Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
ACS Chem Neurosci. 2020 Dec 16;11(24):4254-4261. doi: 10.1021/acschemneuro.0c00523. Epub 2020 Dec 1.
α-Synuclein (α-syn) aggregates are pathologically associated with the hallmarks found in brains affected by synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA). Therefore, the detection of α-syn aggregates using radiolabeled probes is useful for the comprehension of and medical intervention for synucleinopathies. In the present study, we identified a bisquinoline scaffold as a new promising structure for targeting α-syn aggregates by a screening assay. Then, based on the scaffold, novel bisquinoline derivatives, BQ1 and BQ2, were designed and synthesized, and we evaluated their utilities as α-syn imaging probes. Both compounds showed high affinity for recombinant α-syn aggregates in binding assays and clearly detected α-syn aggregates in human brain sections. BQ2 showed higher affinity for α-syn aggregates than BQ1, leading to performing F-labeling to obtain [F]BQ2. In a biodistribution study using normal mice, [F]BQ2 displayed moderate uptake (1.59% ID/g at 2 min postinjection) into but subsequent retention (1.35% ID/g at 60 min postinjection) in the brain. The results of this study suggest that a bisquinoline derivative may be a new candidate as an α-syn-PET imaging probe after appropriate structure modification for further improvement in the pharmacokinetics.
α-突触核蛋白（α-syn）聚集体与帕金森病（PD）和多系统萎缩（MSA）等突触核蛋白病中发现的标志性病变有关。因此，使用放射性标记探针检测 α-syn 聚集体对于理解和干预突触核蛋白病是有用的。在本研究中，我们通过筛选试验鉴定了双喹啉支架作为靶向 α-syn 聚集体的新的有前途的结构。然后，基于该支架，设计并合成了新型双喹啉衍生物 BQ1 和 BQ2，并评估了它们作为 α-syn 成像探针的应用。在结合实验中，这两种化合物都对重组 α-syn 聚集体表现出高亲和力，并且在人脑切片中清楚地检测到 α-syn 聚集体。BQ2 对 α-syn 聚集体的亲和力高于 BQ1，导致进行 F 标记以获得 [F]BQ2。在使用正常小鼠的生物分布研究中，[F]BQ2 在注射后 2 分钟（1.59% ID/g）时进入大脑，但随后保留（1.35% ID/g）。这项研究的结果表明，在进一步改善药代动力学的适当结构修饰后，双喹啉衍生物可能成为一种新的 α-syn-PET 成像探针候选物。
