Copper-Mediated Radiocyanation of Unprotected Amino Acids and Peptides

This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of [C-11]CN into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1-27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [C-11]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV > 1 at 60 min post injection), consistent with the known distribution of NOP receptors in the rhesus brain.

Automated summary

This report presents a copper-mediated radiocyanation method for aryl halides that can be applied to complex molecules. The reaction demonstrates a broad tolerance to various functional groups, including unprotected amino acids, making it possible to introduce [C-11]CN into specific sites of peptides. The use of a diamine-ligated copper(I) mediator is essential for achieving high radiochemical yield under mild conditions, while minimizing unwanted side reactions. The method has been successfully scaled and automated for the synthesis of radiolabeled peptides, and has been applied to the preparation of [C-11]cyano-NOP for biodistribution studies using positron emission tomography.