Rapid and mild synthesis of unsymmetrical [¹¹C]ureas from [¹¹C]carbonyl difluoride and amines

Objectives: Ureas are prevalent biologically active compounds. Many ureas labeled with carbon-11 (t_1/2 = 20.4 min) are therefore potentially useful for PET imaging. However, there is currently no versatile and reliable route for accessing a broad range of [carbonyl-¹¹C]ureas. Our aim was to investigate whether the novel building block [¹¹C]carbonyl difluoride ([¹¹C]COF₂) [1, 2] can be used for synthesizing acyclic unsymmetrical [¹¹C]ureas.

Methods: [¹¹C]CO was synthesized in 11‒12 min in 71 ± 2% (n = 37) yield by passing cyclotron-produced [¹¹C]CO₂ over molybdenum at 875 °C. [¹¹C]CO was then quantitatively converted into [¹¹C]COF₂ by passage over AgF₂ [1,2] and bubbled into a reaction vial holding an aniline (5-10 µmol) or ammonium tosylate (1-3 µmol) in acetonitrile with or without added pyridine. After introduction of all [¹¹C]COF₂ into the reaction vial (5.5 min from release of [¹¹C]CO), a second amine was added (1-10 µmol) and left for 1 min. The reaction mixture was analyzed with HPLC. The time from radionuclide production to HPLC injection was 18-20 min. Radiochemical yields of purified labeled products from starting [¹¹C]CO were calculated.

Results: Unsymmetrical [¹¹C]ureas from one aniline and one aliphatic amine or from two different aliphatic amines were all produced in excellent selectivity (>90%) over symmetrical [¹¹C]ureas, and in high radiochemical yields (typically 50-90%) via sequential amine addition. Use of a single aliphatic amine as precursor gave the symmetrical [¹¹C]urea. The reaction between [¹¹C]COF₂ and ammonium tosylates, as with anilines, stopped at the intermediate [¹¹C]isocyanate to which addition of a second amine yielded the unsymmetrical [¹¹C]urea. The methods proved compatible with a range of functional groups (e.g., hydroxyl, amide, amine, and carboxyl). Added pyridine was found to generally increase the yield of intermediate [¹¹C]isocyanates by improving the trapping efficiency of [¹¹C]COF₂. A structurally complex soluble epoxide hydrolase inhibitor AR-9281 was labeled in 80 ± 2% yield. Conclusion: This study demonstrates that [¹¹C]COF₂ can be used to efficiently and quickly synthesize acyclic unsymmetrical [¹¹C]ureas from a broad range of amines via intermediate [¹¹C]isocyanates. The room temperature reaction tolerates water well, is mild, and therefore compatible with a range of functional groups. The reaction provides excellent selectivity over symmetrical byproducts. Acknowledgements: This work was supported by the Intramural Research Program of the National Institutes of Health (NIMH; ZIA MH002793). References: [1] J. E. Jakobsson, S. Lu, S. Telu, V. W. Pike, Angew. Chem. Int. Ed. 2020. 59, 7256-7260. [2] J. E. Jakobsson, S. Lu, S. Telu, V. W. Pike, J. Nucl. Med. 2020, 61 (Suppl. 1), 136

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