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

[Speaker] Ryuchi Harada:1,2
[Co-author] Nobuyuki Okamura:3,4, Shozo Furumoto:4, Hiroyuki Arai:2, Yukitsuka Kudo:2, Kazuhiko Yanai:1,4
1:Pharmacology, Tohoku University Graduate School of Medicine, Japan, 2:Institute of Development, Aging and Cancer, Tohoku University, Japan, 3:Pharmacology, Tohoku Medical and Pharmaceutical University, School of Medicine, Japan, 4:Cyclotron and Radioisotope Center, Tohoku University, Japan

Background/Aims: Validation studies have shown that 18F-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 18F-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 18F-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.

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