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Objectives: The trifluoromethyl group can improve physicochemical properties, such as metabolic stability, lipophilicity and pharmacokinetics of targeted probes. Radiolabeling by trifluoromethyl group is an attractive method to synthesize a useful PET probe. Recently, Haskali et al. have developed the synthetic method of [11C]fluoroform from [11C]CH4 with a CoF3 column and the application route of [11C]fluoroform for various trifluoromethylation reactions [1]. However, those application reactions were not automated and the synthesis of [11C]CF3-aryl derivatives is difficult because preparation of [11C]CuCF3 as a trifluoromethylation reagent was conducted in a glove box to avoid air and moisture. Herein, we developed a synthetic method of [11C]CF3-aryl derivatives using a fully-automated system equipped with [11C]CuCF3 without glove box.
Methods: [11C]Trifluoromethylation of aryl precursor was performed by using a fully-automated synthesis system (Scheme 1). [11C]Fluoroform was produced by passing [11C]CH4 through a column that was precoated with cobalt(III) fluoride (24 g) and heated at 350 oC. CuOtBu was generated by mixing t-BuOK (15 mol) with CuBr (5 mol) in DMF (0.3 mL) in a sealed vial under N2. Preparation of [11C]CuCF3 was performed by bubbling [11C]fluoroform into the CuOtBu solution at -45 oC. After the radioactivity of [11C]fluoroform reached a plateau, the reaction mixture was warmed to room temperature for 2 min and then added Et3N-3HF (0.82 L) in DMF (0.2 mL). The trifluoromethylation was performed by the reaction of [11C]CuCF3 with aryl precursor (10 mg) at room temperature or 130 oC for 5 min. After the preparative HPLC mobile phase (1.0 mL) was added, the reaction mixture was applied to the HPLC system for separation. The HPLC fraction of [11C]1 was directly collected in a vial. The radioactive product was analyzed by HPLC with radioactivity and UV-VIS detectors.
Scheme 1. Preparation of [11C]CuCF3 and synthesis of [11C]CF3-aryl derivatives
Results: We prepared CuOtBu without a glove box by carefully treating the all reaction reagents under N2. Reaction of aryl precursor and [11C]CuCF3 did not proceed because HF that was produced by the decomposition of CoF3 prevented the [11C]trifluoromethylation reaction. To solve this problem, we tested various Sep-Pak cartridges to trap HF. Of them, silica plus Sep-Pak cartridge completely removed HF. When using aryl boronic acid as a precursor, [11C]1 was synthesized in 3 ± 1% (n = 5) radiochemical yield from [11C]CH4 at the end of irradiation, with > 99% radiochemical purity. The average total synthesis time from the end of bombardment was 35 min.. On the other hand, when using aryl iodide as a precursor, [11C]1 was only obtained in trace amount. The application scope of [11C]trifluoromethylation is under investigation.
Conclusions: We succeeded in the [11C]trifluoromethylation of aryl precursors with [11C]CuCF3 using a full-automated system. We are currently optimizing reaction conditions to improve the radiochemical yield of [11C]1.
Acknowledgements: This research is supported by QST President’s Strategic Grant Exploratory Research.
The fully-automated synthesis of [11C]CF3-aryl derivatives with [11C]fluoroform
