Production at the Curie Level of No-Carrier-Added 6-18F-Fluoro-l-Dopa

Abstract

6-(18)F-fluoro-L-dopa ((18)F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. In this paper, 2 important chemical improvements are proposed to simplify production of (18)F-FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. First, a fast, simple, and reliable synthesis of 2-(18)F-fluoro-4,5-dimethoxybenzyl iodide on a solid-phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon-carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of (18)F-FDOPA (≈ 97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% ± 3% (n = 8). By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA (18)F-fluoride, high activities of (18)F-FDOPA (>45 GBq) with high specific activity (≥ 753 GBq/μmol) are now available at the end of synthesis for use in clinical investigations.