Synthesis of 6-[18F]fluoroveratraldehyde by nucleophilic halogen exchange at electron-rich precursors

Abstract

Fluorodehalogenation reactions were used to prepare 6-[18F]fluoroveratraldehyde. The synthesis of 6-[18F]fluoroveratraldehyde is the first step in the multi-step synthesis of the clinically important tracer 6-[18F]fluoro-L-dopa. In the literature yields ranging from 20-50% are reported when using nitro and trimethylammoniumtriflate precursors. However, no data exist concerning the use of different leaving groups such as halogens. Therefore, 6-bromo, 6-chloro and 6-fluoroveratraldehyde were tested in the nucleophilic aromatic substitution by [18F]fluoride. In DMF, 6-[18F]fluoroveratraldehyde was obtained with radiochemical yields of (57±1.0)% and (66±3.6)% in 20 minutes at 160 °C using 50 mg/ml bromo and chloro precursor, respectively. The fluoro precursor gave a radiochemical yield of (87±0.8)% at 140 °C. Temperature, solvent and concentration strongly affected the 18F-labeling. Among the halogens the ability as a leaving group was F>>Cl>Br. The halogenated veratraldehydes provide a good alternative for the synthesis of ca and nca 6-[18F]fluoroveratraldehyde, as the first step of the synthesis for [18F]FDOPA since they are inexpensive, commercially available, stable, sustain hard conditions in the labeling step, and give yields better or equal to other precursors previously reported.