In-loop flow [C-11]CO2 fixation and radiosynthesis of N,N-[C-11]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 ([C-11]CO2), which is most commonly converted into a more reactive precursor for synthesis of PET radiotracers. The development of [C-11]CO2 fixation methods has more recently enabled the direct radiolabelling of a diverse array of structures directly from [C-11]CO2, and the advantages afforded by the use of a loop-based system used in C-11-methylation and C-11-carboxylation reactions inspired us to apply the [C-11]CO2 fixation in-loop. In this work, we developed and investigated a new ethylene tetrafluoroethylene (ETFE) loop-based [C-11]CO2 fixation method, enabling the fast and efficient, direct-from-cyclotron, in-loop trapping of [C-11]CO2 using mixed DBU/amine solutions. An optimised protocol was integrated into a proof-of-concept in-loop flow radiosynthesis of N,N-[C-11]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 3minutes from end of bombardment. This proof-of-concept reaction has demonstrated that efficient [C-11]CO2 fixation can be achieved in a low-volume (150L) 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 [C-11]CO2 trapping/fixation reactions for the production of PET radiotracers.