Three-Step, “One-Pot” Radiosynthesis of 6-Fluoro-3,4-Dihydroxy-l-Phenylalanine by Isotopic Exchange

Abstract

The (18)F-labeled aromatic amino acid 6-fluoro-3,4-dihydroxy-L-phenylalanine (6-(18)F-fluoro-L-DOPA) is widely used as a radiopharmaceutical in neurologic and oncologic PET. In this study, a novel approach to the preparation of carrier-added (CA) 6-(18)F-fluoro-L-DOPA in 3 radiosynthesis steps was developed and evaluated; in this approach, direct nucleophilic (18)F fluorination of a protected amino acid derivative was used. The method currently used for the routine preparation of 6-(18)F-fluoro-L-DOPA by electrophilic labeling is limited to the production of small amounts of activity at high costs. Alternative syntheses based on the advantage of large-scale production of nucleophilic (18)F-fluoride, however, either have resulted in insufficient enantiomeric purity or are difficult to automate because of the complexity of the necessary multiple steps. An isotopic exchange reaction on the precursor (2S,5S)-tert-butyl-5-(4-benzyloxy-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate was used. The formyl group served as the activating group in the (18)F-for-(19)F exchange with tetrabutylammonium bicarbonate for anion activation in N,N-dimethylformamide. The intermediate was converted to a hydroxy group by Baeyer-Villiger oxidation with meta-chloroperbenzoic acid. After final deprotection with hydrobromic acid, CA 6-(18)F-fluoro-L-DOPA was isolated by high-performance liquid chromatography. The precursor was obtained by an 11-step organic synthesis. The optimized isotopic (18)F exchange proceeded with a radiochemical yield of about 50%. The complete preparation and isolation of CA 6-(18)F-fluoro-L-DOPA thus far are possible with a radiochemical yield of about 22%, within a synthesis time of 105 min, and at a much higher specific activity than with the electrophilic method. The enantiomeric excess of the desired L-isomer was greater than 96%. The pathway to 6-(18)F-fluoro-L-DOPA by isotopic exchange not only is more efficient but also is suited to automation as a "one-pot" procedure.