Fast and reliable method for the preparation of ortho- and para-[18F]fluorobenzyl halide derivatives: Key intermediates for the preparation of no-carrier-added PET aromatic radiopharmaceuticals

A fast and reliable method suitable for the automated preparation of (substituted) [18F]fluorobenzyl halides from several [18F]fluorobenzaldehydes was developed. Aromatic nucleophilic substitution of trimethylammonium benzaldehyde triflate and nitro precursors was realized with no-carrier-added [18F]fluoride. After labeling, fluorine-18 containing aldehydes were trapped on a Solid Phase Extraction (SPE) cartridge and the subsequent conversion into benzyl halide was directly realized, on-line, on the support. Reduction of the aldehydes (>95%) was near-quantitative with an aqueous solution of NaBH4. Halogenation was performed on the same support with different aqueous solutions of concentrated acid (HI, HBr, HCl). The conversion of benzyl alcohols into [18F]fluorobenzyl halides (X = Cl, Br, I) usually proceeded within 2 min at high yields. The halogenation proceeded at room temperature, with the exception of the 2-[18F]fluoro-3-methoxybenzyl, 2- and 4-[18F]fluorobenzyl halides, which required the use of HBr/HOAc (33%). With this method, various [18F]fluorobenzyl chloride, bromide and iodide compounds were obtained with high radiochemical purities (>90%) and with overall radiochemical yields of 15–70%. The radiosynthesis was completed in 30 or 45 min from EOB, starting from the ammonium or nitro precursor, respectively. By using the same solid support, 2- and 4-[18F]fluorobenzyl bromide and iodide derivatives were near-quantitatively converted (>95%) into the corresponding azido compounds (60 °C, 5 min). As the reduction and halogenation steps were performed on solid supports, automation of the whole synthesis was straightforward.

Conversion of various [18F]fluorobenzaldehydes into the corresponding [18F]fluorobenzyl halides (X = Cl, Br, I) is described. The aldehydes were reduced and halogenated on line on a solid support by using an aqueous solution of NaBH4 and an aqueous concentrated acid solution (HCl, HBr, HI). This two step synthesis path proceeds fast and delivers the nca radiofluorinated aromatic products in high yields.Figure optionsDownload as PowerPoint slideHighlights
► General strategy for the synthesis of various [18F]fluorine labeled benzyl halides.
► Easy room temperature reactions on solid support including purification.
► High yields and easy automation.