Conversion of pyridine N-oxides to trialkylammonium precursors of 2-fluoropyridines and application to [18F]labeling of PET tracers

Objectives The emergence of 2-[18F]fluoropyridines as a common functionality in PET imaging agents has become a driving force to identify new synthetic methods that produce fluoropyridines from readily available starting materials, and can be applied to both ¹⁹F and ¹⁸F syntheses. We envisioned using trialkylammonium pyridine salts as intermediates to synthesize 2-fluoropyridines from pyridine N-oxides. The isolable trialkylammonium salts could be used as radiofluorination precursors, and the generality of this method could be evaluated through the preparation of several known [18F]PET tracers.

Methods 2-Trialkylammonium pyridine salts can be prepared from pyridine N-oxides by treatment with a tertiary amine and trifluoroacetic anhydride in CH₂Cl₂ and isolated by trituration. 2-Fluoropyridines can be prepared from 2-trialkylammonium pyridine salts by treatment with a fluoride source in DMF, and isolated by column chromatography. [18F]Labeling can be achieved by exposure of a 2-trialkylammonium pyridine salt to a nucleophilic source of [18F] (e.g., K[18F]) with K_2.2.2 and K₂CO₃ in DMSO at an appropriate temperature followed by yield determination and/or purification by HPLC.

Results We identified mild and metal-free reaction conditions for the synthesis of a diverse collection of 2-fluoropyridines. Notably, this method was not applicable to 4-monosubstituted pyridine N-oxides. The stable 2-trialkylammonium pyridine intermediates also serve as effective radiosynthesis precursors for several known PET tracers, including [18F]AV-1451 (a.k.a. [18F]T807).

Conclusions The method of converting pyridine N-oxides into 2-fluoropyridines via their trialkylammonium salts features inexpensive reagents, and also provides strategic access to both the [19F]fluoride analogue as well as the trialkylammonium pyridine salt radiolabeling precursor. Finally, the applicability of this method was demonstrated by the successful preparation of several known [18F]PET tracers ([18F]AV-1451, [18F]CABS13 and 6-[18F]PBR28).