Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression

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 I-125-labeled celecoxib analogue with a sulfonamide moiety (I-125-IATP). Methods: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of I-125-IMTP and I-125-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 (IC50=5.16 mu M) and IATP (IC50=8.20 mu M) was higher than that of meloxicam (IC50-29.0 mu M) and comparable to that of SC-58125 (IC50=1.36 mu M). The IC50 ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of I-125-IMTP and 125 MATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of I-125-IMTP was much faster than that of I-125-IATP. Distribution of (125) I-IATP to blood cells (88.0%) was markedly higher than that of I-125-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 I-125-IMTP. I-123-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression. (c) 2006 Elsevier Inc. All rights reserved.