Design, Synthesis, and Evaluation of 18F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes

Zhen Chen; Wakana Mori; Hualong Fu; Michael A Schafroth; Akiko Hatori; Tuo Shao; Genwei Zhang; Richard S Van; Yiding Zhang; Kuan Hu; Masayuki Fujinaga; Lu Wang; Vasily Belov; Daisuke Ogasawara; Pilar Giffenig; Xiaoyun Deng; Jian Rong; Qingzhen Yu; Xiaofei Zhang; Mikhail I Papisov; Yihan Shao; Thomas L Collier; Jun-An Ma; Benjamin F Cravatt; Lee Josephson; Ming-Rong Zhang; Steven H Liang

doi:10.1021/acs.jmedchem.9b00936

Design, Synthesis, and Evaluation of ¹⁸F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes

J Med Chem. 2019 Oct 10;62(19):8866-8872. doi: 10.1021/acs.jmedchem.9b00936. Epub 2019 Sep 26.

Authors

Zhen Chen^{1

2}, Wakana Mori³, Hualong Fu¹, Michael A Schafroth⁴, Akiko Hatori³, Tuo Shao¹, Genwei Zhang⁵, Richard S Van⁵, Yiding Zhang³, Kuan Hu³, Masayuki Fujinaga³, Lu Wang^{1

6}, Vasily Belov^{1

7}, Daisuke Ogasawara⁴, Pilar Giffenig^{1

7}, Xiaoyun Deng¹, Jian Rong¹, Qingzhen Yu¹, Xiaofei Zhang¹, Mikhail I Papisov^{1

7}, Yihan Shao⁵, Thomas L Collier¹, Jun-An Ma², Benjamin F Cravatt⁴, Lee Josephson¹, Ming-Rong Zhang³, Steven H Liang¹

Affiliations

¹ Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School , Boston , Massachusetts 02114 , United States.
² Department of Chemistry, School of Science , Tianjin University , 92 Weijin Road, Nankai District , Tianjin 300072 , China.
³ Department of Radiopharmaceuticals Development , National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology , Chiba 263-8555 , Japan.
⁴ The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , The Scripps Research Institute , SR107, 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
⁵ Department of Chemistry and Biochemistry , University of Oklahoma , Norman , Oklahoma 73019 , United States.
⁶ Department of Nuclear Medicine and PET/CT-MRI Centre, the First Affiliated Hospital of Jinan University & Institute of Molecular and Functional Imaging , Jinan University , Guangzhou 510630 , China.
⁷ Department of Research , Shriners Hospitals for Children , Boston , Massachusetts 02114 , United States.

Abstract

Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound 6 (identified from a therapeutic agent) was advanced for ¹⁸F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel ¹⁸F-labeled MAGL PET probes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Brain / diagnostic imaging
Contrast Media / chemical synthesis*
Contrast Media / metabolism
Drug Design*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Fluorine Radioisotopes / chemistry
Isotope Labeling
Molecular Docking Simulation
Monoacylglycerol Lipases / antagonists & inhibitors*
Monoacylglycerol Lipases / metabolism
Positron-Emission Tomography
Rats
Spiro Compounds / chemistry
Tissue Distribution

Substances

Contrast Media
Enzyme Inhibitors
Fluorine Radioisotopes
Spiro Compounds
Monoacylglycerol Lipases
Fluorine-18

Abstract

Publication types

MeSH terms

Substances

Grants and funding