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

Evens, Nele;Vandeputte, Caroline;Muccioli, Giulio;Lambert, Didier;Bormans, Guy M.;et.al.
(2011) Bioorganic & Medicinal Chemistry : the tetrahedron journal for research at the interface of chemistry and biology — Vol. 19, n° 15, p. 4499-4505 (2011)

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Abstract
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-[¹⁸F]fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27 nM) inverse agonist for hCB₂R. [¹⁸F]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.
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Evens, N., Vandeputte, C., Muccioli, G., Lambert, D., Baekelandt, V., Verbruggen, A. M., Debyser, Z., Van Laere, K., & Bormans, G. M. (2011). Synthesis, in vitro and in vivo evaluation of fluorine-18 labelled FE-GW405833 as a PET tracer for type 2 cannabinoid receptor imaging. Bioorganic & Medicinal Chemistry : the tetrahedron journal for research at the interface of chemistry and biology, 19(15), 4499-4505. https://doi.org/10.1016/j.bmc.2011.06.033 (Original work published 2011)