F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging.

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, ()-(2-methylpyrid-5-yl)-6-[(3-F-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer F-THK-5351. SMBT-1 was radiolabeled with F using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics and metabolism were assessed in normal mice after intravenous administration of F-SMBT-1. A 14-d toxicity study after the intravenous administration of F-SMBT-1 was performed using rats and mice. In vitro binding assays demonstrated a high binding affinity of F-SMBT-1 to MAO-B (dissociation constant, 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of F-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. F-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of F-SMBT-1 for MAO-B. Furthermore, F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. F-SMBT-1 showed no significant binding to various receptors, ion channels, or transporters, and no toxic effects related to its administration were observed in mice and rats. F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.