Efficient 11C-Cyanation of Electron-Rich Arenes via Organic Photoredox Catalysis

Introduction: Carbon-11 is one of the most commonly used positron-emitting isotopes for PET imaging. Although there are some reports on developing PET agents based on alkyl ¹¹C-nitriles, radio-cyanation of arenes, particularly electron-rich arenes, has not been well explored and developed. Based on the photoredox method, here, we report a mild and efficient radiocyanation method that can be used to produce novel PET agents quickly with good radiochemical yield (RCY).

Methods: Different organic photocatalysts were first screened using non-radioactive ¹²C chemistry. The established novel cyanation methods were then tested using TBA⁺[¹¹C]CN^–. The reaction scope was evaluated by testing over 100 different substrates and the yields were determined by radio HPLC analysis. Scale-up ¹¹C-cyanations were performed. Post-functionalization such as hydrolysis and deprotection was also designed and conducted to obtain the most useful and promising ¹¹C-labeled PET agents.

Results: Among the screened catalysts, Riboflavin tetraacetate (RFTA, S1) gave moderate to high RCYs (up to 90%) for electron-rich substrates. Demethoxyl radiocyanation was the major product among the screened substrates. Direct C-H radiocyanation was also observed in some of the substrates. Bioactive drug derivatives (such as guanidine, troxipide, podophyllotoxin, and trimethoprim) were prepared in 20-95% RCYs as potential ¹¹C-PET agents. The yield in scale-up ¹¹C-cyanations was maintained and post-functionalization such as hydrolysis and deprotection was also conducted with good RCYs. While acridinium (S2) catalyst affords lower yields but lends a broader substrate scope.

Conclusions: The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. The newly developed reaction can serve as a powerful tool for generating new PET agents. It also holds the potential to generate ^13/14C labeled agents.

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