Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P.R. China.
Nuclear Medicine Department, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, P.R. China.
J Med Chem. 2024 Aug 8;67(15):12695-12710. doi: 10.1021/acs.jmedchem.4c00686. Epub 2024 Jul 30.
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-][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [I], with moderate binding affinity (IC = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [I], we developed a potential PET tracer, [F] (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC = 245 nM), good brain uptake (SUV = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [F] appears to be a promising candidate for α-syn PET imaging and merits further development.
α-突触核蛋白（α-syn）病理学是包括帕金森病（PD）在内的突触核蛋白病发展的核心。α-突触核蛋白病理学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，但由于缺乏特异性的α-syn PET 探针而受到限制。在这项工作中，我们确定了 2,6-取代的咪唑并[2,1-][1,3,4]噻二唑（ITA）作为一种新的α-syn 结合支架。通过放射自显影研究，我们发现了一种碘化的先导化合物 [I]，它与人 PD 脑切片中的α-syn 病理学具有中等结合亲和力（IC = 55 nM）。在 [I] 的基础上，我们开发了一种潜在的 PET 示踪剂 [F]（放射化学产率>25%，摩尔活性>110GBq/μmol），它在人 PD 脑组织中α-syn 丰富的区域显示出清晰的信号（IC = 245 nM），具有良好的脑摄取（SUV = 2.80 ± 0.45），并且在大鼠体内清除率快。总的来说，[F] 似乎是一种很有前途的α-syn PET 成像候选物，值得进一步开发。
