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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.

Authors :
Shih, Kai-Ting
Huang, Ya-Yao
Yang, Chia-Ying
Cheng, Mei-Fang
Tien, Yu-Wen
Shiue, Chyng-Yann
Yen, Rouh-Fang
Hsin, Ling-Wei
Source :
PLoS ONE; 12/14/2020, Vol. 15 Issue 12, p1-21, 21p
Publication Year :
2020

Abstract

(4S)-4-(3-[<superscript>18</superscript>F]Fluoropropyl)-L-glutamic acid ([<superscript>18</superscript>F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system x<subscript>C</subscript><superscript>−</superscript> transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [<superscript>18</superscript>F]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 <superscript>18</superscript>F nuclide, [<superscript>18</superscript>F]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 [<superscript>18</superscript>F]FSPG for clinical use. To manufacture cGMP-compliant [<superscript>18</superscript>F]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/CuSO<subscript>4(aq)</subscript> 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 [<superscript>18</superscript>F]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 [<superscript>18</superscript>F]FSPG. Based on the above accomplishments, cGMP-compliant [<superscript>18</superscript>F]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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19326203
Volume :
15
Issue :
12
Database :
Complementary Index
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
147599334
Full Text :
https://doi.org/10.1371/journal.pone.0243831