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 (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP).

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.

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.

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.