Synthesis of [18F]xenon difluoride as a radiolabeling reagent from [18F]fluoride ion in a micro-reactor and at production scale

Abstract

[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 (t1/2=109.7min) 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 94s. These results enabled us to develop a method for obtaining [18F]XeF2 on a production scale (up to 25mCi) through reaction of [18F]fluoride ion with xenon difluoride in acetonitrile at 90°C for 10min. [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.