Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC), potential PET ligands for tumor detection.

Abstract

syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC, 16 and 17), analogues of anti-1-amino-3-[18F]fluorocyclobutyl-1-carboxylic acid (FACBC), were prepared to evaluate the contributions of C-3 substitution and configuration on the uptake of these radiolabeled amino acids in a rodent model of brain tumors. Radiofluorinated targets [18F]16 and [18F]17 were prepared by no-carrier-added radiofluorination from their corresponding methanesulfonyl esters 12 and 13, respectively, with decay-corrected radiochemical yields of 30% for [18F]16 and 20% for [18F]17. In amino acid transport assays performed in vitro using 9L gliosarcoma cells, both [18F]16 and [18F]17 were substrates for L type amino acid transport, while [18F]17 but not [18F]16 was a substrate for A type transport. Biodistribution studies in normal Fischer rats with [18F]16 and [18F]17 showed high uptake of radioactivity (>2.0% dose/g) in the pancreas while other tissues studied, including liver, heart, lung, kidney, blood, muscle, and testis, showed relatively low uptake of radioactivity (<1.0% dose/g). In rats implanted intracranially with 9L gliosarcoma cells, the retention of radioactivity in tumor tissue was high at 5, 60, and 120 min after intravenous injection of [18F]16 and [18F]17 while the uptake of radioactivity in brain tissue contralateral to the tumor remained low (<0.3% dose/g). Ratios of tumor uptake to normal brain uptake for [18F]16 were 7.5:1, 7:1, and 5:1 at 5, 60, and 120 min, respectively, while for [18F]17 the ratios were 7.5:1, 9:1, and 9:1 at the same time points. This work demonstrates that like anti-[18F]FACBC, [18F]16 and [18F]17 are excellent candidates for imaging brain tumors.

• Authors: Laurent Martarello, Jonathan McConathy, Vernon M Camp, Eugene J Malveaux, Nicholas E Simpson, Chiab P Simpson, Jeffrey J Olson, Geoffrey D Bowers, Mark M Goodman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 11 Pg. 2250-9 (May 23 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12014963 (Publication Type: Journal Article)

Chemical References

• 1-amino-3-fluoromethylcyclobutane-1-carboxylic acid
• Amino Acid Transport System A
• Amino Acid Transport System L
• Amino Acids
• Carboxylic Acids
• Cyclobutanes
• Fluorine Radioisotopes
• Ligands
• Propionates
• Radiopharmaceuticals

Topics

• Amino Acid Transport System A (antagonists & inhibitors, metabolism)
• Amino Acid Transport System L (antagonists & inhibitors, metabolism)
• Amino Acids (chemical synthesis, chemistry, pharmacokinetics)
• Animals
• Brain (metabolism)
• Brain Neoplasms (metabolism)
• Carboxylic Acids (chemical synthesis, chemistry, pharmacokinetics)
• Crystallography, X-Ray
• Cyclobutanes (chemical synthesis, chemistry, pharmacokinetics)
• Fluorine Radioisotopes
• Gliosarcoma (metabolism)
• Isotope Labeling
• Ligands
• Male
• Neoplasm Transplantation
• Propionates (chemical synthesis, chemistry, pharmacokinetics)
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Rats
• Rats, Inbred F344
• Stereoisomerism
• Tissue Distribution
• Tomography, Emission-Computed
• Tumor Cells, Cultured