Radiosynthesis and Analysis of (S)-4-(3-[18F]Fluoropropyl)-L-Glutamic Acid

Abstract

Purpose (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is an L-glutamate derivative used as a PET biomarker to assess intracellular redox status in vivo through targeting of the cystine/glutamate antiporter protein, xc− transporter. In this report, we describe a radiosynthesis of [18F]FSPG for use in PET studies that address specific challenges in relation to the radiotracer purity, molar activity, and quality control testing methods. Procedures The radiosynthesis of [18F]FSPG was performed using a customised RNPlus Research automated radiosynthesis system (Synthra GmbH, Hamburg, Germany). [18F]FSPG was labelled in the 3-fluoropropylmoiety at the 4-position of the glutamic acid backbone with fluorine-18 via substitution of nucleophilic [18F]fluoride with a protected naphthylsulfonyloxy-propyl-L-glutamate derivative. Radiochemical purity of the final product was determined by radio HPLC using a new method of direct analysis using a Hypercarb C18 column. Results The average radioactivity yield of [18F]FSPG was 4.2 GBq (range, 3.4–4.8 GBq) at the end of synthesis, starting from 16 GBq of [18F]fluoride at the end of bombardment (n = 10) in a synthesis time of 50 min. The average molar activity and radioactivity volumetric concentration at the end of synthesis were 66 GBq µmol−1 (range, 48–73 GBq µmol−1) and 343–400 MBq mL−1, respectively. Conclusion Stability tests using a 4.6 GBq dose with a radioactivity volumetric concentration of 369 MBq mL−1 at the end of synthesis showed no observable radiolysis 3 h after production. The formulated product is of high radiochemical purity (> 95%) and higher molar activity compared to previous methods and is safe to inject into mice up to 3 h after production.

Simplified and highly-reliable automated production of [18F]FSPG for clinical studies

“…Radio-HPLC analysis of the produced [ 18 F]FSPG for injection showed > 95% radiochemical purity. In line with previous reporting, the major impurity can be attributed to [ 18 F]Fluoride (Brown et al 2023 ). Further analysis after 8 h confirmed that the product remained stable (Fig.…”

“…We have achieved the cGMP-compliant automated production of [ 18 F]FSPG with optimal synthesis procedure for both GE TRACERlab™ FXFN and FASTlab™ synthesizer. While several commercially available modules for [ 18 F]FSPG production have been previously published (Koglin et al 2011 ; Kavanaugh et al 2016 ; Mittra et al 2016 ; McCormick et al 2019 ; Shih et al 2020 ; Edwards et al 2021 ; Brown et al 2023 ), our method has consistently produced [ 18 F]FSPG at high radiochemical purity and high molar activity. In particular, our adaptation of the SPE purification method was elegantly simplified in setup and with minimal processing time, making it attractive for centralized and large-scale production of [ 18 F]FSPG at a manufacturing facility.…”

“…Producing radiotracers with highly consistent radiochemical yield and quality is required to bring promising radiotracers from bench to bedside. Although several groups have described automated procedures to produce [ 18 F]FSPG, previous reports were focused on small-scale production (up to 4.8 GBq of the final product) and with complex modifications of commercially available cartridges (Koglin et al 2011 ; Kavanaugh et al 2016 ; Mittra et al 2016 ; McCormick et al 2019 ; Shih et al 2020 ; Edwards et al 2021 ; Brown et al 2023 ), making it challenging to directly implement at a manufacturing facility. Here, we report a detailed and highly robust technical protocol to produce the large-scale, cGMP-compliant radiosynthesis of [ 18 F]FSPG using GE TRACERlab™ FXFN and FASTlab™, the most widely used synthesis modules for routine clinical radiopharmaceutical production.…”

Simplified and Highly-reliable automated production of [18F]FSPG for clinical studies

“…We have achieved the cGMP-compliant automated production of [ 18 F]FSPG with optimal synthesis procedure for both GE TRACERlab ™ FXFN and FASTlab ™ synthesizer. While several commercially available modules for [ 18 F]FSPG production have been previously published ( Brown et al, 2023 ; Edwards et al, 2021 ; Kavanaugh et al, 2016 ; Koglin et al, 2011 ; McCormick et al, 2019 ; Mittra et al, 2016 ; Shih et al, 2020 ), our method has consistently produced [ 18 F]FSPG at high radiochemical purity and high molar activity. In particular, our adaptation of the SPE purification method was elegantly simplified in setup and with minimal processing time, making it attractive for centralized and large-scale production of [ 18 F]FSPG at a manufacturing facility.…”

“…Producing radiotracers with highly consistent radiochemical yield and quality is required to bring promising radiotracers from bench to bedside. Although several groups have described automated procedures to produce [ 18 F]FSPG, previous reports were focused on small-scale production (less than 400 MBq of the final product) and with complex modifications of commercially available cartridges ( Brown, Soloviev, & Lewis, 2023 ; Edwards, Greenwood, McRobbie, Khan, & Witney, 2021 ; Kavanaugh et al, 2016 ; Koglin et al, 2011 ; McCormick et al, 2019 ; Mittra et al, 2016 ; Shih et al, 2020 ), making it challenging to directly implement at a manufacturing facility. Here, we report a detailed and highly robust technical protocol to produce the large-scale, cGMP-compliant radiosynthesis of [ 18 F]FSPG using GE TRACERlab ™ FXFN and FASTlab ™ , the most widely used synthesis modules for routine clinical radiopharmaceutical production.…”