Radiolabeled amino acids for tumor imaging with PET: radiosynthesis and biological evaluation of 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid

J Med Chem. 2002 May 23;45(11):2240-9. doi: 10.1021/jm010241x.

Abstract

Novel radiopharmaceuticals, including amino acids, that target neoplasms through their altered metabolic states have shown promising results in preclinical and clinical studies. Two fluorinated analogues of alpha-aminoisobutyric acid, 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP), have been radiolabeled with fluorine-18, characterized in amino acid uptake assays, and evaluated in vivo in normal rats and a rodent tumor model. The key steps in the syntheses of both radiotracers involved the preparation of cyclic sulfamidate precursors. Radiosyntheses of both [18F]FAMP and [18F]N-MeFAMP via no-carrier-added nucleophilic substitution provided high yields (>78% decay-corrected) in high radiochemical purity (>99%). Amino acid transport assays using 9L gliosarcoma cells demonstrated that both compounds are substrates for the A type amino acid transport system, with [18F]N-MeFAMP showing higher specificity than [18F]FAMP for A type transport. Tissue distribution studies in normal Fischer rats and Fischer rats implanted intracranially with 9L gliosarcoma tumor cells were also performed. At 60 min postinjection, the tumor vs normal brain ratio of radioactivity was 36:1 in animals receiving [18F]FAMP and 104:1 in animals receiving [18F]N-MeFAMP. On the basis of these studies, both [18F]FAMP and [18F]N-MeFAMP are promising imaging agents for the detection of intracranial neoplasms via positron emission tomography.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Transport System A / antagonists & inhibitors
  • Amino Acid Transport System A / metabolism
  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacokinetics
  • Aminoisobutyric Acids / chemical synthesis*
  • Aminoisobutyric Acids / chemistry
  • Aminoisobutyric Acids / pharmacokinetics
  • Animals
  • Brain / metabolism
  • Brain Neoplasms / metabolism
  • Fluorine Radioisotopes
  • Gliosarcoma / metabolism
  • Isotope Labeling
  • Ligands
  • Male
  • Neoplasm Transplantation
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacokinetics
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Inbred F344
  • Structure-Activity Relationship
  • Tissue Distribution
  • Tomography, Emission-Computed
  • Tumor Cells, Cultured

Substances

  • 2-amino-3-fluoro-2-methylpropanoic acid
  • 3-fluoro-2-methyl-2-(methylaminio)propanoic acid
  • Amino Acid Transport System A
  • Amino Acids
  • Aminoisobutyric Acids
  • Fluorine Radioisotopes
  • Ligands
  • Propionates
  • Radiopharmaceuticals