11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice
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概要
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There is great potential in the use of positron emission tomography (PET) and suitable radiotracers for the study of cyclooxygenase type 2 (COX-2) enzyme in living subjects. In the present study, we prepared and evaluated five 11C-labeled ester and amide analogs derived from indomethacin as potential PET imaging agents for the in vivo visualization of the brain COX-2 enzyme. Five 11C-labeled COX-2 inhibitors, with different lipophilicities and moderate COX-2 inhibitory activity, were prepared by treatment of the corresponding O-desmethyl precursors with [11C]methyl triflate and purified by HPLC (radiochemical yields of 55—71%, radiochemical purity of >93%, and the specific activities of 22—331 GBq/μmol). In mice, radioactivity in the brain for all radiotracers was low, with very low brain-to-blood ratios. A clear inverse relationship was observed between brain uptake at 1 min postinjection and the lipophilicity (experimental log P7.4) of the studied 11C-radiotracers. Pretreatment of mice with cyclosporine A to block P-glycoproteins caused a significant increase in brain uptake of radioactivity following injection of the 11C-radiotracer compared to control. HPLC analysis showed that each radiotracer was rapidly metabolized, and a few metabolites, which were more polar than the original radiotracers, were found in both plasma and brain. No specific binding of the tracers towards the COX-2 enzyme in the brain was clearly revealed by in vivo blocking study. Further structural refinement of the tracer agent is necessary for better enhancement of brain uptake and for sufficient metabolic stability.
著者
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TOYOHARA Jun
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology
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ISHIWATA Kiichi
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology
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Ishiwata Kiichi
東京都老人総合研究所ポジトロン医学研究施設
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Ishiwata Kiichi
Positron Medical Center Tokyo Metropolitan Institute Of Gerontology
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Ishiwata Kiichi
筑波大学陽子線医学利用研究センター
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Toyohara Jun
Positron Medical Center Tokyo Metropolitan Institute Of Gerontology
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Ishii Kenji
Positron Medical Center Tokyo Metropolitan Institute Of Gerontology
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MUKAI Takahiro
Graduate School of Biomedical Sciences, Nagasaki University
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YAMAMOTO Fumihiko
Graduate School of Pharmaceutical Sciences, Kyushu University
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MAEDA Minoru
Graduate School of Pharmaceutical Sciences, Kyushu University
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Ishii K
Positron Medical Center Tokyo Metropolitan Institute Of Gerontology
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Ishii Keizo
Tohoku Univ. Miyagi Jpn
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Maeda Minoru
Graduate School Of Pharmaceutical Sciences Kyushu University
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Yamamoto Fumihiko
Graduate School Of Pharmaceutical Sciences Kyushu University
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Ishii K
Department Of Radiology Osaka City University Graduate School Of Medicine
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Yamamoto Yumi
Graduate School of Pharmaceutical Sciences, Kyushu University
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Sano Kohei
Graduate School of Pharmaceutical Sciences, Kyushu University
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Ishii Kenji
Pet Center Tokyo Metropolitan Institute Of Gerontology
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Maeda Minoru
Graduate School Of Pharmaceutical Sciences Kyushu Univ.
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Yamamoto Fumihiko
Graduate School of Pharmaceutical Sciences
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Mukai Takahiro
Graduate School of Pharmaceutical Sciences, Kyushu University
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Maeda Minoru
Graduate School of Pharmaceutical Sciences
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