In vitro autoradiography and PET studies of ischemic rat brain revealed higher binding of [¹⁸F]7d with TSPO on the ipsilateral side, as compared to the contralateral side, and improved brain kinetics compared with our previously developed radiotracers. Metabolite study of [¹⁸F]7d showed 93% of unchanged form in the ischemic brain at 30 min after injection. Moreover, PET study with [¹⁸F]7d provided a clear tumor image in a glioma-bearing rat model. We demonstrated that [¹⁸F]7d is a useful PET radiotracer for visualizing not only neuroinflammation but also glioma and will translate this radiotracer to a “first-in-human” study in our facility.

中文翻译：

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¹⁸ F标签放射性示踪剂的开发，具有改进的脑动力学，用于缺血性脑和神经胶质瘤中转运蛋白（18 kDa）的正电子发射断层显像成像。

我们设计了四种新颖的乙酰氨基苯并恶唑酮化合物7a – d作为正电子发射断层扫描（PET）示踪剂的候选物，以对缺血性脑和神经胶质瘤中的转运蛋白（18 kDa，TSPO）进行成像。在这些化合物中，2-（5-（6-氟吡啶-3-基）-2-氧代苯并[ d ]恶唑-3（2H）-基）-N-甲基-N-苯基乙酰胺（7d）显示出高结合亲和力（K _i = 13.4 nM），具有TSPO和中等的亲脂性（log  D = 1.92）。通过[ ¹⁸ F]溴代吡啶前体7h的氟化来放射性合成[ ¹⁸ F] 7d[ ¹⁸ F] F ^–放射化学产率为12±5％（n = 6，经过衰减校正）。体外放射自显影和缺血大鼠脑的PET研究显示，与对侧相比，[ ¹⁸ F] 7d与TSPO在同侧的结合更高，并且与我们以前开发的放射性示踪剂相比，脑动力学得到改善。[ ¹⁸ F] 7d的代谢产物研究显示，注射后30分钟，缺血性脑中93％的未改变形式。此外，[ ¹⁸ F] 7d的PET研究在带有神经胶质瘤的大鼠模型中提供了清晰的肿瘤图像。我们证明了[ ¹⁸ F] 7d 是一种有用的PET放射性示踪剂，不仅可以可视化神经炎症，还可以显示神经胶质瘤，并将这种放射性示踪剂转化为我们设施中的“人类首创”研究。