title: Synthesis, Biodistribution andIn vitroEvaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3.
abstract: The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allowsin vivovisualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution andin vitroevaluation of a carbon-11 ([11C]MA2) and a fluorine-18 ([18F]MA3) labeled analog of a highly potentN-arylamide oxadiazole CB2 agonist (EC50= 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and theirin vitrobinding affinity forhCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50values when compared to the originally reported trifluoromethyl analog12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes forin vivoimaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven Leuven, Belgium.
authors.forename: Muneer
authors.initials: M
authors.lastname: Ahamed
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven Leuven, Belgium.
authors.forename: Daisy
authors.initials: D
authors.lastname: van Veghel
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
authors.affiliation: Division of Nuclear Medicine, University Hospital and KU Leuven Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven Leuven, Belgium.
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.affiliation: Laboratory for Radiopharmacy, KU Leuven Leuven, Belgium.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
keywords: CB2 agonists; Positron emission tomography; Radiosynthesis; Type 2 cannabinoid receptor