Synthesis, Radiolabeling and Biological Evaluation of (R)- and (S)-2-Amino-3-[18F]Fluoro-2-Methylpropanoic Acid (FAMP) and (R)- and (S)-3-[18F]Fluoro-2-Methyl-2-N-(Methylamino)propanoic Acid (NMeFAMP) as Potential PET Radioligands for Imaging Brain Tumors

• Authors: Weiping Yu, Emory University; Jonathan McConathy, Emory University; Larry Williams, Emory University; Vernon M. Camp, Emory University; Eugene J Malveaux Sr., Emory University; Zhaobin Zhang, Emory University; Jeffrey James Olson, Emory University; Mark M. Goodman, Emory University
• Journal Title: Journal of Medicinal Chemistry
• Volume: Volume 53, Number 2
• Publisher: American Chemical Society | 2010-01-28, Pages 876-886
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/jm900556s
• Subjects: Biology, Neuroscience

Abstract

The non-natural amino acids (R)- and (S)-2-amino-3-fluoro-2-methylpropanoic acid 5 and (R)- and (S)-3-fluoro-2-methyl-2-N-(methylamino)propanoic acid 8 were synthesized in shorter reaction sequences than in the original report starting from enantiomerically pure (S)- and (R)-α-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[18F]5 and (R)- and (S)-[18F]8 in fewer steps than in the original report. (R)- and (S)-[18F]5 and(R)- and (S)-[18F]8 were synthesized by no-carrier-added nucleophilic [18F]fluorination in 52–66% decay-corrected-yields with radiochemical purity over 99%. The cell assays showed that all four compounds were substrates for amino acid transport and enter 9L rat gliosarcoma cells in vitro at least in part by system-A amino acid transport. The biodistribution studies demonstrated that in vivo tumor to normal brain ratios for all compounds were high with ratios of 20:1 to115:1 in rats with intracranial 9L tumors. The (R)- enantiomers of [18F]5 and [18F]8 demonstrated higher tumor uptake in vivo compared to the (S)- enantiomers.