脳の病変診断を目指した新規COX-2イメージング剤開発に関する研究

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  • 山本 由美
    東北医科薬科大学薬学部 東京都健康長寿医療センター研究所神経画像研究チーム

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  • Development of Novel COX-2 Imaging Agents for the Diagnosis of Brain Lesions
  • ノウ ノ ビョウヘン シンダン オ メザシタ シンキ COX-2 イメージングザイ カイハツ ニ カンスル ケンキュウ

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<p>Cyclooxygenase-2 (COX-2) has attracted attention as a biomarker for neurodegenerative brain diseases. The aim of this study was to develop a COX-2 imaging agent for positron emission tomography (PET) that binds to and emits radiation from COX-2 in the central nervous system to diagnose brain lesions related to COX-2. To this end, the development of PET imaging probes by derivatizing non-steroidal anti-inflammatory drugs that bind to COX-2 was investigated. Herein, we present the findings of a series of studies on indomethacin and nimesulide derivatives. All five 11C-labeled indomethacin derivatives showed low brain uptake and were rapidly metabolized in vivo, indicating that they are inadequate COX-2 imaging agents. However, the evaluation of 11C-labeled indomethacin derivatives revealed an inverse relationship between the amount taken up by the brain and the lipophilicity of the compound, and that P-glycoprotein (P-gp) may be responsible for the low brain uptake of 11C-labeled indomethacin derivatives. To overcome the problems associated with 11C-labeled indomethacin derivatives, nimesulide was selected as a novel COX-2 imaging agent. Although the nimesulide derivatives were less lipophilic and unaffected by P-gp, all three 11C-labeled nimesulide derivatives showed low brain uptake and were rapidly metabolized. However, the 11C-labeled nimesulide derivatives were partially useful as brain-targeted COX-2 imaging agents because they bound specifically to COX-2 in the brain of mice and successfully imaged the regional brain distribution associated with COX-2. In the development of COX-2 imaging agents, in vivo stability of the compounds is a future objective.</p>

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  • 薬学雑誌

    薬学雑誌 143 (12), 983-987, 2023-12-01

    公益社団法人 日本薬学会

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