Simple synthesis and use of [¹¹C]carbonyl difluoride for the intracyclic labeling of heterocycles

Objectives: Methods for the intracyclic labeling of heterocycles with carbon-11 (t_1/2 = 20.4 min) have garnered considerable interest, and various methods with differing scope, advantages, and limitations have been developed based on direct use of [¹¹C]carbon dioxide, [¹¹C]carbon monoxide, or [¹¹C]phosgene.^[1] Further simplified and efficient methods are desirable. Here we explored the synthesis of a new labeling synthon, [¹¹C]carbonyl difluoride ([¹¹C]COF₂), and its utility for the intracyclic labeling of heterocycles.

Methods: [¹¹C]CO was synthesised from cyclotron-produced [¹¹C]CO₂ as described by Zeisler et al.^[2] We passed [¹¹C]CO in a helium stream over AgF₂^[3] and led the radioactive effluent into 1,2-diaminobenzene (1) solution. [¹¹C]1,3-Dihydro-2H-benzo[d]imidazol-2-one ([¹¹C]2) was produced, implying that [¹¹C]COF₂ had been produced. We investigated how much AgF₂ was required to achieve optimal yield of [¹¹C]2 and further optimized the reaction to use only 0.25 mg of 1 in acetonitrile. We tested a wide range of other precursors for similar ring-closing reactions with [¹¹C]COF₂. We reported radiochemical yields (RCY) from [¹¹C]CO based on recovery of the desired labeled heterocycle from the HPLC purification of a reaction mixture aliquot. Results: [¹¹C]COF₂ was obtained in quantitative yield from [¹¹C]CO when using at least 0.4 g of AgF₂. Several [carbonyl-¹¹C]heterocycles were labeled rapidly at room temperature in high RCYs and with excellent radiochemical purities. A prominent β-adrenoceptor radioligand, [¹¹C](S)-CGP12177, was produced in 72 ± 15% RCY and with a molar activity of 218 ± 58 GBq/µmol. Conclusion: This study demonstrates the simple synthesis and use of [¹¹C]COF₂ for the intracyclic labeling of heterocycles. The high reproducibility and efficiency of [¹¹C]COF₂ synthesis and of its incorporation into ¹¹C-carbonyl heterocycles renders it to be a very attractive labeling synthon for implementation in regular radiotracer synthesis. Acknowledgements: This work was supported by the Intramural Research Program of the National Institutes of Health (NIMH; ZIA MH002793). References: [1] S. Lu, F. G. Siméon, S. Telu, L. Cai, V. W. Pike, Adv. Het. Chem. In press. [2] S. K. Zeisler, M. Nader, A. Theobald, F. Oberdorfer, Appl Radiat Isot. 1997, 48, 1091. [3] O. V. Ruff, G. Miltschitzky, Z. Anorg. Allg. Chem. 1934, 221, 154.