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

Autor: Chia-Ying Yang, Ya-Yao Huang, Kai-Ting Shih, Yu-Wen Tien, Rouh-Fang Yen, Chyng-Yann Shiue, Mei-Fang Cheng, Ling-Wei Hsin
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Biochemistry
High-performance liquid chromatography
Diagnostic Radiology
Metastasis
Isomers
chemistry.chemical_compound
Glutamates
Stereochemistry
Basic Cancer Research
Medicine and Health Sciences
Stereoisomers
Tomography
Chromatography
High Pressure Liquid
Liquid Chromatography
Multidisciplinary
Radiology and Imaging
Chromatographic Techniques
Chemical Synthesis
Stereoisomerism
Lipids
Imaging agent
Chemistry
Oncology
Physical Sciences
Medicine
Crystallization
Research Article
Chemical Elements
Imaging Techniques
Science
Neuroimaging
Lithium
Research and Analysis Methods
Injections
Isomerism
Diagnostic Medicine
Humans
Derivatization
Enantiomeric excess
Chromatography
Elution
Chemical Compounds
Biology and Life Sciences
Glutamic acid
High Performance Liquid Chromatography
Chiral column chromatography
chemistry
Oils
Positron Emission Tomography
Neuroscience
Zdroj: PLoS ONE, Vol 15, Iss 12, p e0243831 (2020)
PLoS ONE
ISSN: 1932-6203
Popis: (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.
Databáze: OpenAIRE
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