In‐loop flow [¹¹C]CO₂ fixation and radiosynthesis of N,N′‐[¹¹C]dibenzylurea

Abstract

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

Recent progress in [11C]carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) chemistry

“…N,N′-[ 11 C]Dibenzylurea was obtained in high decay-corrected radiochemical yield (RCY) of up to 72% and crude radiochemical purity (RCP) of up to 83% under ambient temperature and pressure within short synthesis time (<3 minutes from end of delivery [EOD]). 51 A very similar approach has been recently reported by Dahl et al to produce a diverse range of compounds, including [ 11 C]carbamates, [ 11 C]oxazolidinones, and [ 11 C]ureas in good decay-corrected RCYs (18%-50%) and high isolated RCPs (>99%). 52 This work together with the results presented by Downey et al demonstrates the utility of a simple and efficient "in-loop" [ 11 C]CO 2 trapping method allowing the reliable production of a diverse array of 11 C-products with minimal loss in radioactivity.…”

“…36,37 A similar approach has been also recently discovered for the synthesis of [ 11 C]amides via rapid addition of Grignard regents after Mitsunobu reaction, Scheme 10 (C). 49 Based on the potential of Mitsunobu reactions, a continuous-flow loop setup for [ 11 C]CO 2 trapping and [ 11 C] ureas synthesis has been recently presented by Downey et al 50,51 This work demonstrated the rapid and efficient [ 11 C]CO 2 trapping in DBU/amine solutions (average of 78%) at a high delivery flow rate (70 mL/min) within a low volume polymer loop (150 μL). This [ 11 C]CO 2 trapping system was integrated into a continuous-flow 11 Clabelling of a model symmetric urea, N,N′-[ 11 C] dibenzylurea via Mitsunobu reaction, Scheme 11.…”

“…This [ 11 C]CO 2 trapping system was integrated into a continuous‐flow 11 C‐labelling of a model symmetric urea, N,N′‐ [ 11 C]dibenzylurea via Mitsunobu reaction, Scheme . N,N′‐ [ 11 C]Dibenzylurea was obtained in high decay‐corrected radiochemical yield (RCY) of up to 72% and crude radiochemical purity (RCP) of up to 83% under ambient temperature and pressure within short synthesis time (<3 minutes from end of delivery [EOD]) …”

Rapid and Efficient Synthesis of 11C‐Labeled Benzimidazolones Using [11C]Carbon Dioxide

“…We next applied Mitsunobu reaction conditions for the transformation, since this had been recently applied for the efficient N‐ 11 C‐carbonylation of aromatic amines . Thus, following the literature method, the conversion of 3 a into [ 11 C] 4a was investigated in MeCN at 50 °C in the presence of DBU, followed by treatment with a mixture of di‐ tert ‐butyl azodicarboxylate (DBAD) and tri‐ n ‐butylphosphine ( n Bu 3 P).…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[32] This procedure was applied in the synthesis of abroad scope of bioactive molecules, [9,12] including [ 11 C]CURB,[ 11 C]PF-04457845, and [ 11 C]SL25.1188. [33,34] Another method to obtain unsymmetrical 11 C-labeled ureas under Mitsunobu conditions was developed by Gee and coworkers in 2013 (Scheme 4C2). [33,34] Another method to obtain unsymmetrical 11 C-labeled ureas under Mitsunobu conditions was developed by Gee and coworkers in 2013 (Scheme 4C2).…”