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In Vitro and in Vivo Evaluation of 11 C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Mar 22; Vol. 61 (6), pp. 2278-2291. Date of Electronic Publication: 2018 Mar 09. - Publication Year :
- 2018
-
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 <superscript>11</superscript> C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [ <superscript>11</superscript> C]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.
- Subjects :
- Animals
Azetidines pharmacokinetics
Brain diagnostic imaging
Brain enzymology
Brain metabolism
Carbon Radioisotopes
Fluorine Radioisotopes
Macaca mulatta
Male
Mice
Radioactive Tracers
Radiopharmaceuticals pharmacokinetics
Rats
Rats, Sprague-Dawley
Substrate Specificity
Tissue Distribution
Azetidines chemical synthesis
Monoacylglycerol Lipases antagonists & inhibitors
Monoacylglycerol Lipases chemistry
Positron-Emission Tomography methods
Radiopharmaceuticals chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29481079
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01400