title: Radiosynthesis and in vivo evaluation of 11C-labeled 1,5-diarylpyrazole derivatives for mapping cyclooxygenases.
abstract: We prepared 11C-labeled 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole ([11C]1) and 4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide ([11C]2) for imaging COX-1 and COX-2 isoforms, respectively, by positron emission tomography. [11C]1 and [11C]2 were synthesized in high radiochemical yields by O-[11C]methylation with [11C]methyl triflate in acetone containing an equivalent of NaOH as a base with respect to the phenolic precursors. In vivo evaluation in rats bearing AH109A hepatoma demonstrated minimal specific binding of [11C] to COX-1 in peripheral organs, such as the spleen and small intestine. Carrier-saturable uptake of [11C]2 was found in the spleen, but COX-2-specific binding of [11C]2 was not identifiable in the brain, AH109A hepatoma or other peripheral organs, although ex vivo autoradiography showed regionally different distribution in the brain and AH109A. The results suggest that neither [11C]1 nor [11C]2 is a suitable radioligand for in vivo biomarkers of COX enzymes, mainly because of marked non-specific binding.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujisaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Wei-Fang
authors.initials: WF
authors.lastname: Wang
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging* / Q000378:metabolism*; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat