Synthesis of [F]xenon difluoride as a radiolabeling reagent from [F]fluoride ion in a micro-reactor and at production scale

¹⁸F]Xenon difluoride (¹⁸F]XeF₂), was produced by treating xenon difluoride with cyclotron-produced ¹⁸F]fluoride ion to provide a potentially useful agent for labeling novel radiotracers with fluorine-18 (t_1/2 = 109.7 min) for imaging applications with positron emission tomography. Firstly, the effects of various reaction parameters, for example, vessel material, solvent, cation and base on this process were studied at room temperature. Glass vials facilitated the reaction more readily than polypropylene vials. The reaction was less efficient in acetonitrile than in dichloromethane. Cs⁺ or K⁺ with or without the cryptand, K 2.2.2, was acceptable as counter cation. The production of ¹⁸F]XeF₂ was retarded by K₂CO₃, suggesting that generation of hydrogen fluoride in the reaction milieu promoted the incorporation of fluorine-18 into xenon difluoride. Secondly, the effect of temperature was studied using a microfluidic platform in which ¹⁸F]XeF₂ was produced in acetonitrile at elevated temperature (≥85 °C) over 94 s. These results enabled us to develop a method for obtaining ¹⁸F]XeF₂ on a production scale (up to 25 mCi) through reaction of ¹⁸F]fluoride ion with xenon difluoride in acetonitrile at 90 °C for 10 min. ¹⁸F]XeF₂ was separated from the reaction mixture by distillation at 110 °C. Furthermore, ¹⁸F]XeF₂ was shown to be reactive towards substrates, such as 1-((trimethylsilyl)oxy)cyclohexene and fluorene.