title: Synthesis, in vitro and in vivo evaluation of fluorine-18 labelled FE-GW405833 as a PET tracer for type 2 cannabinoid receptor imaging.
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.
authors: Laboratory for Radiopharmacy, IMIR K.U. Leuven, O&N2, Herestraat 49, Bus 821, BE-3000 Leuven, Belgium.
authors: Nele
authors: N
authors: Evens
authors: Caroline
authors: C
authors: Vandeputte
authors: Giulio G
authors: GG
authors: Muccioli
authors: Didier M
authors: DM
authors: Lambert
authors: Veerle
authors: V
authors: Baekelandt
authors: Alfons M
authors: AM
authors: Verbruggen
authors: Zeger
authors: Z
authors: Debyser
authors: Koen
authors: K
authors: Van Laere
authors: Guy M
authors: GM
authors: Bormans
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000032:analysis* / Q000378:metabolism
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D005462:Fluorine Radioisotopes; D007211:Indoles; D009025:Morpholines; D043885:Receptor, Cannabinoid, CB2