title: Radiosynthesis and ex vivo evaluation of [(11)C-carbonyl]carbamate- and urea-based monoacylglycerol lipase inhibitors.
abstract: BACKGROUND
  Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are the two primary enzymes that regulate the tone of endocannabinoid signaling. Although new PET radiotracers have been discovered for imaging FAAH in vivo, no such radiotracer exists for imaging MAGL. Here we report the radiosynthesis of five candidate MAGL radiotracers and their ex vivo evaluations in mice and rats.
  
  
  METHODS
  Candidate carbamate and urea MAGL inhibitors were radiolabeled at the carbonyl position by [(11)C]CO2 fixation. Radiotracers were administered (tail-vein injection) to rodents and brain uptake of radioactivity measured at early and late time points ex vivo. Specificity of uptake was explored by pretreatment with unlabeled inhibitors (2 mg/kg, ip) 30 min prior to radiotracer administration.
  
  
  RESULTS
  All five candidate MAGL radiotracers were prepared in high specific activity (>65 GBq/μmol) and radiochemical purity (>98%). Moderate brain uptake (0.2-0.8 SUV) was observed for each candidate while pretreatment did not reduce uptake for four of the five tested. For two candidates ([(11)C]12 and [(11)C]14), high retention of radioactivity was observed in the blood (ca. 10 and 4 SUV at 40 min) which was blocked by pretreatment with unlabeled inhibitors. The most promising candidate, [(11)C]18, demonstrated moderate brain uptake (ca. 0.8 SUV) which showed circa 50% blockade by pretreatment with unlabeled 18.
  
  
  CONCLUSIONS
  One putative and four reported potent and selective MAGL inhibitors have been radiolabeled via [(11)C]CO2 fixation as radiotracers for this enzyme. Despite the promising in vitro pharmacological profile, none of the five candidate radiotracers exhibited in vivo behavior suitable for PET neuroimaging.
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada, M5S 1A8.
authors: Justin W
authors: JW
authors: Hicks
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8.
authors: Jun
authors: J
authors: Parkes
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8.
authors: Junchao
authors: J
authors: Tong
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8.
authors: Sylvain
authors: S
authors: Houle
authors: Department of Radiology, Harvard Medical School and Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Boston, MA, USA, 02114.
authors: Neil
authors: N
authors: Vasdev
authors: Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada, M5T 1R8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada, M5S 1A8. Electronic address: alan.wilson@camhpet.ca.
authors: Alan A
authors: AA
authors: Wilson
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D014508:Urea / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002219:Carbamates; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D014508:Urea; D008994:Monoacylglycerol Lipases
keywords: CO(2) fixation; Carbon-11; Monoacylglycerol lipase; Positron emission tomography; Radiotracer development