Radiosynthesis of the tumor hypoxia marker [ 18F]TFMISO via O-[ 18F]trifluoroethylation reveals a striking difference between trifluoroethyl tosylate and iodide in regiochemical reactivity toward oxygen nucleophiles

The MRI hypoxia marker trifluoromisonidazole (TFMISO) [1-(2-nitro-1 H-imidazol-1-yl)-3-(2,2,2-trifluoroethoxy)propan-2-ol] was successfully labeled with 18F to expand its role into a bimodal PET/MRI probe. 18F-Labeling was achieved via a three-step procedure in which 2,2,2-[ 18F]trifluoroethyl p-toluenesulfonate prepared by 18F- 19F exchange served as the [ 18F]trifluoroethylating agent. The O-[ 18F]trifluoroethylation reaction proceeded efficiently to give the intermediate 1,2-epoxy-3-(2,2,2-[ 18F]trifluoroethoxy)propane, with approximately 60% of 18F incorporated from the tosylate precursor, which was condensed with 2-nitroimidazole to yield [ 18F]TFMISO. Approximately 40% of the [ 18F]trifluoroethyl tosylate precursor was converted into the final product. In stark contrast, 2,2,2-[ 18F]trifluoroethyl iodide failed to produce [ 18F]TFMISO, giving instead 1,1-[ 18F]difluoro-2-iodoethoxy and 1-[ 18F]fluoro-2-iodovinyloxy analogs of [ 18F]TFMISO. Thus, this investigation has identified 2,2,2-[ 18F]trifluoroethyl tosylate as an excellent [ 18F]trifluoroethylating agent, which can convert efficiently an alcohol into the corresponding [ 18F]trifluoroethyl ether.