Radiosynthesis of [ 18 F]ATPFU: a potential PET ligand for mTOR

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)‐1 H ‐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)‐1 H ‐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]FCH 2 CH 2 NH 2 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).