Radiolabeling with [11C]HCN for Positron emission tomography

Hydrogen cyanide (HCN) is a versatile synthon for generating carbon‑carbon and carbon-heteroatom bonds. Unlike other one-carbon synthons (i.e., CO, CO₂), HCN can function as a nucleophile (as in potassium cyanide, KCN) and an electrophile (as in cyanogen bromide, (CN)Br). The incorporation of the CN motif into organic molecules generates nitriles, hydantoins and (thio)cyanates, which can be converted to carboxylic acids, aldehydes, amides and amines. Such versatile chemistry is particularly attractive in PET radiochemistry where diverse bioactive small molecules incorporating carbon-11 in different positions need to be produced. The first examples of making [¹¹C]HCN for radiolabeling date back to the 1960s. During the ensuing decades, [¹¹C]cyanide labeling was popular for producing biologically important molecules including ¹¹C-labeled α-amino acids, sugars and neurotransmitters. [¹¹C]cyanation is now reemerging in many PET centers due to its versatility for making novel tracers. Here, we summarize the chemistry of [¹¹C]HCN, review the methods to make [¹¹C]HCN past and present, describe methods for labeling different types of molecules with [¹¹C]HCN, and provide an overview of the reactions available to convert nitriles into other functional groups. Finally, we discuss some of the challenges and opportunities in [¹¹C]HCN labeling such as developing more robust methods to produce [¹¹C]HCN and developing rapid and selective methods to convert nitriles into other functional groups in complex molecules.