A Gas Phase Route to [¹⁸F]fluoroform with Limited Molar Activity Dilution

Positron emission tomography (PET) is an important imaging modality for biomedical research and drug development. PET requires biochemically selective radiotracers to realize full potential. Fluorine-18 (t_1/2 = 109.8 min) is a major radionuclide for labeling such radiotracers but is only readily available in high activities from cyclotrons as [¹⁸F]fluoride ion. [¹⁸F]fluoroform has emerged for labeling tracers in trifluoromethyl groups. Prior methods of [¹⁸F]fluoroform synthesis used difluoro precursors in solution and led to high dilution with carrier and low molar activity (A_m). We explored a new approach for the synthesis of [¹⁸F]fluoroform based on the radiosynthesis of [¹⁸F]fluoromethane from [¹⁸F]fluoride ion and then cobalt^III fluoride mediated gas phase fluorination. We estimate that carrier dilution in this process is limited to about 3-fold and find that moderate to high A_m values can be achieved. We show that [¹⁸F]fluoroform so produced is highly versatile for rapidly and efficiently labeling various chemotypes that carry trifluoromethyl groups, thereby expanding prospects for developing new PET radiotracers.