18F-labeled 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid imaging probes

This study reported the design, synthesis and bio-evaluation of 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as beta-amyloid (A beta) imaging probes. This strategy of introducing two hydroxyls offered a simplified method for effectively reducing the lipophilicity. The probes (R, S)/(S, R)-14-15 with benzothiazole scaffold displayed good binding affinities toward A beta(1-42) aggregates with K-i values ranging from 47.63 to 56.28 nM. Further biological studies shown that (R, S)/(S, R)-[(18) F]14 have no obvious chirality-related discrepancy in binding ability and mice bio-distribution, while (S, R)-enantiomer exhibited slightly faster brain washout rate than (R, S)-enantiomer. Compared to the FDA approved [F-18]Florbetapir and the fluoro-peglated 2-phenylbenzothiazole derivatives, (S, R)-[F-18]14 displayed improved brain kinetics (6.40% ID/g at 2 min, brain(2 min)/brain(60 min) = 7.80) that is favorable for further application. In vitro autoradiography studies validated its high affinity and specificity to A beta plaques. Overall, (S, R)-[F-18]14 deserved further detailed study as a potential PET imaging probe for AD early diagnosis.

Automated summary

This study focused on designing 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as beta-amyloid imaging probes, which exhibited good binding affinities and improved brain kinetics compared to existing derivatives. The (S, R)-[F-18]14 probe showed high affinity and specificity to A beta plaques, making it a promising potential PET imaging probe for early diagnosis of Alzheimer's disease.