Development of [18F]ATPFU as a potential PET tracer for mTOR

1166 Objectives Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation and growth including neurodegeneration, neurogenesis, synaptic plasticity, apoptosis and autophagy. Recent evidence suggests that altered mTOR signaling pathway plays a central role in aging, tumor/cancer, neuropsychiatric and neurodegenerative disorders. Availability of a specific mTOR PET tracer may facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. This study describes the radiosynthesis of [18F]ATPFU, a selective PET radiotracer for mTOR. Methods The reference standard ATPFU and the radiolabeling precursor were synthesized by the Suzuki coupling reactions phenyl boronates with 3-(6-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. The radiosynthesis was achieved in 2-steps by reacting [18F]FCH2CH2NH2 with the triphosgene activated precursor amine. Results The syntheses of ATPFU and its radiolabeling precursor proceeded in 4 steps from commercial pyrimidine-2,4,6(1H,3H,5H)trione with 35% overall yield. The attempted radiosynthesis of [18F]ATPFU from the tosyl precursor was not successful due to a rapid intramolecular cyclization. The radiosynthesis was however successfully achieved in 30% yield at EOS by a 2-step process by distilling [18F]FCH2CH2NH2 into precursor amine in methylene chloride activated with triphosgene at room temperature. Conclusions ATPFU, a high affinity mTOR ligand amenable for radiolabeling with [18F] has been identified, synthesized and radiolabeled. The details of synthesis, radiosynthesis and in vitro evaluation of the radioligand will be presented.