Journal of Chemistry

Journal of Chemistry / 2018 / Article

Research Article | Open Access

Volume 2018 |Article ID 7641304 | 4 pages |

Direct Incorporation of [11C]CO2 into Asymmetric [11C]Carbonates

Academic Editor: Zhen Cheng
Received31 Jul 2018
Revised13 Oct 2018
Accepted22 Oct 2018
Published10 Dec 2018


A novel carbon-11 radiolabelling methodology for the synthesis of the dialkylcarbonate functional group has been developed. The method uses cyclotron-produced short-lived [11C]CO2 (half-life 20.4 min) directly from the cyclotron target in a one-pot synthesis. Alcohol in the presence of base trapped [11C]CO2 efficiently forming an [11C]alkylcarbonate intermediate that subsequently reacted with an alkylchloride producing the di-substituted [11C]carbonate (34% radiochemical yield, determined by radio-HPLC) in 5 minutes from the end of [11C]CO2 cyclotron delivery.

1. Introduction

Positron emission tomography (PET) is an imaging technique able to detect and monitor specific target proteins in vivo [15]. The use of PET imaging has advanced in the last few decades to become a valuable tool in clinical diagnostics, medical research, and drug discovery [68]. PET relies on the use of tracer amounts of imaging probes (radiotracers). The administration of radiotracers allows the biochemical process to be imaged and quantified in vivo without manifestation of pharmacological or toxicological effects [913].

Carbon-11 (11C) is one of the most common radionuclides used for the synthesis of PET radiotracers. The short half-life of 11C (20.4 min) makes it an attractive radionuclide as it enables the collection of a sufficient amount of PET data while keeping the subject radiation dose and exposure time to minimum. Furthermore, it allows orthologous substitution with carbon-12 in biologically active molecules with no alteration of the parent molecule’s physicochemical and pharmacological properties. Carbon-11 is commonly produced in the form of [11C]carbon dioxide ([11C]CO2) [14, 15]. [11C]CO2 is usually converted into more reactive secondary precursors such as [11C]methyl iodide ([11C]CH3I), [11C]carbon monoxide ([11C]CO), and [11C]phosgene ([11C]COCl2) [1619]. As these multistep conversion processes are time-consuming, the use of [11C]CO2 for directly radiolabelling functional groups is highly attractive.

[11C]CO2 is a weak electrophile with an affinity for electron-donating reagents such as amines and organometallics [20]. However, due to the thermodynamic and kinetic properties of [11C]CO2, it has high activation energy which requires the use of highly reactive reagents, temperatures, pressures, or the presence of a catalyst [2123]. Nevertheless, the primary synthon, [11C]CO2, has been deployed successfully for the synthesis of 11C-compounds that contain carbonyl groups such as [11C]carbamates [24, 25], amide [26], and [11C]ureas [23, 2729]. However, the radiolabelling of the carbonyl group of carbonates from [11C]CO2 has not yet been established. To date, the synthesis of [11C]carbonates has relied on the use of [11C]COCl2 which is produced from a multistep process starting from cyclotron-produced [11C]CO2 or [11C]CH4, conversion to [11C]CCl4 and then to [11C]COCl2 [30, 31]. Although this 11C-carbonate reaction is rapid and efficient, routine production of [11C]COCl2 requires multistep syntheses and specialized equipment, thereby restricting its widespread use [30, 31].

As the carbonate functional group is found in prodrug compounds as well as being an intermediate in organic synthesis [3235], we aimed at developing a simple and robust radiolabelling methodology that uses [11C]CO2 for the synthesis of [11C]carbonates. Here we present a rapid, one-pot radiosynthetic strategy using [11C]CO2 directly from the cyclotron, avoiding the need for specialized equipment and multistep syntheses.

2. Materials and Methods

All purchased chemicals were used without further purification. Chemicals were purchased in highest available purity from Sigma-Aldrich and Alfa Aesar and used as received (>99 % purity). All solvents were purchased as anhydrous in highest available purity (>99.8 % purity) from Sigma-Aldrich.

[11C]CO2 was produced by a Siemens RDS112 cyclotron (St Thomas’ Hospital, London, United Kingdom) via the 14N(p,α)11C nuclear reaction. Typical irradiation time for exploratory work was 1 minute, 10 µA, bombardment typically yielding ca. 300 MBq [11C]CO2 at end of cyclotron bombardment. Radiolabelling reactions were performed in a 1.5 mL screw top vial with a “V” internal shape. HPLC analysis was performed on an Agilent 2060 Infinity HPLC system with a variable wavelength detector (254 nm was used as default wavelength) [10] An Agilent Eclipse XDB-C18 reverse-phase column (4.6 × 150 mm, 5 µm) was used at a flow rate of 1 mL/min and H2O/MeOH (HPLC-grade solvents with 0.1 % TFA) gradient elution (flow rate: 1 mL/min, 0–2 min: 5 % MeOH, 2–11 min: 5 to 95% MeOH linear gradient, 11–13 min: 90 % MeOH, 13–14 min: 90% to 5% MeOH linear gradient, and 14–15 min: 5 % MeOH). The RCY was estimated by radio-HPLC and defined as the area under the 11C-product peak expressed as a percentage of the total 11C labelled peak areas observed in the chromatogram. Molar radioactivity was calculated from analytical HPLC sample of 25 μL. A calibration curve of known mass quantity versus HPLC peak area (254 nm) was used to calculate the mass concentration of the 25 μL radiolabelled compound. The identity of the radiolabelled compound peak was confirmed by HPLC coinjection of a nonradioactive reference compound and yielded a single peak.

3. Results and Discussion

As the starting point, we selected the method developed by Salvatore et al. [2123] (Figure 1) for the synthesis of carbonates. The established method used nonradioactive CO2, an alcohol derivative, and benzylchloride (BzCl) in the presence of Cs2CO3, TBAI in DMF to produce the corresponding carbonate derivative efficiently. By substituting CO2 with [11C]CO2 and applying the same reaction conditions, the synthesis of di-substituted [11C]carbonates was investigated.

[11C]CO2 was trapped in isopropyl alcohol in the presence of Cs2CO3, forming an [11C]isopropylcarbonate intermediate that subsequently reacted with BzCl to produce [11C]benzyl isopropyl carbonate ([11C]1) in a moderate radiochemical yield (RCY). The RCY is the nonisolated radiochemical yield determined by radio-HPLC analysis of the crude product of 24% (Table 1, entry 1). Interestingly, almost all the cyclotron-produced [11C]CO2 was trapped within the reaction mixture at room temperature (>95%); any unreacted radioactive [11C]CO2 was immobilized on an ascarite trap connected to the vial vent needle. The trapping efficiency is the amount of radioactivity trapped in the reaction vial as a percentage of the overall radioactivity produced by the cyclotron.

EntryaBaseTrapping efficiency (%)Temperature (°C)SolventRCY (%)b

11cCs2CO3>95%100DMF82, 74

aReaction conditions: isopropanol (22 µmol), Cs2CO3 (66 µmol), TBAI (66 µmol), and organohalide (66 µmol) in 500 µL DMF, 10 mins from end of delivery (EOD) (). bThe nonisolated radiochemical yield determined by radio-HPLC analysis of the crude product. c.

In an attempt to increase the RCY, Cs2CO3 was replaced with Cs2SO4 (Table 1, entry 2). The trapping efficiency of [11C]CO2 dropped significantly from 95.2% to 1.5%. Since Cs2CO3 contributed towards the trapping of [11C]CO2 efficiently, we investigated whether the Cs+ or the CO32- ion was responsible for the high [11C]CO2-trapping efficiency. Of a number of caesium bases explored (Table 1, entries 3–5), CsI and CsF trapped only minute amounts of [11C]CO2 (4% and 34%, respectively), indicating that the basicity of the reaction mixture had a major effect on trapping efficiency. These results can be explained by the ability of a strong base to deprotonate the alcohol present in the reaction mixture enabling it to react with [11C]CO2 to form a 11C radiolabelled intermediate. The importance of CO32− was then explored by comparing Cs2CO3 with other carbonate bases (K2CO3 and CaCO3, Table 1, entries 6 and 7). The trapping efficiencies were extremely low for both reagents. High trapping in the reaction mixture with Cs2CO3 is therefore most likely due to its superior solubility in organic solvents.

In a further attempt to increase the RCY of [11C]1, a number of aprotic solvents were screened (CH3CN and DMSO, Table 1, entries 8 and 9). However, these solvents did not produce [11C]1, and the trapping efficiency was poor (20% and 65%, respectively). Reaction dependency on temperature was subsequently examined. The RCY of [11C]1 improved from 24% to 33% by increasing the reaction temperature from 25°C to 65°C (Table 1, entry 10). Increasing the temperature to 100°C promoted the product formation and resulted in the highest observed RCY (82%, Table 1, entry 11). This might be rationalised by an increase in Cs2CO3 solubility at higher temperatures. However, due the presence of Cs2CO3 as a reagent, low molar activities (Am) were observed. The low Am (2 GBq/μmol in this case) is likely due to release of nonradioactive CO2 from Cs2CO3. CO32− deprotonates the alcohol to form HCO3, which at high temperature has the potential to decompose releasing nonradioactive CO2 causing isotopic dilution and low Am of the [11C]CO2. We therefore focused on improving Am by substituting Cs2CO3 with an alternative base.

1,8-diazabicyclo[5.4.0]undecene (DBU) is a basic amine that has been shown to retain [11C]CO2 in organic solutions [26]. Replacing Cs2CO3 with DBU (Table 2, entry 1) resulted in [11C]1 formation, but with low RCY (6%). The low RCY could be due to DBU being unable to deprotonate isopropyl alcohol efficiently. We opted for a stronger base, NaH, which was able to deprotonate the isopropyl alcohol. Using a ratio of 1 : 1 NaH : isopropanol (equiv.) at 100°C, [11C]1 was obtained with an RCY of 26% (Table 2, entry 3). Decreasing the temperature from 100°C to 60°C slightly improved the RCY (31%, Table 2, entry 4). [11C]1 was produced with a molar activity (Am) of 10–20 GBq/µmol. This is because short cyclotron bombardments (1 minute) and low beam currents (5–10 µA) were used (0.3 GBq). In clinical productions at our facility, cyclotron bombardment times of 50 minutes and beam currents of 30 µA are used to produce higher amounts of radioactivity (typically 60 GBq). It is therefore estimated that this would increase the Am to > 50 GBq/µmol at end of synthesis. Decreasing the ratio of NaH : isopropanol (from 1 : 1 to 0.5 : 1) reduced the RCY further to 18% (Table 2, entry 5). Increasing the ratio NaH :isopropanol 2 : 1 did not produce the target product (Table 2, entry 6). Increasing the amount of TBAI to 3 equiv. or removing it completely also did not improve the RCY (Table 2, entries 7 and 8).

EntryaBase (eq)TBAI (eq)Temp (°C)RCY (%)b

1cDBU (3)31006
2cDBU (3)1000
3NaH (1)110026
4dNaH (1)16031 ± 2
5cNaH (0.5)16018
6NaH (2)1600
7cNaH (0.5)606
8NaH (1)3607

aIsopropanol (1 equiv., 22 µmol), BzCl (3 equiv.), TBAI (1–3 equiv.), and base (1–3 equiv.) in 500 μL DMF reaction time 5 mins from EOD. bThe nonisolated radiochemical yield determined by radio-HPLC analysis of the crude product. cReaction time of 10 mins from EOD.d.

4. Conclusions

In conclusion, we have developed a radiolabelling methodology for the synthesis of [11C]carbonates using [11C]CO2 directly from the cyclotron. The carbonate [11C]1 was synthesized by bubbling [11C]CO2 into a solution containing alkylchloride, alcohol, and a base in DMF. The choice of the base was critical for maximising the RCY and Am. The first protocol uses Cs2CO3 and produces the target 11C radiolabelled product in a high RCY and low Am. The second strategy, which uses NaH, produced [11C]1 in high Am and moderate RCY. These methodologies are a simple and practical alternative to 11C-phosgene for the synthesis of 11C-carbonates. 11C-phosgene synthesis is technically challenging to implement and requires the use of specialist equipment. The developed strategies described here use readily available labware and converts [11C]CO2 directly to [11C]carbonates in rapid synthesis times.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

Abdul Karim Haji Dheere and Salvatore Bongarzone contributed equally to this work.


This work was supported by the Medical Research Council (MRC; MR/K022733/1) and the European Commission, FP7-PEOPLE-2012-ITN (316882; RADIOMI). The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust and the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC under grant number WT 088641/Z/09/Z.


  1. P. Miller, N. Long, R. Vilar, and A. Gee, “Synthesis of 11C,18F,15O, and 13N radiolabels for positron emission tomography,” Angewandte Chemie International Edition, vol. 47, no. 47, pp. 8998–9033, 2008. View at: Publisher Site | Google Scholar
  2. S. Gambhir, “Molecular imaging of cancer with positron emission tomography,” Nature Reviews Cancer, vol. 2, no. 9, pp. 683–693, 2002. View at: Publisher Site | Google Scholar
  3. K. Kazuo, “From tumor biology to clinical PET: a review of positron emission tomography (PET) in oncology,” Annals of Nuclear Medicine, vol. 15, no. 6, pp. 471–486, 2001. View at: Publisher Site | Google Scholar
  4. L. Zibo and P. Conti, “Radiopharmaceutical chemistry for positron emission tomography,” Advanced Drug Delivery Reviews, vol. 62, no. 11, pp. 1031–1051, 2010. View at: Google Scholar
  5. N. Oriuchi, T. Higuchi, T. Ishikita et al., “Present role and future prospects of positron emission tomography in clinical oncology,” Cancer Science, vol. 97, no. 12, pp. 1291–1297, 2006. View at: Publisher Site | Google Scholar
  6. P. Caroli, C. Nanni, D. Rubello, A. Alavi, and S. Fanti, “Non-FDG PET in the practice of oncology,” Indian Journal of Cancer, vol. 47, no. 2, pp. 120–125, 2010. View at: Publisher Site | Google Scholar
  7. J. Fowler and D. J. Nora, “PET imaging studies in drug abuse,” Journal of Toxicology: Clinical Toxicology, vol. 36, no. 3, pp. 163–174, 1998. View at: Publisher Site | Google Scholar
  8. K. Herholz and D. Heiss, “Positron emission tomography in clinical neurology,” Molecular Imaging & Biology, vol. 6, no. 4, pp. 239–269, 2004. View at: Publisher Site | Google Scholar
  9. A. Gee, “Neuropharmacology and drug development,” British Medical Bulletin, vol. 65, no. 1, pp. 169–177, 2003. View at: Publisher Site | Google Scholar
  10. L. Cai, R. Innis, and V. Pike, “Radioligand development for PET imaging of β-amyloid (Aβ)-current status,” Current Medicinal Chemistry, vol. 14, no. 1, pp. 19–52, 2007. View at: Publisher Site | Google Scholar
  11. A. Nordberg, “PET imaging of amyloid in alzheimer’s disease,” The Lancet Neurology, vol. 3, no. 9, pp. 519–527, 2004. View at: Publisher Site | Google Scholar
  12. E. Aboagye, P. Price, and T. Jones, “In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography,” Drug Discovery Today, vol. 6, no. 6, pp. 293–302, 2001. View at: Publisher Site | Google Scholar
  13. A. Lingford-Hughes, A. Reid, J. Myers et al., “A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions,” Journal of Psychopharmacology, vol. 26, no. 2, pp. 273–281, 2012. View at: Publisher Site | Google Scholar
  14. M. Quade, P. Rowland, D. Lewis, and J. M. Welch, “Positron-emitting isotopes produced on biomedical cyclotrons,” Current Medicinal Chemistry, vol. 12, no. 7, pp. 807–818, 2005. View at: Publisher Site | Google Scholar
  15. B. Rotstein, S. Liang, J. Holland et al., “11CO2 fixation: a renaissance in PET radiochemistry,” Chemical Communications, vol. 49, no. 50, pp. 5621–5629, 2013. View at: Publisher Site | Google Scholar
  16. J. Atack, P. Scott-Stevens, J. Beech et al., “Comparison of Lorazepam [7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one] occupancy of rat brain-aminobutyric acid a receptors measured using in vivo [3H]flumazenil (8-Fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl Ester) binding and [11C]flumazenil micro-positron emission tomography,” Journal of Pharmacology and Experimental Therapeutics, vol. 320, no. 3, pp. 1030–1037, 2007. View at: Publisher Site | Google Scholar
  17. J. Chung, Y. Kim, S. Kim et al., “Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo-or isometabolic on 18F-FDG PET,” European Journal of Nuclear Medicine and Molecular Imaging, vol. 29, no. 2, pp. 176–182, 2002. View at: Publisher Site | Google Scholar
  18. R. J. Bolton, “Isotopic methylation,” Journal of Labelled Compounds and Radiopharmaceuticals, vol. 44, no. 10, pp. 701–736, 2001. View at: Publisher Site | Google Scholar
  19. C. Child, S. Kealey, H. Jones et al., “Binding and photodissociation of CO in iron(ii) complexes for application in positron emission tomography (PET) radiolabelling,” Dalton Transactions, vol. 40, no. 23, pp. 6210–6215, 2011. View at: Publisher Site | Google Scholar
  20. O. Kreye, H. Mutlu, and M. Meier, “Sustainable routes to polyurethane precursors,” Green Chemistry, vol. 15, no. 6, pp. 1431–1455, 2013. View at: Publisher Site | Google Scholar
  21. Z. Yang, L. He, J. Gao, A. Liu, and B. Yu, “Carbon dioxide utilization with C–N bond formation: carbon dioxide capture and subsequent conversion,” Energy & Environmental Science, vol. 5, no. 5, pp. 6602–6639, 2012. View at: Publisher Site | Google Scholar
  22. R. N. Salvatore, F. Chu, A. S. Nagle, E. A. Kapxhiu, R. M. Cross, and K. W. Jung, “Efficient Cs2CO3-promoted solution and solid phase synthesis of carbonates and carbamates in the presence of TBAI,” Tetrahedron, vol. 58, no. 17, pp. 3329–3347, 2002. View at: Publisher Site | Google Scholar
  23. A. Mossine, A. Brooks, I. Jackson et al., “Synthesis of diverse 11C-Labeled PET radiotracers via direct incorporation of [11C]CO2,” Bioconjugate Chemistry, vol. 27, no. 5, pp. 1382–1389, 2016. View at: Publisher Site | Google Scholar
  24. J. Hooker, A. Reibel, S. Hill, M. Schueller, and J. Fowler, “One-Pot, direct incorporation of [11C]CO2into CARBAMATES,” Angewandte Chemie International Edition, vol. 48, no. 19, p. 3482, 2009. View at: Publisher Site | Google Scholar
  25. A. Wilson, S. Houle, and N. Vasdev, “Direct fixation of [11C]-CO2by amines: formation of [11C-carbonyl]-methylcarbamates,” Organic and Biomolecular Chemistry, vol. 8, no. 2, pp. 428–432, 2010. View at: Publisher Site | Google Scholar
  26. S. Bongarzone, A. Runser, C. Taddei, A. Haji Dheere, and A. Gee, “From [11C]CO2 to [11C]amides: a rapid one-pot synthesis via the Mitsunobu reaction,” Chemical Communications, vol. 53, no. 38, pp. 5334–5337, 2017. View at: Publisher Site | Google Scholar
  27. A. Haji Dheere, N. Yusuf, and A. Gee, “Rapid and efficient synthesis of [11C]ureas via the incorporation of [11C]CO2 into aliphatic and aromatic amines,” Chemical Communications, vol. 49, no. 74, p. 8193, 2013. View at: Publisher Site | Google Scholar
  28. E. Van Tilburg, A. Windhorst, M. Van Der Mey, and J. Herscheid, “One-pot synthesis of [11C]ureas via triphenylphosphinimines,” Journal of Labelled Compounds and Radiopharmaceuticals, vol. 49, no. 4, p. 321, 2006. View at: Publisher Site | Google Scholar
  29. A. Haji Dheere, S. Bongarzone, C. Taddei, R. Yan, and A. Gee, “Synthesis of 11C-labelled symmetrical ureas via the rapid incorporation of [11C]CO2 into aliphatic and aromatic amines,” Synlett, vol. 26, no. 16, pp. 2257–2260, 2015. View at: Publisher Site | Google Scholar
  30. L. Lemoucheux, J. Rouden, M. Ibazizene, F. Sobrio, and M. Lasne, “Debenzylation of tertiary amines using phosgene or triphosgene: an efficient and rapid procedure for the preparation of carbamoyl chlorides and unsymmetrical ureas. application in carbon-11 chemistry,” Journal of Organic Chemistry, vol. 68, no. 19, pp. 7289–7297, 2003. View at: Publisher Site | Google Scholar
  31. C. Asakawa, M. Ogawa, K. Kumata et al., “[11C]Sorafenib: radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice,” Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2220–2223, 2011. View at: Publisher Site | Google Scholar
  32. P. Jessop, T. Ikariya, and R. Noyori, “Homogeneous hydrogenation of carbon dioxide,” Chemical Reviews, vol. 95, no. 2, pp. 259–272, 1995. View at: Publisher Site | Google Scholar
  33. J. Tharun, G. Mathai, A. Kathalikkattil, R. Roshan, J. Kwaka, and D. Park, “Microwave-assisted synthesis of cyclic carbonates by a formic acid/KI catalytic system,” Green Chemistry, vol. 15, no. 6, pp. 1673–1677, 2013. View at: Publisher Site | Google Scholar
  34. M. Aresta and A. Dibenedetto, “Utilisation of CO2 as a chemical feedstock: opportunities and challenges,” Dalton Transactions, no. 28, pp. 2975–2992, 2007. View at: Publisher Site | Google Scholar
  35. M. Mikkelsen, M. Jorgensen, and F. Krebs, “The teraton challenge: a review of fixation and transformation of carbon dioxide,” Energy & Environmental Science, vol. 3, no. 1, pp. 43–81, 2010. View at: Publisher Site | Google Scholar

Copyright © 2018 Abdul Karim Haji Dheere et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

613 Views | 268 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.