Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as ?-Synuclein Imaging Probes

Synucleinopathies are characterized by the deposition of alpha-synuclein (alpha-syn) aggregates before the onset of clinical symptoms. Therefore, in vivo imaging of alpha-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 alpha-syn imaging probes. Among them, SQ3, which is a quinoline analogue with a p-(dimethylamino)styryl group and fluoroethoxy group at the 2- and 7- positions of the skeleton, displayed moderate selectivity for alpha-syn aggregates over beta-amyloid (A beta) aggregates (Ki = 230 nM), while maintaining high binding affinity for alpha-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 alpha-syn imaging probe.

Automated summary

Synucleinopathies are characterized by the deposition of alpha-synuclein aggregates before clinical symptoms. In this study, 16 quinoline/quinoxaline derivatives were evaluated to develop an alpha-synuclein imaging probe. Among them, SQ3 showed moderate selectivity for alpha-synuclein aggregates and high binding affinity. [18F]SQ3 exhibited high uptake in a normal mouse brain and has potential as a lead compound for an alpha-synuclein imaging probe.