Access to 18F-labelled isoxazoles by Ruthenium-promoted 1,3-dipolar cycloaddition of 4-[18F]fluoro-N-hydroxybenzimidoyl chloride with alkynes.

4-[18F]Fluoro-N-hydroxybenzimidoyl chloride (18FHBIC) was developed as an 18F-labelled aromatic nitrile oxide precursor. The building block is obtained in a one-pot synthesis in up to 79% radiochemical yield starting from [18F]fluoride in 50 min with 4-[18F]fluorobenzaldehyde (18FBA) and 4-[18F]fluorobenzaldehyde oxime (18FBAO) as intermediates, including the reaction of 18FBAO with N-chlorosuccinimide (NCS) as a key step. 18FHBIC was found to be a suitable and stable synthon to give access to 18F-labelled 3,4-diarylsubstituted isoxazoles by [Cp*RuCl(cod)]-catalyzed 1,3-dipolar cycloaddition with various alkynes. By way of example, the radiosynthesis of a fluorine-18 labelled COX-2 inhibitor [18F]1b, a close derivative of valdecoxib, was performed by 1,3-dipolar cycloaddition of 18FHBIC with 1-ethynyl-4-(methylsulfonyl)benzene, providing purified [18F]1b in RCY up to 40% starting from [18F]fluoride in 85 min. The application of 18FHBIC as a building block in the synthesis of 18F-labelled heterocycles will generally extend the portfolio of available PET radiotracers.