Synthesis and evaluation of a radioiodinated lumiracoxib derivative for the imaging of cyclooxygenase-2 expression

Abstract Introduction 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 of125 I-FIMA were assessed in control and linterfero/interferon-γ-stimulated macrophages. The biodistribution of125 I-FIMA was determined by the ex vivo tissue counting method in rats. Results The COX-2 inhibitory potency of FIMA (IC50 =2.46 μM) was higher than that of indomethacin (IC50 =20.9 μM) and was comparable to lumiracoxib (IC50 =0.77 μM) and diclofenac (IC50 =0.98 μM). The IC50 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 of125 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.