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

Journal of Nuclear Medicine

Johannes Ermert¹  Heinz H. Coenen¹  Franziska M. Wagner¹ 

[1] Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich GmbH, Jülich, Germany Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich GmbH, Jülich, Germany Institut für Neurowissenschaften und Medizin, INM-5: Nuklearchemie, Forschungszentrum Jülich GmbH, Jülich, Germany

关键词: radiochemistry;    radiopharmaceuticals;    6-¹⁸F-fluoro-l-DOPA;    radiosynthesis;   

DOI  :  10.2967/jnumed.109.063297

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The 18F-labeled aromatic amino acid 6-fluoro-3,4-dihydroxy-l-phenylalanine (6-18F-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) 6-18F-fluoro-l-DOPA in 3 radiosynthesis steps was developed and evaluated; in this approach, direct nucleophilic 18F fluorination of a protected amino acid derivative was used. The method currently used for the routine preparation of 6-18F-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 18F-fluoride, however, either have resulted in insufficient enantiomeric purity or are difficult to automate because of the complexity of the necessary multiple steps. Methods: 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 18F-for-19F 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 6-18F-fluoro-l-DOPA was isolated by high-performance liquid chromatography. Results: The precursor was obtained by an 11-step organic synthesis. The optimized isotopic 18F exchange proceeded with a radiochemical yield of about 50%. The complete preparation and isolation of CA 6-18F-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%.Conclusion: The pathway to 6-18F-fluoro-l-DOPA by isotopic exchange not only is more efficient but also is suited to automation as a “one-pot” procedure.

【 授权许可】

Unknown