Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold

J Med Chem. 2021 Oct 14;64(19):14283-14298. doi: 10.1021/acs.jmedchem.1c00747. Epub 2021 Sep 27.

Abstract

Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.

Publication types

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

MeSH terms

  • Animals
  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Haplorhini
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / metabolism
  • Positron-Emission Tomography*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Azetidines
  • Ligands
  • Radiopharmaceuticals
  • Monoacylglycerol Lipases