Synthesis and Monkey-PET Study of (R)- and (S)-18F-Labeled 2-Arylbenzoheterocyclic Derivatives as Amyloid Probes with Distinctive in Vivo Kinetics

This study describes an effective strategy to improve pharmacokinetics of Aβ imaging agents, offering a novel class of (R)- and (S)-18F-labeled 2-arylbenzoheterocyclic derivatives which bear an additional chiral hydroxyl group on the side chain. These ligands displayed binding abilities toward Aβ aggregates with Ki values ranging from 3.2 to 195.6 nM. Chirality-related discrepancy was observed in biodistribution, and (S)-2-phenylbenzoxazole enantiomers exhibited vastly improved brain clearance with washout ratios higher than 20. Notably, (S)-[18F]28 possessed high binding potency (Ki = 7.6 nM) and exceptional brain kinetics (9.46% ID/g at 2 min, brain2min/brain60min = 27.8) that is superior to well-established [18F]AV45. The excellent pharmacokinetics and low nonspecific binding of (S)-[18F]28 were testified by dynamic PET/CT scans in monkey brains. In addition, (S)-[18F]28 clearly labeled Aβ plaques both in vitro and ex vivo. These results might qualify (S)-[18F]28 to detect Aβ plaques with high signal-to-noise ratio.