In‐loop flow [(11)C]CO(2) fixation and radiosynthesis of N,N′‐[(11)C]dibenzylurea

Cyclotron‐produced carbon‐11 is a highly valuable radionuclide for the production of positron emission tomography (PET) radiotracers. It is typically produced as relatively unreactive carbon‐11 carbon dioxide ([(11)C]CO(2)), which is most commonly converted into a more reactive precursor for synthesis of PET radiotracers. The development of [(11)C]CO(2) fixation methods has more recently enabled the direct radiolabelling of a diverse array of structures directly from [(11)C]CO(2), and the advantages afforded by the use of a loop‐based system used in (11)C‐methylation and (11)C‐carboxylation reactions inspired us to apply the [(11)C]CO(2) fixation “in‐loop.” In this work, we developed and investigated a new ethylene tetrafluoroethylene (ETFE) loop‐based [(11)C]CO(2) fixation method, enabling the fast and efficient, direct‐from‐cyclotron, in‐loop trapping of [(11)C]CO(2) using mixed DBU/amine solutions. An optimised protocol was integrated into a proof‐of‐concept in‐loop flow radiosynthesis of N,N′‐[(11)C]dibenzylurea. This reaction exhibited an average 78% trapping efficiency and a crude radiochemical purity of 83% (determined by radio‐HPLC), giving an overall nonisolated radiochemical yield of 72% (decay‐corrected) within just 3 minutes from end of bombardment. This proof‐of‐concept reaction has demonstrated that efficient [(11)C]CO(2) fixation can be achieved in a low‐volume (150 μL) ETFE loop and that this can be easily integrated into a rapid in‐loop flow radiosynthesis of carbon‐11–labelled products. This new in‐loop methodology will allow fast radiolabelling reactions to be performed using cheap/disposable ETFE tubing setup (ideal for good manufacturing practice production) thereby contributing to the widespread usage of [(11)C]CO(2) trapping/fixation reactions for the production of PET radiotracers.