6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine (6-[18F]fluoro-L-DOPA), an analogue of L-DOPA, is an established radiotracer for diagnostic PET-studies of the integrity and function of the nigrostriatal dopaminergic system. The use of this important compound in clinical centers is mainly limited by the lack of a nucleophilic radiofluorination method of preparation using the advantage of large scale production of [18F]fluoride. In this work a new convenient nucleophilic labelling method using [18F]fluoride has been developed. With regard to the synthesis of 6-[18F]fluoro-L-DOPA via nucleophilic 18F-fluorination of carbonylactivated aromatic amino acid derivatives, several O-protected 4-fluoro-2-hydroxy-5-methylbenzaldehydes were prepared as model compounds in order to evaluate the concept of synthesis. The 2-benzyloxy-4-[18F]fluoro-5-methyl-benzaldehyde was prepared via 18F-for-19F substitution with a radiochemical yield of 85 ± 5 % and via 18F-for-N(CH3)3 substitution on (5-benzyloxy-4-formyl-2-methyl-phenyl)-trimethylammoniumtriflate with a radiochemical yield of 92 ± 5 %. Thereof the synthesis of n.c.a. 2-benzyloxy-4-[18]fluoro-5-methyl-phenol was achieved by Baeyer-Villiger oxidation with m-chloroperbenzoic acid with an overall radiochemical yield of 54 ± 5 %within 40 minutes. An appropriate precursor for the synthesis of 6-[18F]fluoro-L-DOPA was synthesized by electrophilic alkylation of the lithiated bis-lactim ether (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 4-benzyloxy-2-fluoro-benzylbromide. The corresponding 5-(4-benzyloxy-2-fluorobenzyl)-(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine, obtained with a diastereomeric excess of 84 %, was formylated in the aromatic 5-position with dichloromethyl methyl ether in the presence of a sixfold excess of tin(IV)chloride. The nucleophilic 18F-fluorination of 5-(4-benzyloxy-2-fluoro-5-formyl-benzyl)-(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine was performed in DMF at 130 °C in the presence of the common Kryptofix 222/potassium carbonate system for 3 minutes. The radiochemical yield of the isotopic exchange was about 30 ± 5 %. Baeyer-Villiger oxidation of 5-(4-benzyloxy-2-[18F]fluoro-5-formyl-benzyl)-(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine to the corresponding formiate with m-chloroperbenzoic acid and subsequent hydrolysis and deprotection under strong acidic conditions led to the formation of c.a. 6-[18F]fiuoro-DOPA with an enantiomeric excess of the L-isomer of about 70 %. The overail radiochemical yield of 6-[18F]fluoro-L-DOPA was 14 to 18 % within 70 minutes. According to the amount of 11 μmol precursor the carrier content is lower by a factor of about 10 in comparison to the electrophilic 18F-fluorination methods commonly used. Furthermore, use can be made of the fivefold higher production of [18F]fluoride compared to [18F]F2. However, the racemic mixture of 6-[18F]fluoro-L-DOPA still requires a chiral HPLC separation
