"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 (t1/2 = 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]CO2 ) 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.