N-heterocyclic carbenes as ligands in palladium-mediated [ 11C]radiolabelling of [11C]amides for positron emission tomography

Article abstract of DOI:10.1002/jlcr.1832

A model palladium-mediated carbonylation reaction synthesizing N-benzylbenzamide from iodobenzene and benzylamine was used to investigate the potential of four N-heterocyclic carbenes (N,N′-bis(diisopropylphenyl)-4, 5-dihydroimidazolinium chloride (I), N,N′-bis(1-mesityl)-4,5- dihydroimidazolinium chloride (II), N,N′-bis(1-mesityl)imidazolium chloride (III) and N,N′-bis(1-adamantyl)imidazolium chloride (IV)) to act as supporting ligands in combination with Pd₂(dba)₃. Their activities were compared with other Pd-diphosphine complexes after reaction times of 10 and 120 min. Pd₂(dba)₃ and III were the best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [¹¹C]N-benzylbenzamide in good radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically unreactive and insoluble [¹¹C]CO which was then released and reacted via the Pd-mediated carbonylation process. Potentially useful side products [¹¹C]N,N′-dibenzylurea and [ ¹¹C]benzoic acid were also observed. Increased amounts of [ ¹¹C]N,N′-dibenzylurea were yielded when PdCl₂ was the Pd precursor. Reduced yields of [¹¹C]benzoic acid and therefore improved RCP were seen for III/Pd₂(dba)₃ over commonly used dppp/Pd₂(dba)₃ making it more favourable in this case. Copyright

Full text of DOI:10.1002/jlcr.1832

Research Article
Received 1 April 2010,
Revised 21 May 2010,
Accepted 19 August 2010
Published online 2 November 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1832
N-heterocyclic carbenes as ligands in
palladium-mediated [11C]radiolabelling
of [11C]amides for positron emission
tomography
Lucy E. Jennings,a Steven Kealey,b Philip W. Miller,a Antony D. Gee,a,b
Ã
and Nicholas J. Longa
A model palladium-mediated carbonylation reaction synthesizing N-benzylbenzamide from iodobenzene and benzylamine
was used to investigate the potential of four N-heterocyclic carbenes (N,N0-bis(diisopropylphenyl)-4,5-dihydroimidazoli-
nium chloride (I), N,N0-bis(1-mesityl)-4,5-dihydroimidazolinium chloride (II), N,N0-bis(1-mesityl)imidazolium chloride (III) and
N,N0-bis(1-adamantyl)imidazolium chloride (IV)) to act as supporting ligands in combination with Pd2(dba)3. Their activities
were compared with other Pd-diphosphine complexes after reaction times of 10 and 120 min. Pd2(dba)3 and III were the
best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [11C]N-benzylbenzamide in good
radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically
unreactive and insoluble [11C]CO which was then released and reacted via the Pd-mediated carbonylation process.
Potentially useful side products [11C]N,N0-dibenzylurea and [11C]benzoic acid were also observed. Increased amounts of
[
improved RCP were seen for III/Pd2(dba)3 over commonly used dppp/Pd2(dba)3 making it more favourable in this case.
11C]N,N0-dibenzylurea were yielded when PdCl2 was the Pd precursor. Reduced yields of [11C]benzoic acid and therefore
Keywords: 11-carbon; carbon monoxide; palladium-catalysis
radiolabelling.11–13 Here, the picomolar amounts of [11C]CO
used mean that the catalyst is actually in vast excess, so the
Introduction
There has been a significant growth in the use of the molecular
imaging technique, positron emission tomography (PET), in
biological research and drug development over the last 20
years.1,2 Radiolabelled compounds can be tracked in real time
giving an insight into drug delivery as well as biochemical
processes. However, significant challenges still remain in the
development of new radiolabelled compounds for imaging
biological processes.3 The most commonly used positron
emitters are 11C, 18F, 15O and 13N and one of the key challenges
in PET is to utilize the radionuclides within approximately three
half-lives in order to maintain enough radioactivity for the scan.
Carbon-11 is of particular interest due to its biocompatibility;
however its short half-lifetime of 20.4 min drives the need for
new methods to accelerate radiolabelling methodologies. The
most common method for 11C incorporation is methylation
using [11C]methyl iodide4 or the more reactive [11C]methyl
triflate5,6 but interest in utilizing [11C]carbon monoxide7 and
[11C]carbon dioxide8 is growing as new techniques open up
process can be considered to be Pd-mediated rather than Pd-
catalysed. The amide functionality is frequently found in
biologically active compounds such as DAA1106 and analogues
which are potential ligands for the peripheral benzodiazepine
receptor.14 Langstrom et al. have extensively studied palladium-
mediated [11C]carboxyamination as a route to [11C]amides,
combining a wide range of organic halides and triflates with
amines, utilizing a microautoclave system and high pres-
sures.15–19 Recent low-pressure trapping and reaction methods
using either borane10 or copper complexes9 present certain
advantages in terms of their simplicity and ease of use.
˚
¨
As an alternative to the commonly used organophosphines,
N-heterocyclic carbenes (NHC) have shown potential as
ancillary ligands for many palladium-catalysed cross-coupling
reactions,20–22 including Suzuki–Miyaura coupling reactions,23
aDepartment of Chemistry, Imperial College London, South Kensington,
London, UK
the field9,10
.
In [11C]radiolabelling, transition metal-mediated processes bGlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, Du Cane
Road, London, UK
play an important role due to their ability to speed up
incorporation via activation of [11C]carbon monoxide. Pd-
mediated [11C]carbonylation reactions have been widely applied
*Correspondence to: Nicholas J. Long, Department of Chemistry, Imperial
College London, South Kensington, London SW7 2AZ, UK.
in Suzuki-Miyaura, Stille and carboxyamination reactions for PET E-mail: n.long@imperial.ac.uk
J. Label Compd. Radiopharm 2011, 54 135–139
Copyright r 2010 John Wiley & Sons, Ltd.

L. E. Jennings et al.
Sonagashira cross-coupling24 and Buchwald–Hartwig amina- the rate of related reactions.32 A model reaction was used in
tion.25 Their use in the carbonylation of aryl halides is a relatively order to evaluate the effect of the catalyst system on the
unexplored area. Some work has been carried out investigating formation of amide. In this case iodobenzene and benzylamine
the use of NHCs in palladium-catalysed carbonylative Suzuki–- (used in excess as the solvent) were combined under static
Miyaura cross couplings26,27 and oxidative carbonylations, 0.2 bar pressure of carbon monoxide to synthesize N,N-
employing a copper co-catalyst to synthesize ureas, carbamates benzylbenzamide (Figure 1). Pd-NHC species were prepared in
and 2-oxazolidinones;28 however, the majority of the research situ by the reaction of imidazolinium or imidazolium salts
has been carried out on hydroformylation reactions.29 NHCs are (Figure 2) with the palladium(0) precursor Pd2(dba)3 in
considered to be more catalytically robust than phosphines and benzylamine. Reaction of the imidazolinium and imidazolium
are found to be generally superior under harsher conditions salts in the presence of excess benzylamine base resulted in the
owing to their greater stability at higher temperatures and deprotonation of the salts and dissolution of the Pd-NHC
greater tolerances to oxygen and moisture.
complex when heated to 1501C. The relatively high tempera-
Amide synthesis from palladium carbonylation using NHCs as tures used for these reactions may be expected to enhance the
ligands has been carried out with aryl diazonium salts and aryl yields over short time periods (10 min) compared with lower
boronic acids in the only reported production of amides temperatures and then eventually degrade the catalyst over
through carbonylation using NHCs.30 The full capability of NHCs sustained periods at this high temperature (2 h).
in Pd-catalysed carbonylation reactions for the synthesis of
A range of well-known and widely used benchmark Pd-
amides – an important functional group found in many phosphine complexes (Figure 3) were also investigated for the
pharmaceuticals – has not yet been fully explored. In this model carbonylation reaction. Pd-monophosphine and chelat-
manuscript, we illustrate the comparable ability of NHC versus ing diphosphine catalysts have been widely investigated for a
commonly used mono- and bi-dentate phosphines in the range of carbonylation reactions33,34 and as such are useful
synthesis of amides over the timeframes of 10 min and 2 h, for comparative purposes with the Pd-NHC catalysts. The
and the novel utilization of these ligands in PET radiolabelling results from the model aminocarbonylation reactions using
experiments using [11C]carbon monoxide via the use of a carbon phosphine ligands are shown in Table 1. In the case of
monoxide trapping complex recently developed in our group.
Results and discussion
Ph2
P
Ph2
P
Cl
Cl
Cl
Cl
Ligand/catalyst evaluation
Pd
Pd
The initial target was to find an efficient Pd-NHC system to be
applied to PET radiolabelling experiments. Thus, a series of
imidazolinium and imidazolium salts were tested as ligands as
well as palladium catalysts with phosphine and diphosphine
ligands. Diphosphines are generally favoured in carbonylation
reactions to monodentate phosphines31 and it has been
suggested that the bite angle plays a key role in improving
P
P
Ph2
Ph2
Pd(dppp)Cl2
Pd(BINAP)Cl2
Cl
Ph2
P
Fe
Pd
Cl
P
Ph2
Pd(dppf)Cl2
Figure 1. The model palladium-catalysed carbonylation reaction for the formation
of N-benzylbenzamide.
Figure 3. Palladium(II) diphosphine chloride complexes used for comparison
within the model carbonylation reaction.
Figure 2. Structures of the four imidazolinium (I) and (II), and imidazolium (III) and (IV) salts used as NHC ligands.
www.jlcr.org
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 135–139

L. E. Jennings et al.
tetrakis(triphenylphosphine)palladium there is no need for preformed catalyst Pd(III)2Cl2 obtained after 10 min, initially
reduction of palladium(II) to form the catalytically active Pd(0) surprising, are likely to be due to the slower reduction of this
species prior to oxidative addition which could account for it complex to the catalytically active Pd(0) species compared with
having the highest yield after 10 min (Table 1, entry 1). its in situ equivalent which is prepared directly from the Pd(0)
Diphosphine ligands such as bis(diphenylphosphino)propane source Pd2(dba)3. There is evidence, however, that having two
(dppp) and bis(diphenylphosphino)ferrocene (dppf) are used IMes moieties on the palladium can result in too strong an
extensively in catalysis and here they show moderate yields after electron-donating effect which can prevent reductive elimina-
10 min. After 2 h, all the Pd-phoshine catalysts performed tion and therefore deactivation of the catalyst.37 Pd2dba3 was
equally well giving yields of between 55 and 57%, suggesting used as the Pd source due to its good solubility in benzylamine
that while the ligand–palladium system is important to the which was used in excess as solvent. The basic environment was
initial rate of the reaction it does not affect the yield over the assumed to aid in the active complex formation although the
longer timeframe.
exact structure of this is unknown. Supporting data for this
Four imidazolinium and imidazolium chloride salts (N,N0-bis assumption is shown by entry 11 in which Pd2dba3 on its own
(diisopropylphenyl)-4,5-dihydroimidazolinium chloride (I), N,N0- gives lower yields of amide after 10 min than the systems with
bis(1-mesityl)-4,5-dihydroimidazolinium chloride (II), N,N0-bis imidazolium and imidazolinium hydrochloride salts (entries 6–9).
(1-mesityl)imidazolium chloride (III) and N,N0-bis(1-adamantyl) The Pd-NHC catalyst system with ligand III (Entry 8) was chosen
imidazolium chloride (IV)) with varying electronic and steric for subsequent radiolabelling studies using [11C]carbon mon-
properties (Figure 2) were investigated for the model carbonyla- oxide as it was the best performing catalyst system overall.
tion reaction. The objective was to examine the effect that the
R groups and the saturated or unsaturated imidazole ring have
on the reaction. It has been established that the electronic
backbone of the imidazole rings can affect the rate of the
Radiolabelling experiments
Although [11C]carbon monoxide is a valuable resource in
oxidative addition step in the catalytic cycle.35 Furthermore,
radiolabelling, the low reactivity of carbon monoxide, as a
result of its low solubility in most organic solvents, and high
dilution in the inert carrier gas has prevented it from widespread
use in PET chemistry. Previously, these issues have been
overcome by the use of microautoclave systems which increase
the pressure and therefore enhance the key carbon monoxide
insertion step effectively but these methods require specialized
equipment.38,39 Chemical complexation can also be an effective
method of improving [11C]CO reactivity by increasing its
solubility at low partial pressures. Such systems include
BH3.THF10 and Cu(I)9 solutions; the latter can trap [11C]CO with
efficiencies of over 95% compared with approximately 1% in
solvent alone. The novel [11C]CO chemical trapping method,
bulky R groups such as adamantyl could aid the reductive
elimination step, while the electronic effect of the R group on
the system is not thought to contribute significantly.36
As seen previously for the phosphine ligands, similar yields in
excess of 50% are observed after 2 h with the Pd-NHC catalysts;
however, considerable variation is observed after 10 min
(Table 2). Yields of the carbonylated product N-benzylbenza-
mide using the Pd-NHC catalysts over the 10-minute timeframe
ranged from a low 4% (entry 10) with the preformed catalyst
Pd(III)2Cl2 to a reasonable 20% (entry 8) for the in situ catalyst
(formed from Pd2(dba)3 and ligand III). The lower yields of the
Ã
exploiting a [Cu(Tp )] complex, recently developed in our
Table 1. Average yields of N-benzylbenzamide calculated
by GC after 10 min and 2 h (average of three runs)
group9 was used to test the best performing Pd-NHC catalyst
Ã
system for [11C] carbonylation radiolabelling. The CuTp
Entry
Pd source
GC Yield (%)
trapping system was chosen for the NHC carbonylation
radiolabelling experiments as the trapping process can be
carried out at room temperature in a one-pot process. Following
10 min
2 h
Ã
formation of the Cu(Tp )[11C]CO complex, the cross coupling
1
2
3
4
5
Pd(PPh3)4
1877
1375
1477
1575
1072
5672
5671
5572
5772
5771
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(dppp)Cl2
Pd(BINAP)Cl2
reagents (Pd precursor, ligand, iodobenzene, benzylamine) were
added to the trapping vial and the reaction mixture heated for
10 min. The reaction was quenched and the crude product
mixture analysed by analytical radio-HPLC (Table 3). The results
Ã
of the [Cu(Tp )] radiolabelling procedure for the model
carbonylation reaction using the best performing NHC ligand
(III) from the initial screening as well as the phosphine ligand
dppp for comparison are shown in Table 3. Labelling reactions
using III and Pd2(dba)3 in situ at 1001C produced three labelled
products; two minor products [11C]benzoic acid and [11C]N,N0-
dibenzylurea along with the major labelled product [11C]N-
benzylbenzamide (Table 3, entry 1). [11C]N,N0-dibenzylurea was
observed in significant yield when using PdCl2, which is in
agreement with previous findings when a Pd(II) starting material
is used9. Interestingly this product is not observed in the
corresponding cold reactions, and the formation is attributed to
the vastly different stoichiometries encountered between the
‘cold’ and ‘hot’ regimes potentially leading to an oxidative
carbonylation mechanism. It is thought that the excess
amount of Pd compared with [11C]CO may cause this effect.
Table 2. Average yields of N-benzylbenzamide after
10 min and 2 h (average of three runs)
Entry
Pd source
Ligand
GC Yield (%)
10 min
2 h
6
7
8
9a
10a
11a
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(IMes)2Cl2
Pd2(dba)3
I
II
III
IV
—
—
1276
1674
2073
1171
470.2
970.1
5673
5571
5871
5570.2
5771
5772
aAverage of two runs.
J. Label Compd. Radiopharm 2011, 54 135–139
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

L. E. Jennings et al.
Table 3. Pd-mediated [11C]carbonylation reactions using [Cu(Tp )11CO] and various Pd precursors and ligands
Ã
]
Pd source Ligand Temp. (1C)
RCP (%)a
[11C]benzoic acid [11C]N,N-dibenzylurea [11C]N,N-benzyl benzamide RCY (%)b
1
2
3
4
Pd2(dba)3
Pd2(dba)3
PdCl2
III
III
III
dppp
100
120
120
120
9
0
3
14
5
1
59
0
86
99
38
86
54710
55710
11710
6175
Pd2(dba)3
Average of two runs for each entry.
aRadiochemical purity determined from radio-analytical HPLC.
Ã
bRadiochemical yield based on the starting radioactivity of the [Cu(Tp )11CO] complex and corrected for decay to end of
bombardment.
The resultant loss of radiolabelled N,N0-benzylbenzamide at catalyst at higher temperatures, which is evident by the
1201C (Entry 3) leads to a lowering of the radiochemical yield suppression of [11C]benzoic acid formation. We are currently
compared with the yields when using Pd2dba3 (Entry 2). This investing the scope of using NHC ligands for a wider range of
could be due to the poor solubility of PdCl2 in DMF, but also substrates for [11C]CO Pd-mediated reactions under high-
because the required oxidative addition of iodobenzene is temperature reaction conditions.
suppressed owing to the slower generation of the active Pd(0)
catalyst from PdCl2 compared with directly using Pd2(dba)3. The Experimental
copper(I) complex used for the trapping step is not thought to
play a role in the oxidative carbonylation process in the case.9
General
An increase in temperature from 100 to 1201C has a
All carbonylation reactions were carried out on a Radley’s
Carousel 12 Place Reaction Station and a Heidolph heating plate
significant effect on the amount of [11C]benzoic acid formed
from the hydrolysis of the Pd(II)-acyl complex. This indicates that
fitted with a temperature probe. Quantitative analysis was
less of the acyl intermediate is present at the end of the reaction
before addition of the aqueous quench due to a more efficient
GC fitted with an Agilent 6690 autosampler and a flame
carried out via gas chromatography on a Hewlett-Packard 5890
reductive elimination at higher temperatures. Interestingly,
when ligand III is used (Entry 2) a significant improvement in
the radiochemical purity of [11C]N-benzylbenzamide formation is
observed compared with when the chelating diphosphine 1,2-
ionization detection system. The products were separated on a
SGE forte BP1 capillary column; length 25 m, I.D. 0.22 mm, film
thickness 0.25 mm. Quantification was achieved by calculating
the response factor from N-benzylbenzamide and diphenylether
bis(diphenylphosphinopropane) is used as the ligand (Entry 4).
Almost full conversion to [11C]N,N0-benzylbenzamide (99%) is
as the internal standard (purchased from Sigma-Aldrich). In all
cases samples for GC analysis were made up in 1.5 mL vials using
observed with the NHC system whereas there is still a significant
0.2 mL of reaction mixture and 1.3 mL of diphenylether in DCM
(0.0126 M) as an internal standard. All other chemicals were
amount of [11C]benzoic acid (14%) using the diphosphine which
diminishes the amount of amide formed. This indicates that the
purchased from Sigma-Aldrich, BOC Ltd. or Strem Chemicals Inc.
reductive elimination step is slower using dppp/Pd2(dba)3 than
for III/Pd2(dba)3 which has a noticeable impact on the yield of
the desired labelled amide compound. The overall, greater
Further purification was carried out where stated. [PdCl2(dppp)],
[PdCl2(dppf)] and [PdCl2(BINAP)] were formed by stirring
[PdCl2(cod)] and 1 equivalent of corresponding diphosphine in
efficiency may be attributed to the greater electron-donating
DCM at room temperature for 30 min. The product was filtered
ability of carbenes versus phosphines and their stability at
higher temperatures.
and washed with hexane and dried in vacuo.
General catalyst evaluation procedures
Conclusion
Iodobenzene (1 mmol, 0.112 mL, 1 eq.) was added to a stirred
solution of the catalyst (0.02 mmol, 2 mol%) dissolved in
benzylamine (5 mL) at 1501C under an atmosphere of carbon
monoxide; this was taken to be the start of the reaction.
Samples (0.5 mL) were taken after 10 min and 2 h and analysed
using gas chromatography.
In conclusion, NHC ligands perform similarly to a range of
commonly used phosphine ligands for palladium-catalysed
aminocarbonylation reactions over a 2 h reaction period. When
reaction times were reduced to 10 min significant differences
were observed with the in situ NHC catalyst system III/Pd2(dba)3
giving the highest yield. When applied to [11C]CO palladium-
Radiochemistry
Ã
mediated aminocarbonylation reactions, using the [Cu(Tp )]
trapping technique, the NHC ligand III proved to give good Radiolabelled [11C]CO2 was produced on a Siemens cyclotron
RCYs and excellent RCPs that surpassed a commonly used Pd- from a N2 (1% O2) target, with a beam current of 5 mA and a
phosphine ligand system. Interestingly, there appears to be an bombardment time of 5 min. The [11C]CO2 was converted to
enhancement of the reductive elimination step for the NHC [11C]CO via an Eckert and Ziegler modular lab system which uses
www.jlcr.org
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 135–139

L. E. Jennings et al.
a molybdenum reductant (8501C) and delivered to the hot cell.
[8] a) S. Lu, J. Hong, V. W. Pike, J. Label. Compd. Radiopharm. 2003,
46, 1249–1259; b) A. A. Wilson, A. Garcia, S. Houle, N. Vasdev, Org.
Biomol. Chem. 2010, 8(2), 428–432; c) J. M. Hooker, A. T. Reibel,
S. M. Hill, M. J. Schueller, J. S. Fowler, Angew. Chem. Int. Ed. 2009,
48, 3482–3485.
Unconverted [11C]CO2 was collected on an ascarite trap.
General radiolabelling procedure
[9] S. Kealey, P. W. Miller, N. J. Long, C. Plisson, L. Martarello,
A. D. Gee, Chem. Commun. 2009, 3696–3698.
[10] H. Audrain, L. Martarello, A. Gee, D. Bender, Chem. Commun.
2004, 558–559.
Ã
CuCl (11 mmol, 1.1 mg, 1 eq.) and KTp (11 mmol, 3.7 mg, 1 eq.)
was weighed into a 5 mL glass vial and placed under a N2
atmosphere. Dry THF (1 mL) was added to form the trapping
solution. A [11C]CO/He gas stream was delivered to the vial,
forming the CuTp [11C]CO complex. Following this, the cross-
˚
[11] P. Lidstrom, T. Kihlberg, B. Langstrom, J. Chem. Soc. Perkin Trans.
¨
Ã
1997, 1, 2701–2706.
[12] F. Karimi, J. Barletta, B. Langstrom, Eur. J. Org. Chem. 2005, 2374–2378.
˚
[13] O. Rahman, J. Llop, B. Langstrom, Eur. J. Org. Chem. 2004,
¨
coupling reagents (Pd2(dba)3 (1.01 mg, 1.1 mmol, 20 mol %),
IMes.HCl (0.75 mg, 2.2 mmol, 20 mol %), iodobenzene (2.3 mg,
11 mmol, 1 eq.), benzylamine (0.1 mL, excess) and triphenylphos-
phine (5.8 mg, 22 mmol, 2 eq.) in 0.9 mL DMF) were added to the
vial using an Argon gas sweep. The vial was sealed and the
mixture heated for 10 min after which time it was quenched by
addition of 1 mL NH4OAc (pH 4.9) under an Argon gas sweep.
Finally, the radioactivity of the reaction vial was measured and
the crude mixture analysed by analytical HPLC. The reaction
mixture was analysed on an analytical radio HPLC (Agilent 1100,
60:40 water:acetonitrile, flow rate 1.5 mL/min, fitted with an
Agilent Eclipse XDBC18, 5 mm, 4.6 ꢀ 150 mm column). During
each step the radioactivity of the waste gases was measured in
order to calculate incorporation of [11C]CO and radiochemical
˚
¨
2674–2678.
[14] O. Rahman, B. Langstrom, J. Label. Compd. Radiopharm. 2007, 50,
1192–1199.
˚
¨
˚
[15] T. Kihlberg, B. Langstro¨m, J. Org. Chem. 1999, 64(25), 9201–9205.
˚
[16] K. Farhad, B. Langstrom, Org. Biomol. Chem. 2003, 1(3), 541–546.
[17] B. Langstrom, O. Itsenko, O. Rahman, J. Labelled Compd.
¨
˚
¨
Radiopharm. 2007, 50(9), 794–810.
[18] Methods and Apparatus for Production and Use of [11C]Carbon
Monoxide in labelling Synthesis: International patent application,
˚
T. Kihlberg, B. Langstrom, T. Ferm, J. Eriksson, PCT/IB2005/
¨
001939, 2005.
[19] E. D. Hostetler, H. D. Burns, Nucl. Med. Biol. 2002, 29(8), 845–848.
[20] R. Singh, S. P. Nolan, Annu. Rep. Prog. Chem. Sect. B 2006, 102,
168–196.
[21] E. B. Kantchev, C. J. O’Brien, M. G. Organ, Angew. Chem. Int. Ed.
2007, 46, 2768–2813.
yields based on the starting radioactivity of the CuTp [11C]CO
Ã
[22] W. A. Hermann, C. Kocher, Angew. Chem. Int. Ed. Eng. 1997, 36,
2162–2187.
solution.
[23] C. Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org. Chem. 1999,
64, 3804–3805.
[24] Z. H. Chohan, M. Praveen, Appl. Organomet. Chem. 2001, 15(17),
617–625.
Acknowledgements
P.W.M. and L.E.J. are grateful to the EPSRC for the award of a Life
Sciences Interface Fellowship (EP/E039278/1) and
[25] S. Caddick, F. G. N. Cloke, P. B. Hitchcock, J. Leonard, A. K. de
K. Lewis, D. McKerrecher, L. R. Titcomb, Organometallics 2002, 21,
4318–4319.
[26] E. Maerten, M. Sauthier, A. Mortreux, Y. Castanet, Tetrahedron
2007, 63, 682–689.
a DTA
Studentship respectively. The Leverhulme Trust is thanked for
the award of a Research Fellowship (4/RFG/2009/0493) to N.J.L.
[27] M. B. Andrus, Y. Ma, Y. Zang, C. Song, Tetr. Lett. 2002, 43,
9137–9140.
[28] S. Zheng, F. Li, J. Liu, C. Xia, Tetr. Lett. 2007, 48, 5883–5886.
[29] A. S. Veige, Polyhedron 2008, 27, 3177–3189.
[30] Y. Ma, C. Song, Q. Chai, C. Ma, M. B. Andrus, Synthesis 2003, 18,
2886–2889.
[31] V. Calo, P. Giannoccaro, A. Nacci, A. Monopoli, J. Organomet.
Chem. 2002, 645(1–2), 152–157.
References
[1] M. E. Phelps, Proc. Natl. Acad. Sci. 2000, 97(16), 9226–9233.
[2] R. L. Wahl, Principles and Practice of PET and PET/CT, 2nd ed.,
Lippincott Williams & Wilkins, Philadelphia, PA, 2009.
[3] P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem. Int. Ed.
2008, 47, 8998–9033.
[32] Z. Freixa, P. W. N. M. Van Leeuwen, J. Chem. Soc., Dalton Trans.
2003, 10, 1890–1901.
[4] a) R. Bolton, J. Label. Compd. Radiopharm, 2001, 44(10), 701–736;
b) F. Wuest, M. Berndt, T. Kniess, Carbon-11 labelling chemistry
based upon [11C]methyl iodide, Ernst Schering Research Founda-
tion Workshop, Vol. 62 (Eds.: Schubiger, P.August; Lehmann, Lutz;
Friebe, Matthias), 2006, pp. 183–213.
[33] P. W. Miller, L. E. Jennings, A. J. deMello, A. D. Gee, N. J. Long,
R. Vilar, Adv. Synth. Catal. 2009, 351(18), 3260–3268.
[34] C. F. J. Barnard, Organometallics 2008, 27, 5402–5422.
[35] S. Diez-Gonzalez, S. P. Nolan, Coord. Chem. Rev. 2007, 251, 874–883.
[36] R. A. III Kelly, H. Clavier, S. Giudice, N. M. Scott, E. D. Stevens,
J. Bordner, I. Samardjiev, C. D. Hoff, L. Cavallo, S. P. Nolan,
Organometallics 2008, 27, 202–210.
[5] D. M. Jewett, Appl. Radiat. Isot. 1992, 43(11), 1383–1385.
[6] W. E. Klunk, H. Engler, A. Nordberg, Y. Wang, G. Blomqvist,
¨
D. P. Holt, M. Bergstrom, I. Savitcheva, G. Huang, S. Estrada,
B. Ausen, M. L. Debnath, J. Barletta, J. C. Price, J. Sandell,
¨
¨
[37] V. W. P. Bohm, C. W. K. Gstottmayr, T. Weskamp, W. A. Herrmann,
J. Orgamomet. Chem. 2000, 595, 186–190.
´
˚
[38] T. Kihlberg, B. Langstrom, PCT Int. Appl. WO, 2 002 102 711 A1,
¨
B. J. Lopresti, A. Wall, P. Koivisto, G. Antoni, C. A. Mathis,
˚
¨
B. Langstrom, Ann. Neurol. 2004, 55(3), 306–319.
2002, 559.
˚
[7] P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, H. Audrain, D. Bender,
J. Passchier, A. Gee, Angew. Chem. Int. Ed. 2007, 46, 2875–2878.
[39] O. Rahman, T. Kihlberg, B. Langstro¨m, Eur. J. Org. Chem. 2004,
474–478.
J. Label Compd. Radiopharm 2011, 54 135–139
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org