Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [¹¹C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 (t_1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human genotype sensitivity. Each ligand was initially labeled by a generic ¹¹C-methylation procedure, thereby enabling speedy screening in mice. Each radioligand was rapidly taken up and well retained in the mouse brain at baseline after intravenous injection. Preblocking of TSPO showed that high proportions of brain uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro analog of [¹¹C]ER176 ([¹¹C]3b) displayed the most promising imaging properties. Therefore, a method was developed to label 3b with [¹⁸F]fluoride ion. [¹⁸F]3b gave similarly promising PET imaging results and deserves evaluation in higher species.

中文翻译：

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用于 TSPO 的含氟 PET 放射性配体在小鼠中的合成和筛选：发现有前景的 18F 标记配体

转运蛋白 18 kDa (TSPO) 是神经炎症的生物标志物。[ ¹¹ C]ER176 通过正电子发射断层扫描 (PET) 对人脑中的 TSPO 进行稳健量化，而与受试者基因型无关。我们的目标是开发一种 ER176 类似物，具有用更长寿命的 fluorine-18 标记的潜力（t _1/2 = 109.8 分钟）。通过简洁的合成策略制备了 ER176 的新氟和三氟甲基类似物。这些配体显示出高 TSPO 亲和力和低人类基因型敏感性。每个配体最初都由通用^11标记C-甲基化过程，从而能够在小鼠中进行快速筛选。静脉注射后，每种放射性配体在基线时被迅速吸收并很好地保留在小鼠脑中。TSPO 的预阻断表明高比例的脑摄取在基线时与 TSPO 特异性结合。^{总体而言，[ 11} C]ER176 ([ ¹¹ C] 3b )的 3-氟类似物显示出最有希望的成像特性。因此，开发了一种用[ ¹⁸ F]氟离子标记3b的方法。[ ¹⁸ F] 3b给出了类似的有希望的 PET 成像结果，值得在高等物种中进行评估。