title: Synthesis and evaluation of a radioiodinated lumiracoxib derivative for the imaging of cyclooxygenase-2 expression.
abstract: BACKGROUND
  Despite extensive attempts to develop cyclooxygenase (COX)-2 imaging radiotracers, no suitable positron emission tomography (PET)/single photon emission computed tomography (SPECT) tracers are currently available for in vivo imaging of COX-2 expression. The aims of this study were to synthesize and evaluate a radioiodinated derivative of lumiracoxib, 2-[(2-fluoro-6-iodophenyl)-amino]-5-methylphenylacetic acid (FIMA), which is structurally distinct from other drugs in the class and has weakly acidic properties, as a SPECT tracer for imaging COX-2 expression.
  
  
  METHODS
  The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation with hydrogen peroxide. Cell uptake characteristics of (125)I-FIMA were assessed in control and linterfero/interferon-gamma-stimulated macrophages. The biodistribution of (125)I-FIMA was determined by the ex vivo tissue counting method in rats.
  
  
  RESULTS
  The COX-2 inhibitory potency of FIMA (IC(50)=2.46 microM) was higher than that of indomethacin (IC(50)=20.9 microM) and was comparable to lumiracoxib (IC(50)=0.77 microM) and diclofenac (IC(50)=0.98 microM). The IC(50) ratio (COX-1/COX-2=182) indicated FIMA has a high isoform selectivity for COX-2. (125)I-FIMA showed a significantly higher accumulation in COX-2 induced macrophages than in control macrophages, which decreased with nonradioactive FIMA in a concentration dependent manner. The biodistribution study showed rapid clearance of (125)I-FIMA from the blood and most organs including the liver and kidneys. No significant in vivo deiodination was observed with radioiodinated FIMA.
  
  
  CONCLUSIONS
  FIMA showed high inhibitory potency and selectivity for COX-2. Radioiodinated FIMA showed specific accumulation into COX-2 induced macrophages, no significant in vivo deiodination and rapid blood clearance. Radioiodinated FIMA deserves further investigation as a SPECT radiopharmaceutical for imaging COX-2 expression.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. kuge@med.hokudai.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Obokata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Katada
authors.forename: Takashi
authors.initials: T
authors.lastname: Temma
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Kazuki
authors.initials: K
authors.lastname: Aita
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Seki
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008264:Macrophages / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007457:Iodine Radioisotopes; D004008:Diclofenac; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C473384:lumiracoxib