Identification and Evaluation of Bisquinoline Scaffold as a New Candidate for α-Synuclein-PET Imaging
Identification and Evaluation of Bisquinoline Scaffold as a New Candidate for α-Synuclein-PET Imaging
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DOI：
10.1021/acschemneuro.0c00523
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发表时间：
2020-12-16
影响因子：
5
通讯作者：
Ono, Masahiro
中科院分区：
文献类型：
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作者：
Kaide, Sho;Watanabe, Hiroyuki;Ono, Masahiro
α-突触核蛋白(α-syn)聚集体在病理上与受帕金森氏病(PD)和多系统萎缩(MSA)等共核病影响的大脑中发现的特征有关。因此，使用放射性标记探针在体内检测α-SYN聚集体对于理解和医学干预突触核病是有用的。在本研究中，我们通过筛选实验确定了双喹啉支架作为靶向α-syn聚集体的一种新的有前途的结构。在此基础上，设计合成了新型双喹啉类化合物BQ1和BQ2，并对其作为α-SYN成像探针的性能进行了评价。在体外结合实验中，这两种化合物都表现出对重组α-SYN聚集体的高亲和力，并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-18标记以获得[F-18]BQ2。在一项使用正常小鼠的生物分布研究中，[F-18]BQ2表现出适度摄取(注射后2分钟为1.59%ID/g)，但随后在大脑中滞留(注射后60分钟为1.35%ID/g)。本研究结果提示，通过适当的结构修饰，双喹啉类化合物有望成为一种新的α-syn-PET显像剂，进一步改善药物动力学。
alpha-Synuclein (alpha-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 in vivo detection of alpha-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 alpha-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 alpha-syn imaging probes. Both compounds showed high affinity for recombinant alpha-syn aggregates in binding assays in vitro and clearly detected alpha-syn aggregates in human brain sections. BQ2 showed higher affinity for a-syn aggregates than BQ1, leading to performing F-18-labeling to obtain [F-18]BQ2. In a biodistribution study using normal mice, [F-18]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 alpha-syn-PET imaging probe after appropriate structure modification for further improvement in the pharmacokinetics.