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-1 H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a 125I-labeled celecoxib analogue with a sulfonamide moiety ( 125I-IATP). Methods The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of 125I-IMTP and 125I-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 μM) and IATP (IC 50=8.20 μM) was higher than that of meloxicam (IC 50=29.0 μM) and comparable to that of SC-58125 (IC 50=1.36 μM). The IC 50 ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of 125I-IMTP and 125I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of 125I-IMTP was much faster than that of 125I-IATP. Distribution of 125I-IATP to blood cells (88.0%) was markedly higher than that of 125I-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 125I-IMTP. 123I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.