α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson’s disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [¹²⁵I]ITA-3, with moderate binding affinity (IC₅₀ = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [¹²⁵I]ITA-3, we developed a potential PET tracer, [¹⁸F]FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC₅₀ = 245 nM), good brain uptake (SUV_peak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [¹⁸F]FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

中文翻译：

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作为 α-突触核蛋白 PET 成像新候选物的咪唑并[2,1-b][1,3,4]噻二唑衍生物的发现和评估


α-突触核蛋白 (α-syn) 病理学对于包括帕金森病 (PD) 在内的突触核蛋白病的发展至关重要。 α-syn 病理的正电子发射断层扫描 (PET) 成像是促进突触核蛋白病的诊断、理解和治疗的一种策略，但由于缺乏特异性 α-syn PET 探针而受到限制。在这项工作中，我们确定了 2,6-二取代咪唑并[2,1- b ][1,3,4]噻二唑（ITA）作为新的 α-syn 结合支架。通过放射自显影研究，我们发现了一种碘化先导化合物 [ ¹²⁵ I] ITA-3 ，对人 PD 脑切片中的 α-syn 病理具有中等的结合亲和力 (IC ₅₀ = 55 nM)。我们对 [ ¹²⁵ I] ITA-3进行了修改，开发了一种潜在的 PET 示踪剂，[ ¹⁸ F] FITA-2 （放射化学产率 >25%，摩尔活性 >110 GBq/μmol），在富含 α-syn 的情况下显示出清晰的信号人 PD 脑组织中的区域（IC ₅₀ = 245 nM）、良好的脑摄取（SUV_峰值= 2.80 ± 0.45）以及大鼠的快速清除率。总体而言，[ ¹⁸ F] FITA-2似乎是 α-syn PET 成像的有前途的候选者，值得进一步开发。