In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

J Med Chem. 2018 Mar 22;61(6):2278-2291. doi: 10.1021/acs.jmedchem.7b01400. Epub 2018 Mar 9.

Abstract

Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [11C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.

Publication types

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

MeSH terms

  • Animals
  • Azetidines / chemical synthesis*
  • Azetidines / pharmacokinetics
  • Brain / diagnostic imaging
  • Brain / enzymology
  • Brain / metabolism
  • Carbon Radioisotopes
  • Fluorine Radioisotopes
  • Macaca mulatta
  • Male
  • Mice
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / chemistry*
  • Positron-Emission Tomography / methods*
  • Radioactive Tracers
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Substrate Specificity
  • Tissue Distribution

Substances

  • Azetidines
  • Carbon Radioisotopes
  • Fluorine Radioisotopes
  • Radioactive Tracers
  • Radiopharmaceuticals
  • Monoacylglycerol Lipases