Tau accumulation is one of the predominant neuropathological biomarkers for in vivo diagnosis of Alzheimer’s disease due to its high correlation with disease progression. In this study, we focused on the structure–activity relationship study of the substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridine to screen ¹⁸F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[¹⁸F]fluorophenyl-substituted tracer [¹⁸F]13 ([¹⁸F]FPND-4) was identified as a promising candidate with high affinity to native Tau tangles (IC₅₀ = 2.80 nM), few appreciable binding to Aβ plaques and MAO-A/B. Validated by dynamic positron emission tomography (PET) imaging in rodents and rhesus monkey, [¹⁸F]13 displayed desirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain_2min/60min = 5.9), minimal defluorination, and few off-target binding, which met the requirements of a Tau-specific PET radiotracer.

中文翻译：

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2-(4-[18F]氟苯基)咪唑并[1,2-h][1,7]萘啶 ([18F]FPND-4) 的合成和临床前评价：氮杂稠合三环衍生物作为正电子发射断层扫描示踪剂神经原纤维缠结成像

Tau 积累是阿尔茨海默病体内诊断的主要神经病理学生物标志物之一，因为它与疾病进展高度相关。在本研究中，我们重点研究氮杂稠合三环核心咪唑并[1,2-h][1,7]萘啶的取代基效应的构效关系，筛选18个F标记的^Tau示踪剂。通过一系列放射自显影研究和生物学评估，4-[ ¹⁸ F]氟苯基取代的示踪剂 [ ¹⁸ F] 13 ([ ¹⁸ F] FPND-4 ) 被确定为对天然 Tau 缠结具有高亲和力的有前途的候选物 (IC ₅₀ = 2.80 nM)，与 Aβ 斑块和 MAO-A/B 的结合很少。通过啮齿动物和恒河猴的动态正电子发射断层扫描 (PET) 成像验证，[ ¹⁸ F] 13显示出理想的大脑摄取（2 分钟时 SUV = 1.75）、快速清除（大脑_{2 分钟/60 分钟}= 5.9）、最少的脱氟和很少的脱靶结合，满足 Tau 特异性 PET 放射性示踪剂的要求。