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Published in final edited form as: Org Lett. 2024 May 10;26(20):4308–4313. doi: 10.1021/acs.orglett.4c01114

Manufacturing 6-[18F]Fluoro-L-DOPA via Flow Chemistry-Enhanced Photoredox Radiofluorination

Xuedan Wu 1, Wei Chen 2, Huaifu Deng 3, Li Wang 4, David A Nicewicz 5, Zibo Li 6, Zhanhong Wu 7
PMCID: PMC12145208  NIHMSID: NIHMS2082754  PMID: 38728659

Abstract

In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[18F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.0% radiochemical purity (RCP) and enantiomeric excess (ee), notably by a simple cartridge-based purification. The flow chemistry-enhanced photolabeling method supplies an efficient and versatile solution for the synthesis of 6-[18F]FDOPA and for more PET tracer development.

Graphical Abstract

graphic file with name nihms-2082754-f0003.jpg

Positron emission tomography (PET) is a powerful medical imaging tool that provides noninvasive, quantitative information about metabolic and biological processes in vivo. Fluorine-18 is the most widely used radioisotope in PET imaging, with relatively high image resolution.1,2 However, the short half-life and harsh fluorination conditions bifurcate 18F-fluorination strategies into late-stage labeling3,4 or early stage 18F-labeling of synthetic precursors followed by rapid multistep sequences to yield the desired radiotracers.1 There has been significant interest in developing novel methods to introduce 18F into (hetero)arenes, aiming to facilitate the discovery of new radiopharmaceuticals and PET agents of high imaging quality.5 More and more attention has been devoted to promoting the use of established radiochemistry methods and PET agents, bridging the gap between excellent basic science results and real clinical manufacturing in radiopharmaceutical sciences.5–7

6-[18F]FDOPA, an FDA-approved radiopharmaceutical agent, finds extensive use in PET imaging for visualizing and measuring dopaminergic neuron activity.8 Its application extends beyond managing neurologic disorders like Parkinson’s disease,9,10 with ongoing research and clinical trials in oncology.11–18 Given its advantageous diagnostic potential, since the 1980s, diverse methods have been developed for 6-[18F]FDOPA synthesis, each with unique advantages and limitations (Scheme S1).8,19 However, the complexity of current methods, involving expensive automated modules and HPLC instruments, impedes the widespread adoption of 6-[18F]FDOPA. Therefore, simplified synthetic protocols are still in high demand for the cGMP synthesis of 6-[18F]-FDOPA.20–25 To overcome the scope limitations of aryl 18F-fluorination, we recently developed several radiolabeling methods including direct C–H/C–18F activation,26 radio-deoxyfluorination,27 and direct halide/18F interconversion28 to construct C(sp2)–18F bonds in electron-rich (hetero)arene substrates via photocatalysis. In particular, the direct 19F/18F conversion method has held the potential to offer a simple and robust protocol for PET probe screening/preparation: this methodology not only immediately facilitated new PET agent discovery29 but also allowed for the simple and high-yield synthesis of the widely used PET agents including 6-[18F]FDOPA if more translational investigation could be followed.28 Therefore, the photoredox-mediated halide/18F interconversion strategy, as an innovative and powerful technique, could be used to prepare new and clinically relevant PET agents that are synthetically inaccessible or cumbersome to achieve by conventional methods if a practical radiosynthesis method was developed.29 We have been dedicated to utilizing this emerging radiochemistry method to produce valuable PET agents, such as 6-[18F]FDOPA, aiming to directly broaden its translational applications.

Recently, we found luminous flux was crucial in the C–H 18F-fluorination in a flow chemistry setting,30 which could be attributed to the increased external surface-to-volume ratio. Since its first report in 2004,31 flow chemistry has held the potential in radiochemistry to increase isolated radiochemical yields (RCYs), reduce reagent use, improve flexibility, and simplify the setup and purification process.32–37 Considering that flow chemistry is easy to automate and compatible with photochemistry and radiochemistry, we hypothesized that a simple applicable protocol could be developed for the preparation of 6-[18F]FDOPA and other 18F-labeled agents when flow chemistry is combined with photoredox radiolabeling (Figure 1).38,39 Here, we use 6-[18F]FDOPA as a working example to develop a practically useful radiolabeling approach that takes advantage of both chemistries for translational usage.

Figure 1.

Figure 1.

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An integration strategy for flow chemistry and photoredox radiochemistry.

To achieve our aim, there are a few limitations that need to be addressed. First, in our previously reported method for 6-[18F]FDOPA synthesis (Scheme S6b),28 the trapping-and-release approach is not compatible with full-batch photoredox radiolabeling due to the excess amount of tetrabutylammonium base used in the elution, leading to a diminished RCY (protocol A, Scheme S7). Our previous solution was to use a quaternary methylammonium (QMA)-free protocol B (Protocol B, Scheme S7) to avoid the use of excess base. However, the long half-life of metal impurities from cyclotron bombardment will complicate cGMP manufacturing, since it adds more quality control steps. Thus, to establish a practical protocol for the high-yielding photoredox radiolabeling method under the cGMP synthesis environment, the 18F elution issue must be first addressed. Second, an expensive laser was generally used as the light source to guarantee 18F-fluorination efficiency in our recent reports (Scheme S6b and Figure 1). An LED light would be much preferred if the RCY could be maintained. Third, a simple full open-to-air system was easily established in our photoredox radiolabeling methods research (Scheme S1a). However, it is not suitable for routine scale-up synthesis due to the potential risk of [18F]fluoride exposure. To tackle these challenges, we need a cGMP protocol utilizing an LED-irradiated reactor to maintain or enhance the labeling efficiency under optimized reaction conditions.

With multiple issues that need to be addressed, we started with the choice of a suitable LED reactor for photoredox radiofluorination. We expect that a suitable flow device could enhance the photoredox radiofluorination due to increased light flux. By adopting the reported 19F/18F exchange labeling conditions (Scheme 1), a series of flow reactors and setups including Q-cell, plastic chips, and flow-Q-cell were tested. After screening, we found that flow chemistry promoted the RCY under LED light irradiation compared with direct LED irradiation of the open-air radiolabeling setup (Table S1). The best flow device was the flow-Q-cell, where a peristaltic pump was used to circulate the reaction mixture for 30 min. The found RCY (54.0%, Table S1) though was still less than that for the reaction irradiated under a 450 nm laser source (68.0%, See Table S1), and we believe it would make a difference to further tune the radiolabeling conditions by using this flow-Q-cell device as a radiolabeling reactor for photoredox radiolabeling.

Scheme 1.

Scheme 1.

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Two-Step Radiolabeling Reactions for Validating the Viability of the Prepared [18F]Fluoride

At the same time, we were also exploring a practical approach to efficiently elute the trapped [18F]fluoride out of a QMA cartridge without decreasing the labeling yield thereafter. Trials were carried out with a variety of eluents and through various QMA cartridges. After exploration, a suitable elution protocol (protocol B, Scheme 2) was found to give an [18F]fluoride recovery rate over 90% and resulted in excellent RCYs for 6-[18F]FDOPA scale-up synthesis through photoredox radiofluorination. Initially, we tried to reduce synthesis time by investigating an aqueous-free elution method (refer to Table S2 for detailed study results).40 In a previous pure organic elution method for photoredox radiofluorination, a relatively large amount of tetrabutylammonium bicarbonate (TBAB) base (25 μL, 1.5 mg in MeCN) is also needed to ensure elution efficiency.30 On the contrary, photoredox radiolabeling is very sensitive to the basicity, so the chance of eliminating the drying step by using this aqueous-free elution strategy is rare.

Scheme 2.

Scheme 2.

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New Approaches to [18F]Fluoride ([18F]TBAF) for Photoredox Radiosynthesis

Instead of further optimizing the anhydrous elution conditions, we refocused on the aqueous eluent. In the existing eluent for full-batch [18F]fluoride (protocol A, Scheme S7), we observed that the organic solvent volume ratio can go up to 80%, and increasing it further could potentially increase the TBAB volume required for high 18F recovery.27,28 Subsequent elution tests with various TBAB, acetonitrile, and water combinations were conducted through a QMA cartridge (Waters, 130 mg of absorbent, chloride), as detailed in Table S3 in the SI. We found that 5–8 μL of TBAB (20 wt %) is sufficient for one photoredox reaction after direct drying.28 To optimize the volume of TBAB (20 wt %) needed to elute a QMA cartridge, we employed a two-portion strategy, aiming for a total volume of 10–16 μL. However, we found that an eluent with over 20 μL of TBAB aqueous content was necessary for optimal [18F]fluoride recovery, even with 90% water in the elution (Table S3). Consequently, we considered investigating a QMA cartridge with a less absorbent material for future studies.

We then identified a mini-QMA (MedChem Imaging, 24 mg absorbent, carbonate, Scheme 2a) containing much less sorbent than the normal QMA cartridges as a suitable candidate for our elution tests. Through similar elution tests, we established that the eluent formula boundary to achieve a good 18F recovery is 3.1 μL of TBAB (20 wt %) in a total volume of 115 μL with 35% water in the eluent (entry 5a in Table S4). As 5–8 μL of TBAB (20 wt %) was needed for one photoredox radiofluorination labeling reaction, a second eluent (3.1 μL, entry 5b in Table S4) was also applied to the same mini-QMA. With the eluent of 6.2 μL of TBAB (20 wt %) and subsequent [18F]TBAF, a significant increase in RCY was observed. The two-step RCY (decay corrected) could reach a competitive value of up to 56.6% under laser irradiation, compared to the previously reported non-decay-corrected HPLC isolation RCY (HI-RCY) value of 28.6 ± 4.9% within 100 min.28

After further enhancements to the labeling reaction setup through device screening (Table S1), the LED-irradiated flow chemistry proved highly efficient, as hypothesized, and was subsequently employed to confirm all subsequent elution tests. It was determined that 7–7.5 μL of TBAB (20 wt %) and 35% water in 232 μL of eluent could elute over 90% of 18F from the mini-QMA on average (see entries 7 and 8 in Table S4). Using the obtained [18F]fluoride, a cartridge-based isolation radiochemical yield (CI-RCY) of over 53.0% for 6-[18F]FDOPA was achieved (See Table S7 in the SI for a detailed study). A flow-Q-cell device (Scheme S2) significantly improved the RCY under LED irradiation and provided a safer closed system.

Although the photoredox radiofluorination protocol was successfully developed using mini-QMA, its application for producing PET agents for human doses is limited by the uncertified simplistic construction of mini-QMA. Nevertheless, the investigation and results have been promising, offering a solid foundation and clues for future exploration. Then, another light-QMA (Waters, 46 mg absorbent, carbonate, Scheme 2b) was identified and evaluated. Only when using over 13 μL of TBAB (20 wt %) in 800 μL of eluent (34.4% water) could close to 95% of 18F radioactivity be eluted from this light-QMA, resulting in an acceptable and promising photoredox radiolabeling RCY. Through additional tests with predictable modifications to increase [18F]fluoride recovery and lower TBAB amounts, a stable elution formula was established with a 91.9 ± 4.5% (n = 7) 18F− recovery rate and a reproducible CI-RCY of 49.0 ± 6.2% (n = 3) under the current optimal LED-flow photoredox fluorination for 6-[18F]FDOPA production (refer to entries 15–21 in Tables S5 and S6). Additionally, HPLC analysis confirmed over 98.0% radiochemical purity (RCP) and 99.0% enantiomeric excess (ee). When using the 18F− in the target water, the molar activity (Am) was determined to be 861 ± 117 MBq/μmol (n = 3) by analyzing the photoredox radiofluorination product (refer to Scheme S5 and the Am calculation in the SI), and Am values can be greatly improved by limiting the amount of the precursor or using scale-up [18F]fluoride,28 though Am has been found to make little difference in in vivo uptakes and imaging results,41 especially for neuroendocrine tumors.42 One remaining concern is the use of hydroiodic acid in the deprotection step, which is not ideal for radiosynthesis. To address this, we aim to explore alternative, milder acids and conditions. This will involve the modification of the protecting groups of the catechol moiety in the precursor. Further research will be conducted to refine this step.

Based on the optimized radiosynthesis conditions above, we then leveraged the method by using the full-batch [18F]fluoride (48.1 GBq to 70.3 GBq) from a single bombardment that would provide the 6-[18F]FDOPA product in a much higher radioactive dose (>11.0 GBq) in high CI-RCY (24.3%, n = 2, none-decay corrected) with over 99.0% RCP and ee. The photoredox radiofluorination reaction and the manufacturing production are listed in Figure 2. All other quality control analyses were also completed, and all results (See Table S8) met the criteria of 6-[18F]FDOPA for human use. In addition, the TBA cation and the photocatalyst residues were both below the detection limit (DL) when they were specially analyzed using Dragendorff’s reagent (DL, 100 μg/mL) and HPLC analysis (DL, 12.3 ng per run), respectively.

Figure 2.

Figure 2.

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(a) The synthesis of L-[18F]F-DOPA and radiolabeling setup (3D printed, provided by LED Radiofluidics Corp.) in a hot cell. (b) [18F]Fluoride preparation and radiolabeling process. (c) Deprotection and cartridge-based isolation for L-[18F]F-DOPA. aNon-decay-corrected CI-RCY, [18F]TBAF (48.1–70.3 GBq), n = 2; a detailed description of the radiolabeling procedure and reagents (S1–S10) can be found in the SI.

In conclusion, we successfully implemented a flow chemistry-enhanced photoredox radiofluorination method, effectively producing the PET agent (6-[18F]FDOPA) for clinical application. This demonstrates the feasibility of the recently developed photoredox radiolabeling methodology. Our advancements in [18F]fluoride preparation, labeling techniques, and purification processes have significantly supported the manufacturing process for clinical use. This protocol offers flexibility and simplicity for photoredox radiofluorination in manufacturing without the need for expensive automated modules or HPLC instruments. We believe that this refined photoredox-catalyzed radiolabeling technology can be swiftly adopted by both radiochemistry centers for radiopharmaceutical manufacturing and research laboratories for developing photoinduced radiolabeling technologies.

Supplementary Material

SI

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c01114.

Detailed radiochemistry procedures, radiosynthesis setups, radiochemistry optimization and screening results, and quality control data (PDF)

ACKNOWLEDGMENTS

We are thankful for the partial financial support from the National Institutes of Health (NIBIB) Grants R01EB029451 (Z.L. and D.A.N.) and 5R01CA233904 (Z.L.); SBIR Grant 1R43EB033720 (X.W.); UNC Lineberger Comprehensive Cancer Center (LCCC) pilot grant (Z.L. and D.A.N.), Grant 1S10OD023611 (Z.L.), and the startup fund from UNC Department of Radiology, Biomedical Research Imaging Center and UNC LCCC (Z.L.); and the National Institutes of Health (NIDDK) Grant 1R01DK128447-01A1 (Z.W.). We also sincerely thank Dr. Gerald T. Bida (UNC–CH) for assistance with the cyclotron operation.

Footnotes

The authors declare the following competing financial interest(s): The authors Z.L., D.A.N., and W.C. have filed a WO patent (patent applicant, The University of North Carolina at Chapel Hill, USA; inventors, Z. Li, D. Nicewicz, and W. Chen; patent no. WO 2020176804) related to the labeling methodology in this manuscript that is under review. Z.L. and D.A.N. are the co-founders of LED Radiofluidics. The author X.W. is currently working at LED Radiofluidics. The remaining authors declare no competing interests.

Complete contact information is available at: https://pubs.acs.org/10.1021/acs.orglett.4c01114

Contributor Information

Xuedan Wu, Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger, Comprehensive Cancer Center, University of North, Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, United States; LED Radiofluidics Corp., Chapel Hill, North, Carolina 27599, United States.

Wei Chen, Biomedical Research Imaging Center, Department, of Radiology, and UNC Lineberger Comprehensive Cancer, Center, University of North Carolina–Chapel Hill, Chapel, Hill, North Carolina 27599, United States.

Huaifu Deng, Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Li Wang, Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, United States.

David A. Nicewicz, Department of Chemistry, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27514, United States

Zibo Li, Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Zhanhong Wu, Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger, Comprehensive Cancer Center, University of North, Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI
NIHMS2082754-supplement-SI.pdf (2.9MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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