Synthesis of l ‐[4‐ 11 C]Asparagine by Ring‐Opening Nucleophilic 11 C‐Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon‐11‐labeled AAs given the short half‐life of carbon‐11 ( 11 C, t 1/2 =20.4 min). A facile synthetic pathway to prepare enantiomerically pure 11 C‐labeled l ‐asparagine was developed using a partially protected serine as a starting material with a four‐step transformation providing a chiral five‐membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X‐ray crystallography. Utilizing a [ 11 C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l ‐[4‐ 11 C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two‐step method for synthesizing l ‐[4‐ 11 C]asparagine was presented: within a 45±3 min ( n =5, from end‐of‐bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69±4 % ( n =5) and overall two‐step radiochemical yield of 53±2 % ( n =5) based on starting [ 11 C]HCN, and with radiochemical purity of 96±2 % ( n =5).