Structure-Activity Relationships and in Vivo Evaluation of Quinoxaline Derivatives for PET Imaging of β-Amyloid Plaques

This letter describes the synthesis, structure-activity relationships, and in vivo evaluation of a new series of 2-phenylquinoxaline (PQ) derivatives for imaging beta-amyloid (A beta) plaques in Alzheimer's disease (AD). In experiments in vitro, the affinity of the derivatives for A beta aggregates varied, with K-i values of 0.895 to 1180 nM. In brain sections from AD patients, derivatives with a K-i of less than 111 nM intensely labeled A beta plaques, while those with values over 242 nM showed no marked labeling. In biodistribution experiments using normal mice, the derivatives showed good uptake into (4-69-7.59 %ID/g at 2 or 10 min postinjection) and subsequent washout from (1.48-3.08 %ID/g at 60 mm postinjection) the brain. In addition, [F-18]PQ-6 labeled A beta plaques in vivo in APP transgenic mice, while it showed nonspecific binding in the white matter. Further structural optimization based on [F-18]PQ-6 may lead to more useful PET probes for imaging A beta plaques.