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Determination of Synthetic Impurities and Metabolic Products of F-ADAM, a Positron Emission Tomography Imaging Agent for Serotonin Transporter (SERT) Using HPLC-Tandem Mass Spectrometry

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Pharmacology & Pharmacy 2020年第10期11卷 282-298页

作者： Wei-Hsi Chen chyng-yann shiue Chemistry 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

A high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analytical method was developed to determine the identity of impurities resulting from the synthesis of N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzyl-amine (F-ADAM), as well as its metabolic products by rat liver microsomes. 18F-ADAM is an important positive electron emission ligand commonly employed as a radio-imaging agent for serotonin transporter (SERT) in the brain. F-ADAM and its derivatives were separated using HPLC on a C4-phenyl column with an ammonium formate aqueous buffer/acetonitrile programmed mobile phase. Synthetic contaminants and metabolic products were identified using fragmentation spectra obtained by tandem mass spectrometry. We show that F-ADAM is unstable in methanol, and propose the use of acetonitrile to generate optimal chromatogram. A Cl-substituted species was found to be the major impurity resulting from the F-ADAM synthetic process. The metabolic products of F-ADAM by rat liver microsomes were characterized by oxidization of the sulfur moiety to sulfoxide, demethylation of the dimethylamine moiety, and oxidative defluorination/deamination. These results elucidate the by-products of F-ADAM synthetic and metabolic processes, and provide direction for the application of this imaging agent to biosystems properly.

关键词： Liver Microsomes Metabolites Impurities F-ADAM Serotonin Transporter

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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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FASTlab磷酸盐药盒用于[18F]FDG质量控制的两中心研究

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中华核医学与分子影像杂志 2017年第3期37卷 190-191页

作者：李梦婷兰晓莉 430022 武汉，华中科技大学同济医学院附属协和医院核医学科

目的 GE FASTlab放射化学合成模块利用可购得的磷酸盐药盒生产18F-FDG。由于在产品失效期前,会发现产品小瓶内的白色沉淀,因此决定重新审查生产的18F-FDG溶液的质量。方法在FASTlab上合成磷酸盐缓冲18F-FDG溶液,并在"国立"台湾大学医院(... 详细信息

目的 GE FASTlab放射化学合成模块利用可购得的磷酸盐药盒生产18F-FDG。由于在产品失效期前,会发现产品小瓶内的白色沉淀,因此决定重新审查生产的18F-FDG溶液的质量。方法在FASTlab上合成磷酸盐缓冲18F-FDG溶液,并在"国立"台湾大学医院(NTUH)和澳大利亚皇家布里斯班妇女医院(RBWH)进行分析。除了标准品质量控制(QC),铝的浓度(Al3+)作为18F-FDG溶液出现沉淀的可能原因外,也通过电感耦合等离子体质谱法(ICP-MS,在RBWH)和电感耦合等离子体发射光谱法(ICP-OES,在NYUH)进行了分析,并且在NTUH使用了3种半定量方法[Advantec(?)矾土检查试纸、Quantofix(?)铝试纸和MColortest?铝测试套件]。结果通过FASTlab合成18F-FDG,38%～100%的批次在24 h(NTUH)和6 h(RBWH)内观察沉淀物。无金属HCl(液体)用以鉴定18F-FDG中所含沉淀物。ICP-MS分析表明,Al3+的浓度为70～80 ppm。Al3+浓度为10～12 ppm的18F-FDG批次并没有出现任何沉淀物。相比之下,通过半定量方法,在所有批次均检测到小于5 ppm的残余Al3+。结论美国、英国、欧洲和日本药典要求用于注射的18F-FDG在保质期内应呈澄清状,不含颗粒。为避免在产品到期产生铝-磷酸盐沉淀,应用FASTlab柠檬酸盐药盒,而不是磷酸药盒生产18F-FDG。虽然在美国、英国和欧洲药典的18F-FDG专论中Al3+的检测并未被列入,但是基于患者安全考虑,残余Al3+的水平应引起重视。

关键词：药盒 FASTlab 磷酸盐沉淀物 18F-FDG

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