Cu-mediated Radiocyanation with [¹¹C]KCN for the Preparation of [¹¹C]LY2795050, a Selective Kappa Opioid Antagonist

Objectives: The ability to use the same precursor with multiple radioisotopes greatly expands the possibilities for potential imaging agents and provides a means to produce compound libraries from a common intermediate. Our objective was to expand our previously developed [¹⁸F]fluorination methodology of arylstannanes[1] to [¹¹C]cyanation and use the method to prepare [¹¹C]LY2795050, a selective kappa opioid antagonist[2].

Methods: For the non-isotopically modified method, all reagents were combined in a glovebox and allowed to stir at 100 °C for 15 min. After cooling to room temperature, yields were analyzed by NMR. For the radiochemistry, [¹¹C]benzonitrile derivatives were prepared in a TRACERlab FX_M from arylstannane precursor through an automated procedure based on adaptation of the previously reported [¹⁸F]fluorination synthetic route[1] and [¹¹C]HCN trap and elute technique[3]. [¹¹C]HCN was prepared and trapped on a platinum wire coated with 0.5 M KOH. To remove excess NH₃, vacuum was applied. The resulting [¹¹C]KCN was eluted with 1 mL of water, azeotropically dried with acetonitrile, and dissolved in the reaction solvent. Arylstannane precursor and copper pyridine complex were then added and heated to generate carbon-11 labeled product. The [¹¹C]cyano intermediate of [¹¹C]LY2795050 was then converted as previously reported to give the desired amide product[2].

Results: Preliminary studies show that 4-fluorobenzonitrile can be obtained in 48% ¹⁹F NMR yield in 15 min, and that [¹¹C]4-methoxybenzonitrile was obtained in 30% HPLC-RCY non-decay corrected. In the two step preparation of [¹¹C]LY2795050, the method was able to produce 38 mCi (9.5% HPLC-RCY; non-decay corrected from 400 mCi of [¹¹C]KCN) of desired product. In addition, the arylstannane precursor for LY2795050 could be fluorine-18 labeled in 9.4% HPLC-RCY non-decay corrected (see Figure).

Conclusion: We report a radiochemical method for synthesizing benzonitrile substrates and radiolabeling [¹¹C]benzonitrile substrates from [¹¹C]KCN, including [¹¹C]LY2795050. It is demonstrated that arylstanane precursors can be used for [¹⁸F]fluorination or [¹¹C]cyanation radiolabeling and give comparable yields. Future studies include exploring the scope of this transformation and improving the automation procedure. References: [1] Sanford, M. S.; Scott, P. J. H.; et. al. Org. Lett. 2016, 18, 5440-5443; [2] Zheng, M.; Huang, Y.; et. al. J. Nucl. Med. 2013, 54,455-463. [3] Carroll, V. N.; Shao, X.; et. al. Chem. Commun., 2016,52, 4888-4890. Research Support: This work was supported by the NIH (R01EB021155).

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