Development of selective tau and MAO-B PET tracers through compound optimization of ¹⁸F-THK5351

Abstract

Background/Aims: Validation studies have shown that 18 F-THK5351 PET signal contribute the binding to monoamine oxidase B (MAO-B) and correlates with tau and astrogliosis in neurodegenerative diseases. The aim of study was to develop selective tau and MAO-B PET tracers through compound optimization from 18 F-THK5351 to visualize tau pathology and astroglisis, respectively. Methods: In vitro competitive binding assay against recombinant MAO-B, MAO-A, and tau aggregates in AD brain homogenates was performed to evaluate binding affinity of test compounds. In vitro autoradiography in frozen human brain tissues was performed using 18 F-labeled compounds to evaluate selective binding to each target. Results: In vitro competitive binding assays demonstrated lower binding affinity of several quinoline derivatives against MAO-B (Ki > 100 nM) than THK5351. On the other hand, we identified several quinoline derivatives that possess higher affinity against MAO-B than THK5351, but little binding to MAO-A and tau aggregates. Furthremore, in vitro autoradiography of AD brain sections showed the selective binding ability of these compounds to tau protein deposits or MAO-B. Conclusions: Compound optimization resulted in successful improvement of binding selectivity of quinoline derivatives as tau and MAO-B selective PET tracers, respectively. Selective imaging of tau and MAO-B would be promising markers for monitoring neurodegeneration and neuroinflammatory changes.