[11C]Carbon disulfide: A versatile reagent for PET radiolabelling

Article abstract of DOI:10.1002/chem.201103128

Quick as a flash! ¹¹CS₂ can now be produced rapidly and with high radiochemical yields and specific radioactivities by the high temperature gas-phase reaction of ¹¹CH₃I with the thionating agent P₂S

Full text of DOI:10.1002/chem.201103128

COMMUNICATION
DOI: 10.1002/chem.201103128
ACHTUNGTRENNUNG
Philip W. Miller*[a] and Dirk Bender[b]
Positron emission tomography (PET) is an important
imaging modality for the clinical diagnosis and staging of a
wide range of conditions such as cancer, neurodegenerative
illnesses and cardiovascular diseases.[1] The preparation of
radiotracers necessary for PET imaging is an exceptionally
challenging area of chemistry principally because of the
short half-lives of the commonly used positron emitting ra-
ever, despite these newer chemical labelling techniques and
the application of technologies such as microfluidics[6] and
microwave reactors,[7] there is still an enormous desire to de-
velop new and innovative chemical methods to radiolabel
tracer molecules.
Carbon disulfide, the sulfur analogue of carbon dioxide, is
a commonly used reagent and solvent in the chemical indus-
try for the production of materials such as rayon and cello-
phane and for the synthesis of a wide range of organosulfur
compounds including dithiocarbamates, xanthates and thio-
ureas.[8] There are obvious parallels between CS2 and its iso-
electronic partner CO2, however, CS2 has distinctly different
physical and chemical properties. Notably, CS2 is a volatile
and flammable liquid at room temperature (b.p.=468C) and
is considered to be more reactive owing to the weaker C=S
double bond. Considering the now widespread use of small
and reactive 11C molecules, such as CO, CO2, HCN, COCl2,
CH3OTf and CH3I, in the PET field it is surprising that
there has only been one previous report of 11CS2, obtained
in low radiochemical yields,[9] even though it has enormous
potential to form a wide range of organic molecules that
may hold promise for potential applications in PET imaging.
Herein, we report a new method for the rapid and high
yielding synthesis of 11CS2 and demonstrate its reactivity for
the first time as an effective route to 11C-labelled organosul-
fur compounds.
ACHTUNGTRENNUNG
dioisotopes (11C t1/2 =20.4 min, 18F=109 min, 13N=9.96 min,
15O=2.04 min).[2] Typically, only one or two discrete chemi-
cal transformations can ever be performed, which can limit
the complexity of the desired tracer molecule. The key chal-
lenge in PET radiochemistry is to convert basic cyclotron-
generated precursors into suitably complex molecules for
imaging studies within a timeframe of minutes.
Carbon-11 is one of the most widely used PET radioiso-
topes because of its favourable physical and biological char-
acteristics, however, its short 20 min half-life necessitates ex-
tremely rapid chemistry.[3] Currently, [11C]methyl iodide is
the most widely used reactive precursor for 11C radiolabel-
ling, with 11C-methylation reactions accounting for the vast
majority of labelled 11C PET tracers. 11C-methylation reac-
tions are, in general, technically straight forward to perform,
are typically fast reactions and can be used to access a wide
variety of 11C-labelled tracer molecules. However, there are
inherent limitations to 11C-methylation chemistry that re-
stricts the range and diversity of tracer molecules that can
ever be labelled using this method. 11C-methylation reac-
tions are always restricted to labelling the periphery of the
target molecule, which can be a disadvantage in terms of
metabolism of the molecule. Consequently, new labelling
protocols and methods are required to expand the types of
labelled molecules used for PET imaging. In recent years
11CS2 was efficiently produced by the gas phase reaction
of the widely used 11C precursor 11CH3I and the thionating
agent P2S5. In a typical reaction, a gas stream of 11CH3I, pro-
duced using a commercial GE TRACERlab fx module, was
passed through a small glass column packed with a mixture
of P2S5 and sand, in a 1:2 ratio, and heated to 3808C. The
gases were vented into a collection vial containing acetoni-
trile at room temperature, which conveniently trapped 11CS2
in solution. A small activated charcoal trap was placed at
the vent of this vial to trap any radioactivity that passed
though the solution. The conversion of 11CH3I was instanta-
neous, and high radiochemical yields (>85%) and high spe-
cific radioactivities (100 GBqmmolÀ1) of 11CS2 were obtained
as determined by radio-HPLC analysis (Figure 1 and
Table 1). The only major contaminant was a small amount
of unreacted 11CH3I. The conversion of 11CH3I to 11CS2 was
found to be dependent on both the oven temperature and
gas flow rate through the column. Reactions at lower tem-
peratures of 1508C failed to give any conversion of 11CH3I,
whereas raising the oven temperature to 3808C was found
to give highly efficient conversions. The gas flow rate of
[5]
the use of 11CO[4] and 11CO2 have become more important
as alternative reagents for the synthesis of 11C tracers, espe-
cially for radiolabelling within the core of a molecule. How-
[a] Dr. P. W. Miller
Department of Chemistry
Imperial College London
London, SW7 2AZ (UK)
Fax : (+44)20-7594-5804
E-mail: philip.miller@imperial.ac.uk
[b] Dr. D. Bender
PET Imaging Division
Aarhus University Hospital PET Center
8000C Aarhus (Denmark)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103128.
Chem. Eur. J. 2012, 18, 433 – 436
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
433

amine. In a typical experiment a small aliquot (200 mL) of
the 11CS2 solution in acetonitrile was added to an amine so-
lution and the reaction mixture was allowed to stand at
room temperature for 5 min prior to radio-HPLC analysis.
All the amines tested were found to react cleanly and effi-
ciently with 11CS2 to give the corresponding dithiocarbamate
salts 1, 2, 5 and 7 (Scheme 1) in almost quantitative yield
Figure 1. Radio-HPLC trace of a typical 11CS2 production reaction.
Table 1. Results of 11CS2 production runs by reaction of thionating
agents 11CH3I.
Entry
Thionating agent
T [8C)
RTE[a]
RCP[b]
RCY[c]
1
2
3
P2S5
P2S5
150
380
380
85 (n=2)
91 (n=6)
5 (n=1)
–
–
93Æ2
87Æ3
Lawessonꢁs reagent
–
–
[a] RTE (radioactive trapping efficiency) is based on activity trapped in
the collection vial expressed as a fraction of total of radioactivity mea-
sured in the system from the end of 11CH3I production. [b] RCP (radio-
chemical purity) is based on the integration of radioactive peaks from
the radio-HPLC trace. [c] RCY (radiochemical yield) is decay corrected
based on total radioactivity in the system corrected for RCP. n=number
of runs.
methyl iodide through the P2S5 column also had a significant
impact on conversions, higher gas flow rates of 15–
20 mLminÀ1 resulted in decreased conversions, whereas an
optimum gas flow rate of 5–6 mLminÀ1 resulted in good
conversions with an acceptable processing time of <10 min
from the end of 11CH3I production. We also investigated the
effect of other thionating agents to further improve 11CS2
production. A mixture of the commonly used thionating
agent, the Lawessonꢁs reagent (2,4-bis(4-methoxyphenyl)-
1,3,2,4-dithiadiphosphetane-2,4-disulfide), and sand (1:2
ratio) was packed into a glass column and the reaction of
11CH3I performed under the previously determined opti-
mised conditions. Disappointingly however, no 11CS2 was
formed under these conditions. The vast majority of radioac-
tivity was found to be retained on the column which ap-
peared blackened as a result of the decomposition of the
Lawessonꢁs reagent. Only a small fraction of radioactivity
(<5%) was trapped in the acetonitrile solution. Subsequent
radio-HPLC analysis revealed a complex mixture of radio-
active peaks.
Scheme 1. Production and reaction of 11CS2.
(Table 2). The radio-HPLC trace of [11C]benzylamine dithio-
carbamate (2) showed quantitative conversion and complete
reaction of 11CS2 with benzylamine (see the Supporting In-
formation). The only observed radioactive by-product from
these reactions was the corresponding 11C methylated qua-
ternary ammonium salt, which is a result of the slight con-
tamination of the 11CS2 solution with 11CH3I. In most cases,
Table 2. Reaction of 11CS2 with amines to form dithiocarbamate salts.
Entry
Amine
N
RCY[a]
1
99 (n=2)
2
99 (n=4)
Carbon disulfide is a small electrophilic molecule that has
found numerous uses in organic synthesis as a one-carbon
building block primarily for the preparation of organosulfur
compounds. Our initial experiments have focused on the re-
action of nucleophilic amines with 11CS2. This is a well-
known and widely used reaction for the high yielding forma-
tion of dithiocarbamate compounds.[10] A range of primary
and secondary amines were selected for reaction with 11CS2,
and included aniline, benzylamine, diethylamine and methyl-
3
4
69 (n=2)[b]
98 (n=2)
[a] RCY is based on the conversion of 11CS2 to [11C]dithiocarbamate and
measured using integration of radioactive peaks from the radio-HPLC
trace. (*) indicates 11C labelling position. n=number of runs.[b] Average
yield is lower due to contamination with 11CH3I.
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Chem. Eur. J. 2012, 18, 433 – 436

ACHTUNGTRENNUNG
[11C]Carbon Disulfide for PET Radiolabelling
COMMUNICATION
however, this accounted for <5% of radioactivity on the
radio-HPLC trace. Interestingly, when an approximate 50:50
mixture of 11CH3I and 11CS2 in acetonitrile was added to a
benzylamine solution (5 mL in 300 mL) and allowed to stand
at room temperature for 5 min the complete reaction of
11CS2 was observed within this time while 11CH3I remained
unreacted, which indicated that 11CS2 is a more potent elec-
trophile than 11CH3I. A significant decrease in the 11CH3I
peak on the radio-HPLC trace was only observed after a
10 min reaction time and only after all the 11CS2 had react-
ed.
Scheme 2. Conversion
of
[11C]benzyldithiocarbamate
(2)
to
[11C]benzylisothiocyanate (3).
bamate to the [11C]benzyldithiocarbamate after only 5 min
(see the Supporting Information).
We believe that 11CS2 will be an extremely useful addition
to the inventory of small and reactive 11C molecules that are
currently being used for PET radiotracer synthesis. Both the
ease and efficiency with which 11CS2 can be formed should
prove particularly appealing to the field of PET chemistry
and radiotracer development. In addition to investigating
further methods to improve 11CS2 synthesis, we are currently
in the process of exploring the scope of 11CS2 labelling reac-
tions for a much wider range of [11C]organosulfur com-
pounds. Of particular interest is the development of meth-
ods to produce [11C]isothiocyanates and the subsequent re-
action of these compounds to form more complex heterocy-
clic ring compounds, which could form the basis of new
Dithiocarbamates have found many uses as chelating lig-
ACHTUNGTRENNUNGands for the formation of a very wide range of metal com-
plexes within the field of inorganic chemistry.[11] They are
also commonly used precursors for a range of organosulfur-
containing compounds and have found large-scale agricul-
tural uses as herbicides and pesticides.[12] Dithiocarbamates,
such as diethyldithiocarbamate (5), are also finding applica-
tions as anticancer agents by acting as zinc and copper che-
lators.[13] 11C-labelled dithiocarbamates, efficiently prepared
by the one-step reaction of 11CS2 with amines, are versatile
precursors for further reaction. A series of dithiocarbamate
alkylation reactions were investigated using either methyl
iodide or benzylamine (Scheme 1). In a typical reaction, a
small amount of alkylhalide solution (5 mL in 150 mL aceto-
nitrile) was added to the 11C dithiocarbamate and allowed to
stand at room temperature for 5 min followed by radio-
HPLC analysis. Both the methylation of benzyldithiocarba-
mate (2) and the benzylation reaction of diethyldithiocarba-
mate (5) and methyldithiocarbamate (7) were found to be
highly efficient and selective resulting in high radiochemical
yields of products (see the Supporting Information). Thus
11C dithiocarbamate salts can be efficiently converted into
their neutral alkylated forms by the simple and rapid reac-
tion with alkylhalides.
radioACTHNUTRGENUGtN racers for PET imaging applications.
Experimental Section
Detailed experimental procedures for the production and reaction of
11CS2 are reported in the Supporting Information.
Acknowledgements
P.W.M. is grateful to the EPSRC for the award of a Life Sciences Inter-
face Fellowship (EP/E039278/1).
Dithiocarbamates are also precursors to highly reactive
isothiocyanates, which can subsequently be converted to im-
portant classes of sulfur-containing organic compounds such
as thioureas, thiosemicarbazones and sulfur containing het-
erocyclic rings. It was, therefore, of high interest for us to
explore the reactivity of 11C dithiocarbamates for the forma-
tion of 11C isothiocyanates owing to their importance as
highly reactive intermediates.[14] Dithiocarbamates may be
converted to isothiocyanates through a desulfurylating reac-
tion by a variety of techniques.[15] Unfortunately, however,
when desulfurylating reactions of [11C]benzyldithio-
carbamate were performed using molecular iodine or lead
nitrate, decomposition of the dithiocarbamate occurred that
resulted in poor radiochemical yields of the labelled isothio-
cyanate. The use of POCl3 as a desulfurylating agent, how-
ever, proved to be more successful in generating
[11C]benzylisothiocyanate (3) (Scheme 2). When a large
excess of POCl3 (100 mL) was added to a solution of
[11C]benzyldithiocarbamate, [11C]benzylisothiocyanate was
efficiently generated (RCY=78%). Radio-HPLC of this re-
action confirmed the complete conversion of the dithiocar-
Keywords: carbon disulfide · carbon-11 · imaging agents ·
positron emission tomography · radiochemistry
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Received: October 4, 2011
Published online: December 12, 2011
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Chem. Eur. J. 2012, 18, 433 – 436