Synthesis, in vitro and in vivo evaluation of fluorine-18 labelled FE-GW405833 as a PET tracer for type 2 cannabinoid receptor imaging

The type 2 cannabinoid receptor (CB2R) is part of the endocannabinoid system and is expressed in tissues related to the immune system. As the CB2R has a very low brain expression in non-pathological conditions, but is upregulated in activated microglia, it is an interesting target for visualization of neuroinflammation using positron emission tomography with a suitable radiolabeled CB2R ligand. In this study, we radiolabelled a fluoroethyl derivative of GW405833, a well known CB2R partial agonist, with fluorine-18 (half-life 109.8 min) by alkylation of the phenol precursor with 1-bromo-2-[F-18] fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27 nM) inverse agonist for hCB(2)R. [F-18] FE-GW405833 showed moderate initial brain uptake in mice and rats, but a slow washout from brain and plasma due to retention of a radiometabolite. Specific binding of the tracer to human CB2R was demonstrated in vivo in a rat model with local CB2R overexpression in the brain. Optimized derivatives of GW405833 that are less susceptible to metabolism will need to be developed in order to provide a useful tracer for CB2R quantification with PET. (C) 2011 Elsevier Ltd. All rights reserved.