https://scholars.lib.ntu.edu.tw/handle/123456789/554381
標題: | Synthesis and analysis of 4-(3-fluoropropyl)-glutamic acid stereoisomers to determine the stereochemical purity of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) for clinical use | 作者: | Shih, Kai-Ting Huang, Ya-Yao Yang, Chia-Ying MEI-FANG CHENG YU-WEN TIEN Shiue, Chyng-Yann RUOH-FANG YEN LING-WEI HSIN |
公開日期: | 2020 | 卷: | 15 | 期: | 12 | 來源出版物: | PloS one | 摘要: | (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC- transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/554381 | ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0243831 | SDG/關鍵字: | florilglutamic acid; florilglutamic acid f 18; 4-(3-fluoropropyl)glutamic acid; glutamic acid derivative; Article; carbon nuclear magnetic resonance; crystallization; drug purity; drug structure; drug synthesis; high performance liquid chromatography; proton nuclear magnetic resonance; scale up; standard; stereoisomerism; chemistry; human; injection; stereoisomerism; synthesis; Chromatography, High Pressure Liquid; Crystallization; Glutamates; Humans; Injections; Stereoisomerism |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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