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Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone Deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPlc-MS/MS

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International Journal of Analytical Mass Spectrometry and Chromatography 2018年第1期6卷 1-19页

作者： Wei-Hsi Chen Yu-Chieh Hsiao Ming-Hsin Li Mu-Chen Tsai Chun-Fang Feng Han-Chih Chang Hung-Wen Yu Chyng-Yann Shiue Chemistry Division Institute of Nuclear Energy Research Taiwan Isotope Application Division Institute of Nuclear Energy Research Taiwan PET Center Department of Nuclear Medicine National Taiwan University Hospital Taiwan PET Center Department of Nuclear Medicine Tri-Service General Hospital Taiwan

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

关键词： Histone Deacetylase Inhibitors Positron Emission Tomography Imaging Agent Dementia lc-tandem MS Fragmentation Mechanism Metabolism Pathways Epigenetics

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