Synthesis of [^sup 18^F]trifluoromethylaryl labeling synthons from boronic acids and [^sup 18^F]fluoroform produced in gas phase

Objectives: The trifluoromethyl (CF3) group is useful for modulating the physical, chemical, and biological properties of drug-like molecules [1], including radiotracers for use with positron emission tomography (PET). Aryl trifluoromethyl groups are also gaining interest as sites for labeling with carbon-11 [2] or fluorine-18 [3]. Here we show the utility of arylboronic acids with [18F]fluoroform produced in the gas phase for directly preparing [18F]trifluoromethylaryl labeling synthons that can be useful for producing radiotracers for PET. Methods: [18F]Fluoromethane was prepared in the gas phase from cyclotron-produced [18F]fluoride ion in a two-step process, as previously described [2]. Under dry nitrogen atmosphere, t-BuOK (50 µL, 0.3 M in DMF) was added to CuBr (0.07 mg, 5 µmol) and capped. [18F]Fluoroform (37-185 MBq) in DMF (100-300 µL) was added to the freshly prepared Cu complex and stabilized with Et3N.3HF (1.64% v/v in DMF; 50 µL) for 1 min. An arylboronic acid precursor (7-10 mg, 50 µmol) in DMF (50 µL) was then added to the [18F]CuCF3 solution and purged with air (10 mL). The reaction was left to proceed at room temperature (20−26ºC) for 10 min and then quenched with 0.1% TFA-MeCN (1:1 v/v) solution. The reaction mixture was filtered and the filtrate was analyzed with HPLC. Results: [18F]Fluoroform was produced in ~ 45% yield from [18F]fluoride ion and with high purity (> 95%). [18F]4-Trifluoromethyl benzaldehyde ([18F]1) was obtained in quantitative yield. All [18F]trifluoromethyl phenol isomers ([18F]2−4) were also obtained in high yield (> 95%). The ortho ([18F]5) and para ([18F]6) bromomethyl derivatives of [18F]benzotrifluoride were obtained in moderate yields ([18F]5 = 35%; [18F]6 = 50%). Conclusions: Labeling synthons were readily prepared in a single step from boronic acids and [18F]fluoroform in mostly very high yields, showing the tolerance of this reaction for other functional groups. The boronic acid substrate scope for the synthesis of other labeling syntions is being further rexplored.