Radiosynthesis and <i>in Vivo</i> and <i>ex Vivo</i> Evaluation of Isomeric [<sup>11</sup>C]methoxy Analogs of Nimesulide as Brain Cyclooxygenase-2-Targeted Imaging Agents

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  • Yamamoto Yumi
    Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology
  • Tago Tetsuro
    Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology
  • Toyohara Jun
    Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology
  • Saito Yohei
    Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
  • Yamamoto Fumihiko
    Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University

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  • Radiosynthesis and in Vivo and ex Vivo Evaluation of Isomeric [¹¹C]methoxy Analogs of Nimesulide as Brain Cyclooxygenase-2-Targeted Imaging Agents

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Abstract

<p>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.</p>

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