title: Radiosynthesis and evaluation of 11C-labeled diaryl-substituted imidazole and indole derivatives for mapping cyclooxygenase-2.
abstract: 11C-labeled analogs of 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole ([11C]1), 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide ([11C]2) and 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole ([11C]3), which have been shown to have excellent potency and high selectivity for cyclooxygenase isoform 2 (COX-2) inhibiting activity, were prepared and evaluated in rats as potential radiopharmaceuticals for imaging the COX-2 enzyme by positron emission tomography. These 11C-labeled COX-2 inhibitors were synthesized in high radiochemical yields by O-[11C]methylation of phenolic precursors with [11C]methyl triflate in acetone containing NaOH as a base. In vivo evaluation in rats bearing AH109A hepatoma showed no specific binding of any tracer to COX-2 in any tissue such as the brain, heart, lung, kidney, and AH109A hepatoma. In ex vivo autoradiography, [11C]1 showed regionally different distribution in the brain, while [11C]2 and [11C]3 were not substantially taken up by the brain. In in vitro monolayer efflux assays, compound 3 was found to be a substrate for the P-glycoprotein (P-gp) efflux pump, but pretreatment of rats with the potent P-gp inhibitor, cyclosporine A, did not have any significant influence on the cerebral uptake of [11C]3. These results indicate that all three tracers were not suitable for in vivo imaging of COX-2. There seem to be some obstacles to finding a useful candidate for in vivo imaging application of COX-2 selective inhibitors only by standard consideration of in vitro affinity and selectivity, and the lipophilicity of the compound.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujisaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.lastname: Qinggeletu
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes; D051546:Cyclooxygenase 2 / Q000032:analysis*; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007553:Isotope Labeling; D008297:Male; D019275:Radiopharmaceuticals / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D007211:Indoles; D019275:Radiopharmaceuticals; D051546:Cyclooxygenase 2