No-Carrier-Added Electrochemical Radio-Fluorination of Thioethers Academic Article uri icon

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abstract

  • Positron emission tomography (PET) is a powerful molecular imaging method for biomedical research such as cancer research, visualizing enzyme activity and receptor occupancy.1–3 Fluorine-18 is the most frequently used PET-radionuclide in both preclinical research and clinical applications due to its ideal half-life (t1/2 = 109.8 min, 97% β + decay), low positron energy and the possibility to obtain the radioisotope in high activities and in high no-carrier-added specific activities. One drawback is the late stage fluorination of molecules that possess a high electron density, which presents a challenge due to the disadvantaged interaction between a negatively charged fluoride and an electron rich reaction center. Electrochemical 18F-fluorination of organic compounds provides a means to synthesize Positron-Emission-Tomography (PET) tracers difficult to obtain otherwise.4–7 Electrochemical oxidation can create an electron-poor carbon, preparing the organic molecules for nucleophilic fluorination. However, previously reports on electrochemical fluorination of the organic molecules have used a high concentration of fluoride which is not desired for radio-fluorination. A high concentration of fluoride introduces carrier [19F] to the minute concentrations of [18F]-labeled radiotracers, reducing molar activity and their imaging efficacy.4,6,7 In our previous study, where acetonitrile was used as solvent, we showed that decreasing concentration of [19F] resulted in a drastic drop in the fluorination yield, rendering no-carrier-added radio-fluorination impossible with this approach.8 In this study, for the first time, we demonstrate no-carrier-added electrochemical radio-fluorination of organic molecules with a thioether moiety such as (phenylthio)acetonitrile, diethyl phenylthiomethylphosphonate, 2-(phenylthio)acetamide, methyl 2-(ethylsulfanyl)acetate, methyl (methylthio)acetate and methyl (phenylthiol)acetate, using 2,2,2-trifluoroethanol (TFE) as solvent instead of acetonitrile. Figure 1 shows the proposed fluoro-Pummerer type mechanism of no-carrier-added electrochemical radio-fluorination of thioethers where AuxO- is the conjugate base of TFE. A scope study with several thioether compounds was performed and radiochemical fluorination efficiency (RCFE) of up to 95 %, was obtained for methyl 2-(ethylsulfanyl)acetate and methyl (methylthio)acetate. Electrochemical radio-fluorinations were performed using an undivided cell and applying constant potential. Synthesis parameters such as oxidation potential, temperature, type of the solvent, supporting electrolyte concentration and precursor concentration were optimized. It was found that increasing temperature can enhance the RCFE. The products were characterized using gas chromatography–mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), radio-thin-layer chromatography (radio-TLC) and high-performance liquid chromatography (HPLC). Figure 1. Proposed mechanism of the no-carrier-added electrochemical 18F-fluorination of thioethers (AuxOH = auxiliary reagent). References Stenhagen, I. S. R. et al. [18F]fluorination of an arylboronic ester using [18F]selectfluor bis(triflate): application to 6-[18F]fluoro-L-DOPA. Chem. Commun. Camb. Engl. 49, 1386–1388 (2013). Phelps, M. E. Positron emission tomography provides molecular imaging of biological processes. Proc. Natl. Acad. Sci. U. S. A. 97, 9226–9233 (2000). Clinical PET and PET/CT | H. Jadvar | Springer. Waldmann, C. M., Lebedev, A., Allison, N. & Sadeghi, S. An automated synthesizer for electrochemical (18)F-fluorination of organic compounds. Appl. Radiat. Isot. Data Instrum. Methods Use Agric. Ind. Med. 127, 245–252 (2017). Sawamura, T., Takahashi, K., Inagi, S. & Fuchigami, T. Electrochemical Fluorination Using Alkali-Metal Fluorides. Angew. Chem. Int. Ed. 51, 4413–4416 (2012). Yin, B., Inagi, S. & Fuchigami, T. Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts. Beilstein J. Org. Chem. 11, 85–91 (2015). Fuchigami, T. & Inagi, S. Selective electrochemical fluorination of organic molecules and macromolecules in ionic liquids. Chem. Commun. 47, 10211–10223 (2011). Balandeh, M. et al. Electrochemical Fluorination and Radiofluorination of Methyl(phenylthio)acetate Using Tetrabutylammonium Fluoride (TBAF). J. Electrochem. Soc. 164, G99–G103 (2017). Figure 1

publication date

  • April 13, 2018