PT  - JOURNAL ARTICLE
AU  - Ryuichi Harada
AU  - Yoshimi Hayakawa
AU  - Michinori Ezura
AU  - Pradith Lerdsirisuk
AU  - Yiqing Du
AU  - Yoichi Ishikawa
AU  - Ren Iwata
AU  - Miho Shidahara
AU  - Aiko Ishiki
AU  - Akio Kikuchi
AU  - Hiroyuki Arai
AU  - Yukitsuka Kudo
AU  - Kazuhiko Yanai
AU  - Shozo Furumoto
AU  - Nobuyuki Okamura
TI  - <sup>18</sup>F-SMBT-1: A Selective and Reversible Positron-Emission Tomography Tracer for Monoamine Oxidase-B Imaging
AID  - 10.2967/jnumed.120.244400
DP  - 2020 Jul 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.120.244400
4099  - http://jnm.snmjournals.org/content/early/2020/07/09/jnumed.120.244400.short
4100  - http://jnm.snmjournals.org/content/early/2020/07/09/jnumed.120.244400.full
AB  - 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, (S)-(2-methylpyrid-5-yl)-6-[(3-[18F]fluoro-2-hydroxy)propoxy]quinoline, (18F-SMBT-1), was successfully developed via lead optimization from first-generation tau positron-emission tomography (PET) tracer 18F-THK-5351. Methods: SMBT-1 was radiolabeled with fluorine-18 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 18F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics (PK) and metabolism were assessed in normal mice after intravenous administration of 18F-SMBT-1. A 14-day toxicity study following the intravenous administration of SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of SMBT-1 to MAO-B (KD = 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 18F-SMBT-1 binding in the Alzheimer’s disease (AD) brain sections than in the control brain sections. 18F-SMBT-1 binding was completely displaced with reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of 18F-SMBT-1 for MAO-B. Furthermore, 18F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. SMBT-1 showed no significant binding to various receptors, ion channels, and transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion: 18F-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.