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 of (125)I-FIMA were assessed in control and linterfero/interferon-gamma-stimulated macrophages. The biodistribution of (125)I-FIMA was determined by the ex vivo tissue counting method in rats.
Results: The COX-2 inhibitory potency of FIMA (IC(50)=2.46 microM) was higher than that of indomethacin (IC(50)=20.9 microM) and was comparable to lumiracoxib (IC(50)=0.77 microM) and diclofenac (IC(50)=0.98 microM). The IC(50) 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 of (125)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.