Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton

J Med Chem. 2019 Apr 11;62(7):3336-3353. doi: 10.1021/acs.jmedchem.8b01778. Epub 2019 Mar 21.

Abstract

Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with 11C or 18F. [11C]8 ([11C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [11C]17 ([11C]PAD) and [18F]37 ([18F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.

Publication types

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

MeSH terms

  • Animals
  • Azetidines / chemical synthesis
  • Azetidines / chemistry*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Mice, Knockout
  • Molecular Docking Simulation
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Piperazines / chemistry*
  • Positron-Emission Tomography / methods*
  • Proof of Concept Study
  • Radioligand Assay
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution

Substances

  • Azetidines
  • Enzyme Inhibitors
  • Piperazines
  • Radiopharmaceuticals
  • azetidine
  • Monoacylglycerol Lipases