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

Abstract

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 K_i 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 (K_i = 7.6 nM) and exceptional brain kinetics (9.46% ID/g at 2 min, brain_2min/brain_60min = 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.

Keywords: Alzheimer’s disease; molecular imaging; positron emission tomography; β-amyloid plaque.