モノアミン酸化酵素BとPET リガンド[18F]SMBT-1/[18F]THK5351複合体の結晶構造解析

• Published in: 日本薬理学会年会要旨集 p. 1-B-O01-1
• Main Authors: 原田, 龍一, 工藤, 楓, 横山, 武司, 工藤, 幸司, 岡村, 信行, 古本, 祥三, 田中, 良和, 後藤, 楓
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• Subjects: binding assay; monoamine oxidase (MAO); positron emission tomography (PET); protein
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_1-B-O01-1

Monoamine oxidase-B (MAOB) is a crucial enzyme not only as a therapeutic target for Parkinson's disease but also as a binding target for PET tracers that image reactive astrogliosis. We have developed a PET tracer named [18F]SMBT-1 designed for in vivo MAOB imaging. This was achieved by altering the chemical structure of tau PET tracer THK5351, which had high affinity for MAOB. To better understand the interaction of MAOB with these PET tracers, we determined the atomic structure of MAOB-SMBT-1 and MAOB-THK5351 complexes by X-ray crystallography with soaking method. Initially, we confirmed the high binding affinity of [18F]SMBT-1 against purified MAOB (KD = 4.4, Bmax = 2.8 nmol/mg protein), which was consistent with previously determined values against commercially available microsomal MAOB (KD = 3.7 nM, Bmax = 0.11 nmol/mg protein). In vitro competitive binding and biochemical assays demonstrated that SMBT-1 and THK5351 possess higher binding affinity and enzymatic inhibitory activity against MAOB than clinically used MAOB inhibitors Rasagiline and Safinamide. The crystal structures of MAOB in complexes with SMBT-1 and THK5351 (determined at 2.25 - 2.6Å) showed that they bind in the active site cavity of the protein in front of the flavin adenine dinucleotide cofactor. The findings achieved in this study would provide a potentially practical guide to avoid off-target binding to MAOB or to develop higher potency radiopharmaceuticals.