ChemComm
Communication
Given the novelty and simplicity of this setup, the methodology
has the potential to enable the widespread routine utilisation of
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2,14,15
[
C]CO in different chemical reactions
leading to a wide
range of PET tracers and their application for in vivo imaging.
This work was supported by European Commission, FP7-
PEOPLE-2012-ITN (316882, RADIOMI) and Medical Research
Council (MRC, MR/K022733/1). 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 & St Thomas’ NHS
Foundation Trust in partnership with King’s College London
and King’s College Hospital NHS Foundation Trust. The
authors would like to thank Dr Robin Fortt for his technical
assistance. Moreover, the authors would like to thank the
referees for their suggestions to improve the manuscript.
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1
Fig. 3 Proposed mechanism of [ C]CO release.
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conditions (argon glovebox) improved the RCY of [ C]3b up to 85%
and the [ C]CO release up to 51% (entry 15). Whereas, in the
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presence of double amount of 2b, [ C]3b was obtained with higher
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1
RCY (95%) but the released [ C]CO was very low (entry 16).
Radio-HPLC analysis of the reaction mixture in Vial B
Notes and references
confirmed the production of [ C]7 with high RCYs of 98% § This work describes a method development study using short cyclo-
1
1
tron irradiations where obtaining high specific activities (SA) were not
the main focus. However, the associated carrier content of compound
(
Table 1, Fig. 1 and Fig. SI4, ESI†).
In order to explore the applicability of the developed method
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12
[
C]7 was in the range of 27–37 mmol. Assuming that the stable
C
in producing functionalised tracers, the synthesis of a selective carrier content would be in the same range for a standard clinical
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1
1
[
C]CO
2
production, it is estimated that specific activities of 70–90 GBq
AMPA receptor ligand, [ C]CX546, was successfully achieved
(
Z90% after 6 min from end of cyclotron [ C]CO
ment (EOB) (entry 17, Fig. SI5, ESI†).
In order to demonstrate the utility of the developed methodology
an automated procedure was implemented using an Eckert & Ziegler
Modular-Lab system (Fig. 2, see ESI† for Experimental details). Using
this apparatus both [ C]7 (entry 18) and [ C]CX546 (entry 19) were
obtained with 490% RCYs (6 min after EOB).
À1
1
1
mmol would be obtained. These are consistent with the SA’s observed
for other C-labelled tracers at our institution.
Scheme 1, example 2). [ C]CX546 was produced with RCYs
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1
1
2
bombard-
1
S. Kealey, S. M. Husbands, I. Bennacef, A. D. Gee and J. Passchier,
J. Labelled Compd. Radiopharm., 2014, 57, 202; A. Brennfuhrer,
H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2009, 48, 4114;
J. R. Martinelli, T. P. Clark, D. A. Watson, R. H. Munday and S. L.
Buchwald, Angew. Chem., Int. Ed., 2007, 46, 8460; D. N. Sawant,
Y. S. Wagh, K. D. Bhatte and B. M. Bhanage, J. Org. Chem., 2011,
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76, 5489; A. M. Tafesh and J. Weiguny, Chem. Rev., 1996, 96, 2035.
2 Y. Andersson and B. Langstrom, J. Chem. Soc., Perkin Trans. 1, 1995, 287.
3 C. Crudden and H. Alper, Angew. Chem., Int. Ed., 1992, 104, 1122.
1
1
2
Based on these findings, we propose that [ C]CO is trapped
4
M. Aresta, Utilizing carbon dioxide as chemical feedstock, John Wiley &
Sons, 2010.
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1
by silane lithium chloride species (2b) forming the [ C]silane
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carboxylate ([ C]3b). After TBAF addition, [ C]3b rearranges to
complex I, which in turn produces complex II. The subsequent
5 J. Medina-Ramos, R. C. Pupillo, T. P. Keane, J. L. DiMeglio and
J. Rosenthal, J. Am. Chem. Soc., 2015, 137, 5021.
6
7
J. M. Lehn and R. Ziessel, Proc. Natl. Acad. Sci. U. S. A., 1982, 79, 701.
B. Hu, C. Guild and S. L. Suib, J. CO Util., 2013, 1, 18.
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1
[
C]CO release from complex II is initiated by TBAF which
2
triggers the intramolecular rearrangement producing salt III
and [ C]CO release (Fig. 3). This is in agreement with the
8 D. S. Laitar, P. Muller and J. P. Sadighi, J. Am. Chem. Soc., 2005,
127, 17196.
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1
9
C. Kleeberg, M. S. Cheung, Z. Y. Lin and T. B. Marder, J. Am. Chem.
Soc., 2011, 133, 19060.
mechanism described by Brook et al. for the release of CO from
1
0
silane derivatives.
In conclusion, a rapid and reliable method for the chemical
10 A. G. Brook and H. Gilman, J. Am. Chem. Soc., 1955, 77, 2322.
11 S. D. Friis, R. H. Taaning, A. T. Lindhardt and T. Skrydstrup, J. Am.
Chem. Soc., 2011, 133, 18114.
1
1
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2
conversion of [ C]CO to [ C]CO using a simple two-vial setup has
12 L. Gu and Y. Zhang, J. Am. Chem. Soc., 2010, 132.
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been developed. This represents the first application of a [ C]silane 13 A. G. Brook, Acc. Chem. Res., 1974, 7, 77; S. D. Friis, T. Skrydstrup
derivative as a [ C]CO source for radiosynthetic applications.
Cyclotron-produced [ C]CO
98%) at 20 1C. Upon TBAF addition, complete depletion of [ C]3b
was obtained (Fig. SI1B, ESI†). The released [ C]CO reacted rapidly
and efficiently in Pd-mediated [ C]carbonylation reactions. Crude
C]7 and [ C]CX546 were obtained in high RCYs (Z97% and 18 P. Lidstrom, T. Kihlberg and B. Langstrom, J. Chem. Soc., Perkin
11
and S. L. Buchwald, Org. Lett., 2014, 16, 4296.
4 O. Rahman, J. Labelled Compd. Radiopharm., 2015, 58, 86.
5 B. Langstom, O. Itsenko and O. Rahman, J. Labelled Compd. Radio-
pharm., 2007, 50, 794.
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2
was quantitatively trapped in Vial A
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(
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16 G. Antoni, J. Labelled Compd. Radiopharm., 2015, 58, 65.
7 S. Kealey, A. Gee and P. W. Miller, J. Labelled Compd. Radiopharm.,
014, 57, 195.
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2
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[
Trans. 1, 1997, 2701.
9 S. K. Zeisler, M. Nader, A. Theobald and F. Oberdorfer, Appl. Radiat.
Z90%, respectively) at 40 1C in short reaction times (6 min
after EOB).§ Furthermore, the automated system was successfully
1
Isot., 1997, 48, 1091.
20 K. Dahl, M. Schou, N. Amini and C. Halldin, Eur. J. Org. Chem., 2013, 1228.
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developed and tested for the production of [ C]7 and [ C]CX546.
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Chem. Commun.