Synthesis and biological evaluation of carbon-11-and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging

Introduction: The type 2 cannabinoid (CB2) receptor is part of the endocannabinoid system and has been Suggested as a mediator of several central and peripheral inflammatory processes. Imaging of the CB2 receptor has been unsuccessful so far. We synthesized and evaluated a carbon-11- and a fluorine-18-labeled 2-oxoquinoline derivative as new PET tracers with high specificity and affinity for the CB2 receptor. Methods: Two 2-oxoquinoline derivatives were synthesized and radiolabeled with either carbon-11 or fluorine-18. Their affinity and selectivity for the human CB, receptor were determined. Biological evaluation was done by biodistribution, radiometabolite and autoradiography studies in mice. Results: In vitro studies showed that both compounds are high affinity CB2-specific inverse agonists. Biodistribution study of the tracers in mice showed a high in vivo initial brain uptake and fast brain washout, in accordance with the low CB2 receptor expression levels in normal brain. A persistently high in vivo binding to the spleen was observed, which was inhibited by pretreatment with two structurally unrelated CB, selective inverse agonists. In vitro autoradiography studies with the radioligands confirmed CB2-specific binding to the mouse spleen. Conclusion: We synthesized two novel CB2 receptor PET tracers that show high affinity/selectivity for CB, receptors. Both tracers show favourable characteristics as radioligands for central and peripheral in vivo visualization of the CB2 receptor and are promising candidates for primate and human CB2 PET imaging. (C) 2009 Elsevier Inc. All rights reserved.