Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes
Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes
复制标题
苯乙烯基喹啉和苯乙烯基喹喔啉衍生物作为 α-突触核蛋白成像探针的构效关系
DOI：
10.1021/acsmedchemlett.2c00279
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ono M.
中科院分区：
文献类型：
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作者：
Nakagawa K;Watanabe H;Kaide S;Ono M.
突触核蛋白病的特征在于在临床症状发作之前α-突触核蛋白（α-syn）聚集体的沉积。因此，α-syn的体内显像可能有助于这些疾病的早期诊断，近年来引起了人们的广泛关注。然而，尚未报道临床上有用的探针。本研究评价了16种具有不同苯乙烯基和氟基的喹啉/喹喔啉衍生物，以开发α-syn成像探针。其中，SQ 3是一种喹啉类似物，在骨架的2-和7-位具有α-（二甲基氨基）苯乙烯基和氟乙氧基，相对于β-淀粉样蛋白（Aβ）聚集体，对α-syn聚集体显示出中等选择性（Ki= 230 nM），同时对α-syn聚集体保持高结合亲和力（Ki= 39.3 nM）。在一项生物分布研究中，[18 F] SQ 3在正常小鼠脑中表现出高摄取（静脉注射后2分钟为2.08% ID/g）。综上所述，我们证明了[18 F] SQ 3具有作为开发有用的α-syn成像探针的先导化合物的基本性质。
Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore,in vivoimaging of α-syn may contribute to early diagnosis of these diseases and has attracted much attention in recent years. However, no clinically useful probes have been reported. In the present study, 16 quinoline/quinoxaline derivatives with different styryl and fluorine groups were evaluated in order to develop α-syn imaging probes. Among them, SQ3, which is a quinoline analogue with ap-(dimethylamino)styryl group and fluoroethoxy group at the 2- and 7- positions of the skeleton, displayed moderate selectivity for α-syn aggregates over β-amyloid (Aβ) aggregates (Ki= 230 nM), while maintaining high binding affinity for α-syn aggregates (Ki= 39.3 nM). In a biodistribution study, [18F]SQ3 exhibited high uptake (2.08% ID/g at 2 min after intravenous injection) into a normal mouse brain. Taken together, we demonstrate that [18F]SQ3 has basic properties as a lead compound for the development of a useful α-syn imaging probe.