The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties. We supplementarily explored the effects of the number and position of nitrogen atoms, types of heteroatoms and aromatic moieties, and radioactive positions on affinity for Tau. Through a structure-activity relationship (SAR) analysis based on 125I-labeled diarylamine derivatives, [125I]A6 was identified as a lead compound due to its desirable binding properties and ability to penetrate the brain, making it suitable for conversion into a18F-labeled PET tracer. Satisfactorily, [18F]FA1 fulfilled critical requirements as a Tau radiotracer, demonstrating high specificity and selectivity for Tau, a clean off-target profile against Aβ plaques and monoamine oxidase B (MAO-B), and favorable in vivo brain kinetics, as confirmed by dynamic PET studies in rodents and non-human primates.

中文翻译：

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二芳胺衍生物作为阿尔茨海默病 Tau-PET 放射性示踪剂的合成和临床前评价


大脑中存在聚集的 Tau 是 Tau 病的主要病理标志，尤其是在阿尔茨海默病 （AD） 中。因此，开发能够特异性和灵敏地结合 Tau 聚集体的配体对于诊断和监测治疗干预至关重要。在这项研究中，我们进一步研究了二芳胺骨架的结构优化，它表现出有希望的结合特性和生物学特性。我们补充探讨了氮原子的数量和位置、杂原子和芳香族部分的类型以及放射性位置对 Tau 亲和力的影响。通过基于 125I 标记的二芳胺衍生物的构效关系 （SAR） 分析，[125I]A6 因其理想的结合特性和穿透大脑的能力而被鉴定为先导化合物，使其适合转化为 a18F 标记的 PET 示踪剂。令人满意的是，[18F]FA1 满足了作为 Tau 放射性示踪剂的关键要求，表现出对 Tau 的高特异性和选择性，对 Aβ 噬菌斑和单胺氧化酶 B （毛-B） 的干净脱靶谱，以及良好的体内脑动力学，正如啮齿动物和非人灵长类动物的动态 PET 研究所证实的那样。