Structure-Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease.

Abstract

Abnormal deposition of amyloid-β and hyperphosphorylated tau protein in the brain are the pathologic hallmark of Alzheimer disease (AD). Noninvasive detection of the lesions is considered an effective tool for early diagnosis and staging of AD. In the past decade, we developed 2-arylquinoline (2-AQ) derivatives as PET tau tracers. In this study, we synthesized new derivatives and evaluated their properties. Fifteen 2-AQ derivatives were labeled with (18)F, and their binding to tau lesions was evaluated by autoradiography using AD brain sections. The binding affinity for the AD brain homogenates was assessed by an in vitro competitive binding assay with (18)F-THK-5105. (18)F-labeled derivatives were injected into mice via the tail vein, and their pharmacokinetics over the first 120 min after injection were evaluated by an ex vivo biodistribution study. Tracer metabolism analysis was also assessed in mice. The average logP value was 2.80. This study revealed that 2-AQ derivatives having (18)F-labeled side chains on benzene or position 7 of the quinoline showed significantly lower binding affinity for tau than 6-substituted quinoline derivatives. The 2-AQ derivatives labeled with (18)F-fluoroethoxy, (18)F-fluoropropoxy, and (18)F-fluoro-polyethyleneglycol groups displayed slow clearance from blood or a high accumulation in bone, whereas derivatives labeled with the (18)F-(3-fluoro-2-hydroxy)propoxyl group did not. (18)F-THK-5151 had outstanding tau binding properties and pharmacokinetics. Furthermore, the properties of its optically pure (S)-enantiomer (THK-5351) were superior to those of the (R)-enantiomer (THK-5451), particularly in terms of its clearance from the brain and its resistance to defluorination in mice. The structure-activity relationship study of 2-AQ derivatives revealed the optimal structural features for tau imaging agents. On the basis of these results, (18)F-THK-5351 ((S)-(18)F-THK-5151) was selected as a potential agent for tau imaging.