Methosulide

Our previous studies identified that nimesulide analogs which bear a methoxy substituent at the para-position of the phenyl ring could be potential radiotracer candidates for detecting disorders related to cyclooxygenase-2 (COX-2) expression and activity in vivo using positron emission tomography (PET) in the brain. The present study was conducted to evaluate the in vivo characteristics of ¹¹C-labeled para-methoxy nimesulide ([¹¹C]1d) as a brain COX-2-targeted imaging agent compared to other isomeric methoxy analogs of nimesulide ([¹¹C]1b and [¹¹C]1c). [¹¹C]1b-d were synthesized with reasonable yield and purity by the methylation of the O-desmethyl precursor with [¹¹C]methyl triflate in the presence of NaOH at room temperature. We performed in vivo biodistribution analysis, brain PET imaging, ex vivo autoradiography, and metabolite analysis in mice. The uptake of [¹¹C]1b-d was lower in the brain than in other tissues, including in the blood, and both [¹¹C]1c and [¹¹C]1d were rapidly metabolized. However, [¹¹C]1d showed a small, but significant, specific signal and heterogeneous distribution in the brain. In vivo evaluation suggested that [¹¹C]1d might correlate with COX-2 expression in the brain. Given its instability in vivo, [¹¹C]1d seems unsuitable as a brain-COX-2 radioimaging agent. Further structural refinement of these radiotracers is necessary to enhance their uptake in the brain and to achieve sufficient metabolic stability.