C-H radiocyanation of bioactive molecules via sequential iodination/copper-mediated cross-coupling

Area of Science:

• Radiochemistry
• Organic Synthesis
• Medicinal Chemistry

Background:

• Radiolabeling is crucial for molecular imaging and drug development.
• Existing methods for introducing Carbon-11 often require complex precursors or harsh conditions.
• Development of efficient C-H functionalization strategies for radiolabeling is highly desirable.

Purpose of the Study:

• To develop a novel, direct C-H radiocyanation reaction for electron-rich (hetero)aromatic compounds.
• To enable the synthesis of Carbon-11 labeled molecules using readily available starting materials.
• To demonstrate the applicability of the method to biologically relevant substrates.

Main Methods:

• The reaction involves a two-step sequence: C(sp2)-H iodination using N-iodosuccinimide followed by Copper-mediated radiocyanation with Potassium-11 cyanide.
• The method was applied to a range of electron-rich (hetero)aromatic substrates.
• Specific applications included nucleobases (uracil, cytosine), amino acids (tyrosine, tryptophan), and a peptide (LYRAGWRAFS).

Main Results:

• A net C-H radiocyanation reaction was successfully developed.
• The method efficiently transformed various (hetero)aromatic substrates into Carbon-11 labeled products.
• Selective radiocyanation was achieved at the tryptophan residue of the peptide LYRAGWRAFS.

Conclusions:

• The developed C-H radiocyanation reaction provides a straightforward route to Carbon-11 labeled (hetero)aromatic compounds.
• This method offers a valuable tool for synthesizing radiotracers for applications in molecular imaging and drug discovery.
• The selective functionalization of peptides demonstrates the potential of this approach for complex biomolecule labeling.