<sup>18</sup>F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging
Ryuichi Harada, Yoshimi Hayakawa, Michinori Ezura, Pradith Lerdsirisuk, Yiqing Du, Yoichi Ishikawa, Ren Iwata, Miho Shidahara, Aiko Ishiki, Akio Kikuchi, Hiroyuki Arai, Yukitsuka Kudo, Kazuhiko Yanai, Shozo Furumoto, Nobuyuki Okamura
Abstract
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, (<i>S</i>)-(2-methylpyrid-5-yl)-6-[(3-<sup>18</sup>F-fluoro-2-hydroxy)propoxy]quinoline (<sup>18</sup>F-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer <sup>18</sup>F-THK-5351. <b>Methods:</b> SMBT-1 was radiolabeled with <sup>18</sup>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 <sup>18</sup>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 <sup>18</sup>F-SMBT-1. A 14-d toxicity study after the intravenous administration of <sup>18</sup>F-SMBT-1 was performed using rats and mice. <b>Results:</b> In vitro binding assays demonstrated a high binding affinity of <sup>18</sup>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 <sup>18</sup>F-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. <sup>18</sup>F-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of <sup>18</sup>F-SMBT-1 for MAO-B. Furthermore, <sup>18</sup>F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. <sup>18</sup>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. <b>Conclusion:</b><sup>18</sup>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.