Synthesis, radiolabeling, and biological evaluation of (R)- and (S)-2-amino-3-[(18)F]fluoro-2-methylpropanoic acid (FAMP) and (R)- and (S)-3-[(18)F]fluoro-2-methyl-2-N-(methylamino)propanoic acid (NMeFAMP) as potential PET radioligands for imaging brain tumors.
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)-alpha-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[(18)F]5 and (R)- and (S)-[(18)F]8 in fewer steps than in the original report. (R)- and (S)-[(18)F]5 and(R)- and (S)-[(18)F]8 were synthesized by no-carrier-added nucleophilic [(18)F]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 [(18)F]5 and [(18)F]8 demonstrated higher tumor uptake in vivo compared to the (S)-enantiomers.
Yu
Weiping
W
Department of Radiology, School of Medicine, Emory University, 1364 Clifton Road NE, Atlanta, Georgia 30322, USA.
McConathy
Jonathan
J
Williams
Larry
L
Camp
Vernon M
VM
Malveaux
Eugene J
EJ
Zhang
Zhaobin
Z
Olson
Jeffrey J
JJ
Goodman
Mark M
MM
D000596:Amino Acids / Q000493:pharmacokinetics; D000621:Aminoisobutyric Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D001932:Brain Neoplasms / Q000175:diagnosis*; D045744:Cell Line, Tumor; D007553:Isotope Labeling / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution
C455819:2-amino-3-fluoro-2-methylpropanoic acid; D000596:Amino Acids; D000621:Aminoisobutyric Acids; D019275:Radiopharmaceuticals