“In‐loop” carbonylation—A simplified method for carbon‐11 labelling of drugs and radioligands

Transition‐metal mediated carbonylation with (11)C‐labelled carbon monoxide ([(11)C]CO) is a versatile method for introducing (11)C (t (1/2) = 20.3 min) into drugs and radioligands for subsequent use in positron emission tomography (PET). The aim of the current study was to perform the (11)C‐carbonylation reaction on the interior surface of a stainless‐steel loop used for high performance liquid chromatography (HPLC). In the experimental setup, cyclotron produced (11)C‐labelled carbon dioxide ([(11)C]CO(2)) was converted to [(11)C]CO by reduction over heated Molybdenum and swept into an HPLC loop pre‐charged with the appropriate reaction mixture. Following a 5 min reaction, the radiochemical purity (RCP) and the trapping efficiency (TE) of the reaction mixture was determined. After optimization, [(11)C]N‐Benzylbenzamide was obtained in quantitative radiochemical yield (RCY) following a 5 min reaction at room temperature. The methodology was further applied to label [(11)C]benzoic acid (RCP≥99%, TE>91%), [(11)C]methyl benzoate (RCP≥99%, TE>93%) and [(11)C]phthalide (RCP≥99%, TE>88%). A set of pharmaceuticals was finally radiolabelled using non‐optimized conditions. Excellent yields were obtained for the histamine‐3 receptor radioligand [(11)C]AZ13198083, the oncology drug [(11)C]olaparib and the dopamine D2 receptor radioligand [(11)C]raclopride, whereas a moderate yield was observed for the high‐affinity dopamine D2 receptor radioligand [(11)C]FLB457. The presented “in‐loop” process proved efficient for diverse (11)C‐carbonylations, providing [(11)C]amides, [(11)C]esters and [(11)C]carboxylic acids in moderate to excellent RCYs. Based on the advantages associated with performing the radiolabelling step as an integrated part of the purification system, this methodology may become a valuable addition to the toolbox of methodologies used for (11)C‐carbonylation of drugs and radioligands for PET.