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

Abstract

The MRI hypoxia marker trifluoro-misonidazole (TFMISO) [1-(2-nitro-1H-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 3-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.

Chemie der Positronenemissionstomographie: Aktuelle Fortschritte bei 11C‐, 18F‐, 13N‐ und 15O‐Markierungsreaktionen

“…18 F‐markiertes Trifluorethyltosylat kann entweder durch einen 19 F/ 18 F‐Austausch oder aber durch die 18 F‐Addition von 2,2‐Difluorvinyltosylat erhalten werden (Schema A,B) . Unter Anwendung des Verfahrens in Schema B konnte das 18 F‐markierte Trifluorethyltosylat mit Nucleophilen, wie z.…”

Recent Advances on Radionuclide Labeled Hypoxia-Imaging Agents

“…TFMISO is a FMISO analogue and is used as a hypoxia probe for MRI because the three magnetically equivalent 19 F atoms in the molecule make it possible to be detected by 19 F-magnetic resonance spectroscopy (MRS). The success of labeling TFMISO with fluorine-18 made it a PET radiotracer as well, expanding its role into a bimodal PET/MRI probe [78]. …”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…18 F-Labeled trifluoroethyl tosylate can be obtained either by 19 F/ 18 Fe xchange [170] or 18 F-addition of 2,2-difluorovinyl tosylate (Scheme 31 A,B). [171,172] Using the procedure in Scheme 31 B, 18 F-labeled trifluoroethyl tosylate could further react with nucleophiles,i ncluding phenols,c arboxylic acids, and amines,in77-93 %RCY.Scott and co-workers used this strategy to produce [ 18 F]lansoprazole in 4-14 %R CY with 37 GBq mmol À1 molar activity for application in PET imaging.…”