title: Investigations into the synthesis, radiofluorination and conjugation of a new [¹⁸F]fluorocyclobutyl prosthetic group and its in vitro stability using a tyrosine model system.
abstract: The [(18)F]fluorocyclobutyl group has the potential to be a metabolically stable prosthetic group for PET tracers. The synthesis of the radiolabeling precursor cis-cyclobutane-1,3-diyl bis(toluene-4-sulfonate) 8 was obtained from epibromohydrin in 7 steps (2% overall yield). The radiolabeling of this precursor 8 and its conjugation to L-tyrosine as a model system was successfully achieved to give the new non-natural amino acid 3-[(18)F]fluorocyclobutyl-L-tyrosine (L-3-[(18)F]FCBT) [(18)F]17 in 8% decay-corrected yield from the non-carrier-added [(18)F]fluoride. L-3-[(18)F]FCBT was investigated in vitro in different cancer cell lines to determine the uptake and stability. The tracer [(18)F]17 showed a time dependent uptake into different tumor cell lines (A549, NCI-H460, DU145) with the best uptake of 5.8% injected dose per 5×10(5) cells after 30min in human lung carcinoma cells A549. The stability of L-3-[(18)F]FCBT in human and rat plasma and the stability of the non-radioactive L-3-FCBT in rat hepatocytes were both found to be excellent. These results show that the non-natural amino acid L-3-[(18)F]FCBT is a promising metabolically stable radiotracer for positron emission tomography.
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Franck
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Sabine
authors.initials: S
authors.lastname: Zitzmann-Kolbe
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
authors.forename: Keith
authors.initials: K
authors.lastname: Graham
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D003503:Cyclobutanes; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D014443:Tyrosine