title: Radiosynthesis of [18F]ATPFU: a potential PET ligand for mTOR.
abstract: Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR-specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [(18)F]1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-(2-fluoroethyl)urea [(18)F]ATPFU ([(18)F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4-(4-8-oxa-3-azabicyclo[3.2.1]-octan-3yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6yl)aniline (10), were achieved from beta-chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25-28%. [(18)F]Fluoroethylamine was prepared by heating N-[2-(toluene-4-sulfonyloxy)ethyl]phthalimide with [(18)F]fluoride ion in acetonitrile. [(18)F]1 was obtained by slow distillation under argon of [(18) F]FCH2CH2NH2 into amine 10 that was pre-treated with triphosgene at 0-5 °C. The total time required for the two-step radiosynthesis including semi-preparative HPLC purification was 90 min, and the overall radiochemical yield of [(18)F]1 for the process was 15 ± 5% based on [(18)F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37-74 GBq/µmol (N = 6).
authors.affiliation: Division of Molecular Imaging and Neuropathology New York State Psychiatric Institute, New York, USA.
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Norman R
authors.initials: NR
authors.lastname: Simpson
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008024:Ligands; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000600159:ATPFU compound; D005462:Fluorine Radioisotopes; D008024:Ligands; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; D058570:TOR Serine-Threonine Kinases; D000225:Adenine
keywords: PET; fluorine-18; mTOR; radiotracer