Rapid and efficient synthesis of [11C]ureas via the incorporation of [11C]CO2 into aliphatic and aromatic amines

Article abstract of DOI:10.1039/c3cc44046j

A rapid urea radiolabelling methodology has been developed. [ ¹¹C]CO₂ was activated by 1,8-diazabicycloundec-7-ene (DBU) in the presence of aliphatic and aromatic amines and reacted with Mitsunobu reagents to produce asymmetric ¹¹C radiolabelled ureas in high radiochemical yields.

Full text of DOI:10.1039/c3cc44046j

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Rapid and efficient synthesis of [11C]ureas via
the incorporation of [11C]CO2 into aliphatic
and aromatic amines†
Cite this: Chem. Commun., 2013,
49, 8193
Received 29th May 2013,
Accepted 29th July 2013
Abdul Karim Haji Dheere, Nadiya Yusuf and Antony Gee*
DOI: 10.1039/c3cc44046j
www.rsc.org/chemcomm
A rapid urea radiolabelling methodology has been developed.
11C]CO2 was activated by 1,8-diazabicycloundec-7-ene (DBU) in
[
the presence of aliphatic and aromatic amines and reacted with
Mitsunobu reagents to produce asymmetric 11C radiolabelled
ureas in high radiochemical yields.
Scheme 1 Synthesis of [11C]urea with [11C]CO2.
Positron emission tomography (PET) is a non-invasive molecular
We report herein a rapid [11C]CO2 radiolabelling methodology
imaging technique that is used for medical diagnosis, drug which overcomes these limitations. DBU was used to trap the
development, and the understanding of normo- and patho- cyclotron-produced [11C]CO2 which was subsequently reacted with
physiology.1 Carbon-11 (t1/2 = 20.4 min) is a commonly used aliphatic, benzylic and aromatic amines (Scheme 1) to synthesise
radio-isotope for PET imaging, the ubiquity of carbon in all [11C]ureas in a highly efficient manner.
naturally occurring organic compounds making it an attractive
Ureas are found in a plethora of biologically active mole-
radio-isotope for molecular imaging. Substituting carbon-12 cules as has been extensively reported in the literature.7 The
(12C) in biologically active molecules with radioactive 11C has method reported herein provides a methodology to label this
no effect on the chemistry or the biological activity of the class of compounds with carbon-11.
molecule.2 Cyclotron-produced 11C is commonly prepared in
Model reactions were initially conducted using nonradio-
the form of [11C]carbon dioxide ([11C]CO2) by the 14N(p,a)11C active CO2.8 Compound 3 was subsequently chosen as the
nuclear reaction. Due to its poor reactivity, [11C]CO2 is typically initial model reaction for optimisation with [11C] CO2.
converted into more reactive synthons such as [11C]methyl
[11C]CO2 from the cyclotron target was bubbled in a stream
iodide or triflate and subsequently used to radiolabel molecules of helium gas at a flow rate of 1.4 ml minÀ1 post target
of biological interest.3 Although these labelling synthons are depressurisation directly into a solution containing a primary
useful, not all target molecules are accessible by these synthons amine, a secondary amine and DBU in acetonitrile for one
and their preparation takes several minutes with a concomitant minute. The solution was stirred for one minute prior to the
decrease in 11C radioactivity due to decay. The development of addition of Mitsunobu reagents di-tert-butyl azodicarboxylate
methods to efficiently label compounds directly with [11C]CO2 (DBAD) and tributylphosphine (PBu3).
is therefore of significant interest.
Initially, experiments were performed in a number of different
To overcome the low reactivity of CO2, bases such as solvents at 40 1C (Table 1, entries 1–3) with the aim of identifying
1,8-diazabicycloundec-7-ene (DBU) or 2-tert-butylimino-2-diethyl- the best solvent for the reaction. Acetonitrile trapped cyclotron-
amino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) have produced [11C]CO2 very efficiently when bubbled directly into the
recently been utilised as CO2 activating agents in the synthesis of reaction mixture (>95%), while DMSO and DMF were slightly less
11C-labelled organic molecules.4,5 These methods, however, pro- efficient (80–90%).
duce very poor yields for unreactive aromatic amines, or the
reactions are limited to a specific product.6
Moderate radiochemical yields (46%) of the desired
[11C]ureas were observed using acetonitrile as a solvent while
DMF and DMSO gave yields of 13% and 18% respectively,
despite good [11C]CO2 trapping (Table 1). Acetonitrile was
therefore selected as the solvent of choice for subsequent
reactions.
Division of Imaging Sciences and Biomedical Engineering, King’s College London,
UK SE1 7EH. E-mail: antony.gee@kcl.ac.uk; Fax: +44 (0)20 718 85442;
Tel: +44 (0)20 718 88366
RCY was determined by radio-HPLC and defined as the amount
of labelled [11C]urea as a percentage of the cyclotron-produced
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc44046j
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Table 1 Reaction optimisation
Table 2 Radiolabelling various aliphatic, benzylic and aromatic amines with
[
11C]CO2
Entrya
Product
RCYb (%)
1
74 Æ 9
Entrya
Solvent
T (1C)
Time (min)
RCYb (%)
1
2
3
4c
5
6
7
8
MeCN
DMF
40
40
40
25
25
60
50
50
5
5
5
5
5
5
5
1
46 Æ 7
13 Æ 3
18 Æ 6
0
8 Æ 1
26 Æ 12
95 Æ 3
96 Æ 2
2
3
4
5
6
94 Æ 2
69 Æ 6
85 Æ 6
83 Æ 5
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
a
Reaction conditions: primary amine (18.3 mmol), secondary amine
(27.5 mmol), DBU (0.8 mmol), Mitsunobu reagents (36.6 mmol) in
b
c
400 mmol acetonitrile. n = 3. Determined by radio-HPLC. Reduced
concentration.9
[11C]CO2 trapped in solution obtained directly from the cyclotron
and corrected for radioactive decay.
When the reactions were carried out at lower reagent
concentrations (Table 1, entry 4), no [11C]radiolabelled product
was observed despite efficient [11C]CO2 trapping.9
The temperature dependency of the reaction was subse-
quently examined. Loss of [11C]CO2 from the reaction vial was
observed when the reactions were performed at 60 1C. Reac-
tions at 50 1C avoided these losses and resulted in over 95%
incorporation of the [11C]CO2 into the target radiolabelled
80 Æ 10
19 Æ 15
7
a
b
n = 3. Determined by radio-HPLC. Reaction conditions: [11C]CO2,
primary amine (18.3 mmol), secondary amine (27.5 mmol), DBU
(0.8 mmol) in 400 mmol acetonitrile heated at 50 1C for 1 min.
Mitsunobu reagents (36.6 mmol) added and stirred for 1 min.
molecules (Table 1, entry 7). Reducing the reaction time from
5 to 1 minute still resulted in a RCY of 96% (Table 1, entry 8 and
Fig. 1).
The conditions for the model reaction were subsequently
applied to the radiosynthesis of various asymmetric ureas using
a range of aliphatic, benzylic and aromatic amines (Table 2).
The reactions between benzylic primary amines and the
secondary amine, tetrahydroisoquinoline (Table 1, entry 8)
resulted in high RCY while the reaction with N-methylbenzyl-
amine produced slightly lower yields of the [11C]urea (Table 2,
entry 1). The high yields for tetrahydroisoquinoline can be
explained by the rigidity of the molecule, having a locked
planer confirmation and less steric hindrance.
Interestingly, RCYs of similar magnitudes were observed
when a less reactive aromatic primary amine was used in place
of a benzylic amine to form the target radiolabelled molecules
(Table 2, entries 2 and 3).
The effect of functional groups on aromatic amines was
also studied. Reactions with the electron rich aromatic amines
m-toluidine, and p-anisidine resulted in over 80% RCY
(Table 2, entries 5 and 6) and even poor nucleophiles such as
Fig. 1 HPLC chromotogram of the crude radiolabelled product (Table 1, entry 8).
(A) Radioactivity (counts per second) target compound 3 at Rt 7.30 min. (B) UV
absorption (254 nm) of compound 1 at Rt 3.25 min, compound 2 Rt 3.45 min and
by-products at 5.00 min, 5.30 min and 5.50 min.
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F. I. Aigbirhio, J. Pharmacol. Exp. Ther., 2007, 320, 1030–1037;
(c) J.-K. Chung, Y. Kim, S.-k. Kim, Y. Lee, S. Paek, J. Yeo, J. Jeong,
D. Lee, H. Jung and M. Lee, Eur. J. Nucl. Med., 2002, 29, 176–182;
(d) R. Bolton, J. Labelled Compd. Radiopharm., 2001, 44, 701–736.
4 (a) J. M. Hooker, A. T. Reibel, S. M. Hill, M. J. Schueller and
J. S. Fowler, Angew. Chem., Int. Ed., 2009, 48, 3482–3485;
(b) A. A. Wilson, A. Garcia, S. Houle and N. Vasdev, Org. Biomol.
Chem., 2010, 8, 428–432; (c) P. J. Riss, S. Lu, S. Telu, F. I. Aigbirhio and
V. W. Pike, Angew. Chem., Int. Ed., 2012, 51, 2698–2702;
(d) D. J. Heldebrant, P. G. Jessop, C. A. Thomas, C. A. Eckert and
C. L. Liotta, J. Org. Chem., 2005, 70, 5335–5338; (e) M. L. Gray,
K. J. Champagne, D. Fauth, J. P. Baltrus and H. Pennline, Int. J.
Greenhouse Gas Control, 2008, 2, 3–8.
5 (a) L. D. Field, E. T. Lawrenz, W. J. Shaw and P. Turner, Inorg. Chem.,
2000, 39, 5632–5638; (b) M. R. Sievers and P. B. Armentrout, Inorg.
Chem., 1999, 38, 397–402; (c) Y. Hori, H. Wakebe, T. Tsukamoto and
O. Koga, Surf. Sci., 1995, 335, 258–263; (d) Y. Gu, F. Shi and Y. Deng,
J. Org. Chem., 2003, 69, 391–394; (e) W. McGhee and D. Riley, J. Org.
Chem., 1995, 60, 6205–6207.
4-nitroaniline reacted efficiently, producing high RCY of 85%
(Table 2, entry 4). The reaction favours the formation of
asymmetric [11C]ureas despite primary amines being present
in excess of [11C]CO2. In the absence of secondary amines,
various by-products are observed resulting in reduced RCY
(Table 2, entry 7).
In conclusion, a rapid and robust methodology for the
radiosynthesis of ureas has been developed. The method incor-
porates [11C]CO2 directly into aliphatic, benzylic and aromatic
amines producing the target radiolabelled ureas in high RCY.
Overcoming limitations of previous methods, even poorly reac-
tive aromatic amines gave excellent RCY’s of asymmetric
[11C]ureas within one minute after the addition of Mitsunobu
reagents.
This novel radiolabelling methodology opens up new possi-
bilities for 11C radiolabelling molecules for in vivo molecular
imaging applications.
6 (a) E. W. van Tilburg, A. D. Windhorst, M. van der Mey and
J. D. M. Herscheid, J. Labelled Compd. Radiopharm., 2006, 49,
321–330; (b) A. A. Wilson, A. Garcia, S. Houle, O. Sadovski and
N. Vasdev, Chem.–Eur. J., 2011, 17, 259–264.
7 (a) C. P. Decicco, J. L. Seng, K. E. Kennedy, M. B. Covington,
P. K. Welch, E. C. Arner, R. L. Magolda and D. J. Nelson, Bioorg.
Med. Chem. Lett., 1997, 7, 2331–2336; (b) Q.-Z. Zheng, K. Cheng,
X.-M. Zhang, K. Liu, Q.-C. Jiao and H.-L. Zhu, Eur. J. Med. Chem.,
2010, 45, 3207–3212; (c) K. Sanphanyaa, S. Wattanapitayakul,
O. Prangsaengtongc, M. Joc, K. Koizumi, N. Shibaharac,
A. Pripremd, V. Fokine and O. Vajragupta, Bioorg. Med. Chem. Lett.,
2012, 22, 3001–3005.
8 (a) S. L. Peterson, S. M. Stucka and C. J. Dinsmore, Org. Lett., 2010, 12,
1340–1343; (b) C. J. Dinsmore and S. P. Mercer, Org. Lett., 2004, 6,
2885–2888; (c) K. C. K. Swamy, N. N. B. Kumar, E. Balaraman and
K. V. P. P. Kumar, Chem. Rev., 2009, 109, 2551–2651.
Notes and references
1 (a) C. R. Child, S. Kealey, H. Jones, P. W. Miller, A. J. P. White,
A. D. Gee and N. J. Long, Dalton Trans., 2011, 40, 6210–6215;
(b) V. J. Cunningham, C. A. Parker, E. A. Rabiner, A. D. Gee and
R. N. Gunn, Drug Discovery Today, 2005, 2, 311–315; (c) J. Wang and
L. Maurer, Curr. Top. Med. Chem., 2005, 5, 1053–1075; (d) N. Oriuchi,
T. Higuchi, T. Ishikita, M. Miyakubo, H. Hanaoka, Y. Iida and
K. Endo, Cancer Sci., 2006, 97, 1291–1297.
2 (a) P. W. Miller, N. J. Long, R. Vilar and A. D. Gee, Angew. Chem., Int.
Ed., 2008, 47, 8998–9033; (b) F. Lodi, C. Malizia, P. Castellucci,
G. Cicoria, S. Fanti and S. Boschi, Nucl. Med. Biol., 2012, 39, 447–460.
3 (a) A. A. Wilson, A. Garcia, L. Jin and S. Houle, Nucl. Med. Biol., 2000,
27, 529–532; (b) J. R. Atack, P. Scott-Stevens, J. S. Beech, T. D. Fryer,
J. L. Hughes, M. C. Cleij, J.-C. Baron, J. C. Clark, R. J. Hargreaves and
9 Reduced concentration conditions: primary amine (6.1 mmol),
secondary amine (9.1 mmol), DBU (0.3 mmol), Mitsunobu reagents
(12.2 mmol) and 400 mmol acetonitrile.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8193--8195 8195