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

• 作者: Chyng-Yann Shiue Wei-Hsi Chen
• 来源期刊: 药理与制药(英文)
• 学科: 化学
• 关键词: Liver Microsomes METABOLITES IMPURITIES F-ADAM Serotonin Transporter
• 年，卷（期）: 2020,（10）
• 页码范围: 282-298
• 页数: 17页
• 分类号: O62

摘要

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<span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;">-</span></span></span><span><span><span style="font-family:;" "=""><span style="font-family:Verdana;">amine (F-ADAM), as well as its metabolic products by rat liver microsomes. </span>^{<span style="font-family:Verdana;">18</span>}<span style="font-family:Verdana;">F-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 </span><span style="font-family:Verdana;">products of F-ADAM by rat liver microsomes were characterized by oxidization of the sulfur moiety to sulfoxide, demethylation of the dimethylamine</span><span style="font-family:Verdana;"> 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.</span></span></span></span>