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

Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore, in vivo imaging 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 a p-(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 (K _i = 230 nM), while maintaining high binding affinity for α-syn aggregates (K _i = 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.