title: 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.affiliation: Emory Center for Positron Emission Tomography, Department of Radiology, Emory University, 1364 Clifton Road, Northeast, Atlanta, Georgia 30322, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martarello
authors.forename: Jonathan
authors.initials: J
authors.lastname: McConathy
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Camp
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Malveaux
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Simpson
authors.forename: Chiab P
authors.initials: CP
authors.lastname: Simpson
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Bowers
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D026924:Amino Acid Transport System A / Q000037:antagonists & inhibitors / Q000378:metabolism; D027062:Amino Acid Transport System L / Q000037:antagonists & inhibitors / Q000378:metabolism; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes; D018316:Gliosarcoma / Q000378:metabolism; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D009368:Neoplasm Transplantation; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
chemical_list: C455821:1-amino-3-fluoromethylcyclobutane-1-carboxylic acid; D026924:Amino Acid Transport System A; D027062:Amino Acid Transport System L; D000596:Amino Acids; D002264:Carboxylic Acids; D003503:Cyclobutanes; D005462:Fluorine Radioisotopes; D008024:Ligands; D011422:Propionates; D019275:Radiopharmaceuticals