Copper‐Mediated Radiofluorination of the Excitatory Amino Acid Transporter 2 (EAAT2)–Targeted PET Tracer [ 18 F]RP‐115: Alternate Synthetic Method
Sang Hee Lee, Joseph Blecha, Jung Min Kim, Ryan Michael Nillo, Robert R. Flavell, Chih‐Kai Chao, John R. Forsayeth, John M. Gerdes, Henry F. VanBrocklin, David M. WilsonABSTRACT
Excitatory amino acid transporter 2 (EAAT2) is a key regulator of extracellular glutamate in the central nervous system. Dysregulated EAAT2 is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), highlighting EAAT2 as a potential target for PET imaging. We previously reported a multistep radiosynthesis of [ 18 F]RP‐115, a CNS‐permeable prodrug that undergoes esterase‐mediated hydrolysis in the CNS to yield the active EAAT2‐binding carboxylate. Motivated by recent advances in copper‐mediated radiofluorination (CMRF), we sought to develop a more efficient late‐stage radiosynthesis of [ 18 F]RP‐115. A two‐step radiosynthesis of [ 18 F]RP‐115 using CMRF provided [ 18 F]RP‐115 in high radiochemical yield (52.8% ± 2.1 %, decay‐corrected from starting [ 18 F]fluoride ion, n = 4), high molar activity (355 ± 61 GBq/μmol), and high radiochemical purity (> 99%) with a total synthesis time of 70 min. Chiral HPLC analysis demonstrated that the configuration of the aspartic acid residue remained intact without racemization during both the CMRF and trifluoroacetic acid mediated deprotection. We developed an efficient radiosynthesis of [ 18 F]RP‐115 via CMRF, achieving high radiochemical yield and molar activity. This efficient synthesis may serve as a basis for the future implementation of a CMRF‐based automated radiosynthesis of [ 18 F]RP‐115.