TY - JOUR
T1 - 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
AU - Hattori, Yasushi
AU - Aoyama, Kazunobu
AU - Maeda, Jun
AU - Arimura, Naoto
AU - Takahashi, Yasuko
AU - Sasaki, Masako
AU - Fujinaga, Masayuki
AU - Seki, Chie
AU - Nagai, Yuji
AU - Kawamura, Kazunori
AU - Yamasaki, Tomoteru
AU - Zhang, Ming Rong
AU - Higuchi, Makoto
AU - Koike, Tatsuki
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b01576
DO - 10.1021/acs.jmedchem.8b01576
M3 - Article
C2 - 30753069
AN - SCOPUS:85062821437
SN - 0022-2623
VL - 62
SP - 2362
EP - 2375
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -