title: Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression.
abstract: Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP).
  
  
  METHODS
  The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of (125)I-IMTP and (125)I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured.
  
  
  RESULTS
  The COX-2 inhibitory potency of IMTP (IC(50) = 5.16 microM) and IATP (IC(50) = 8.20 microM) was higher than that of meloxicam (IC(50) = 29.0 microM) and comparable to that of SC-58125 (IC(50) = 1.36 microM). The IC(50) ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of (125)I-IMTP and (125)I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of (125)I-IMTP was much faster than that of (125)I-IATP. Distribution of (125)I-IATP to blood cells (88.0%) was markedly higher than that of (125)I-IMTP (18.1%), which was decreased by CA inhibitors.
  
  
  CONCLUSIONS
  Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in (125)I-IMTP. (123)I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. kuge@pharm.kyoto-u.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Katada
authors.forename: Sayaka
authors.initials: S
authors.lastname: Shimonaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Temma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kiyono
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yokota
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minematsu
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Seki
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
authors.forename: Kazue
authors.initials: K
authors.lastname: Ohkura
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000493:pharmacokinetics*; D005240:Feasibility Studies; D007457:Iodine Radioisotopes; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: C510967:5-(4-iodophenyl)-1-(4-(aminosulfonyl)phenyl)-3-trifluoromethyl-1H-pyrazole; C510966:5-(4-iodophenyl)-1-(4-(methylsulfonyl)phenyl)-3-trifluoromethyl-1H-pyrazole; D052246:Cyclooxygenase 2 Inhibitors; D007457:Iodine Radioisotopes; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D013450:Sulfones; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat