High output 18F-FDOPA production on AllInOne (Trasis) at commercial scale

Objectives: Effective commercial production of FDOPA requires producing large enough amounts, implying high yield at high activity. This objective, currently pursued by several groups, is not easily achieved. Lemaire et al have proposed an n.c.a enantioselective FDOPA synthetic route using a chiral phase-transfer catalyst (1, 2). This method, optimized and implemented by Trasis on the AllInOne synthesizer, has proved to meet this goal. Methods: [18F]FDOPA, is prepared from the 6-Nitroveratraldehyde. This precursor reacts with dried [18F]fluoride to give 2-[18F]fluoro-4,5-dimethoxybenzaldehyde. After purification of the compound on a tC18 cartridge, and subsequent reduction of the aldehyde moiety to a primary alcohol using NaBH4, the resulting hydroxyl group is iodinated with concentrated HI. The iodinated compound is then eluted from the cartridge with dichloromethane, purified and reacted with a Schiff's base in the presence of a phase transfer catalyst. Alkylation reaction occurs and gives the protected [18F]FDOPA which is subsequently de-protected with concentrated HI at 160°C. Finally the crude solution is purified by HPLC to isolate the [18F]FDOPA and formulated for injection (Figure 1). Results: The average NDC yield gathered from over 10 users across the world is 38% over 5 steps at starting activities ranging from 100 to 400 GBq, with highest values around 45%. The radiochemical purity is higher than 99% and the enantiomeric purity always above 97%. The formulated product is stable over at least 16 hours. Conclusion: The FDOPA "Liege method", automated and optimized by Trasis on an AllInOne synthesis module is efficient and appropriate for routine commercial scale purposes.