Design, Synthesis, and Evaluation of (4 R)-1-{3-[2-(18F)Fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one ([18F] T-401) as a Novel Positron-Emission Tomography Imaging Agent for Monoacylglycerol Lipase

Yasushi Hattori, Kazunobu Aoyama, Jun Maeda, Naoto Arimura, Yasuko Takahashi, Masako Sasaki, Masayuki Fujinaga, Chie Seki, Yuji Nagai, Kazunori Kawamura, Tomoteru Yamasaki, Ming Rong Zhang, Makoto Higuchi, Tatsuki Koike

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase involved in endocannabinoid and inflammatory signaling. Positron-emission tomography (PET) imaging of MAGL serves to validate target engagement of therapeutic MAGL inhibitors as well as to investigate MAGL levels under normal and disease conditions. However, PET radioligands with reversible binding kinetics for MAGL, which allow quantitative assessment of MAGL, are hitherto unavailable. In this study, we designed and synthesized fluoro-containing PET probes starting from a recently identified piperazinyl pyrrolidine-2-one derivative with reversible binding to MAGL. By tailoring the lipophilicity of the molecule to optimize nonspecific binding and blood-brain barrier permeability, we successfully identified two compounds that show high uptake to regions enriched with MAGL. PET imaging of wild-type and MAGL-deficient mice as well as a macaque monkey indicated that [18F]5 ((4R)-1-{3-[2-(18F)fluoro-4-methylpyridin-3-yl]phenyl}-4-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-yl]pyrrolidin-2-one, [18F]T-401) specifically binds to MAGL with adequate reversibility, yielding a high contrast for MAGL within an appropriate imaging time.

Original languageEnglish
Pages (from-to)2362-2375
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
DOIs
Publication statusPublished - 14-03-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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