Identification and Development of an Irreversible Monoacylglycerol Lipase (MAGL) Positron Emission Tomography (PET) Radioligand with High Specificity

J Med Chem. 2019 Sep 26;62(18):8532-8543. doi: 10.1021/acs.jmedchem.9b00847. Epub 2019 Sep 16.

Abstract

Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed throughout the brain, serves as a key gatekeeper regulating the tone of endocannabinoid signaling. Preclinically, inhibition of MAGL is known to provide therapeutic benefits for a number of neurological disorders. The availability of a MAGL-specific positron emission tomography (PET) ligand would considerably facilitate the development and clinical characterization of MAGL inhibitors via noninvasive and quantitative PET imaging. Herein, we report the identification of the potent and selective irreversible MAGL inhibitor 7 (PF-06809247) as a suitable radioligand lead, which upon radiolabeling was found to exhibit a high level of MAGL specificity; this enabled cross-species measurement of MAGL brain expression (Bmax), assessment of in vivo binding in the rat, and nonhuman primate PET imaging.

MeSH terms

  • Animals
  • Binding Sites
  • Brain / diagnostic imaging*
  • Brain / enzymology
  • Carbamates / pharmacology
  • Dogs
  • Drug Design
  • Endocannabinoids / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Ligands
  • Madin Darby Canine Kidney Cells
  • Magnetic Resonance Imaging
  • Monoacylglycerol Lipases / chemistry*
  • Positron-Emission Tomography*
  • Rats
  • Rats, Sprague-Dawley
  • Solvents

Substances

  • Carbamates
  • Endocannabinoids
  • Enzyme Inhibitors
  • Ligands
  • Solvents
  • Monoacylglycerol Lipases