Ammonium [11C]thiocyanate: revised preparation and reactivity studies of a versatile nucleophile for carbon-11 radiolabelling

Article abstract of DOI:10.1039/c7md00425g

Herein we report the preparation of ammonium [¹¹C]thiocyanate via the reaction of [¹¹C]CS₂ with ammonia. The [¹¹C]SCN^- ion is demonstrated as a potent nucleophile that can be used to readily generate a range of ¹¹C-labelled thiocyanate molecules in high conversions. Furthermore, novel ¹¹C-labelled thiazolone molecules can be easily prepared from the intermediate α-thiocyanatophenones via an acid mediated cyclisation reaction.

Full text of DOI:10.1039/c7md00425g

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RESEARCH ARTICLE
Ammonium [11C]thiocyanate: revised preparation
and reactivity studies of a versatile nucleophile for
Cite this: DOI: 10.1039/c7md00425g
carbon-11 radiolabelling†
a
Tom Haywood,a Sara Cesarec,
Steven Kealey,a
Christophe Plissonb and Philip W. Miller
a
*
Herein we report the preparation of ammonium [11C]thiocyanate via the reaction of [11C]CS2 with ammonia.
The [11C]SCN− ion is demonstrated as a potent nucleophile that can be used to readily generate a range of
11C-labelled thiocyanate molecules in high conversions. Furthermore, novel 11C-labelled thiazolone mole-
cules can be easily prepared from the intermediate α-thiocyanatophenones via an acid mediated
cyclisation reaction.
Received 18th August 2017,
Accepted 11th May 2018
DOI: 10.1039/c7md00425g
rsc.li/medchemcomm
Positron emission tomography (PET) is now a widely used
clinical and research imaging technique for the study and
diagnosis of a range of neurological, oncological and cardiac
conditions.1–5 The expansion of PET imaging centres
worldwide over the past decade has led to an accompanying
increase in demand for both new and existing PET tracers.
The development of PET tracers presents a number of key
chemical and biological challenges due to the short half-lives
of positron-emitting nuclides, the peculiarity of tracer level
chemical reactions, the complexity of biological interactions,
and the strict working environment required for safe han-
dling of radioactive substances. The synthetic chemistry hur-
dles are particularly apparent considering that the half-lives
of the two most common PET nuclides, carbon-11 and fluo-
rine-18, are only 20.4 min and 109.7 minutes, respectively.
For example, a clinical radiopharmaceutical carbon-11 tracer
production involving radiosynthesis, purification and formu-
lation, typically needs to be complete within a 30–45 min
timeframe. The development of new tracers is further con-
founded by the limited number of available PET precursors
and methods for labelling, meaning that there are only a cer-
tain number of reactions that can be used to introduce the ra-
dionuclide.6 This limitation clearly restricts access to what
can ultimately be radiolabelled and where on the target mole-
cule the radionuclide can be introduced.
cally incorporated into tracers via well-established methyla-
tion protocols using [11C]CH3I or the more reactive
[11C]CH3SO3CF3.6,13 Carbon-11 methylation is, however, un-
suitable for labelling many interesting biological molecules,
either due to the absence of a methyl group on the target
molecule or due to unfavourable metabolism of the labelled
methyl group in vivo. A range of other reactive small mole-
cule carbon-11 reagents have therefore been developed to la-
bel in different positions. For example [11C]CO2,14 [11C]CO,15
[11C]HCN,11 [11C]CH2O16 and [11C]COCl2 have been used to
17
radiolabel carbonyl and cyano functional groups. Recently,
our group reported the production of a novel carbon-11 la-
belling reagent, [11C]carbon disulfide, and described its
initial reactivity studies for the efficient labelling of
organosulfur compounds such as dithiocarbamates, thio-
ureas and other biological molecules.18–20 Herein, we report
the facile production of ammonium [11C]thiocyanate, pre-
pared via the reaction of [11C]CS2 with ammonia, and de-
scribe preliminary radiolabelling reactions of this versatile
nucleophilic reagent.
The thiocyanate ion is a ‘pseudohalide’ and potent nu-
cleophile that can react either via the nitrogen atom or
Despite these challenges, an array of novel fluorine-18 and
carbon-11 labelling methods have been reported in recent
years to try overcome these challenges.7–12 Carbon-11 is typi-
a Department of Chemistry, Imperial College London, South Kensington, SW7 2AZ,
London, UK. E-mail: philip.miller@imperial.ac.uk; Tel: +44 (0)2875942847
b Imanova Limited, Imperial College London, Hammersmith Hospital, Burlington
Danes Building, Du Cane Road, London, W12 0NN, UK
† Electronic supplementary information (ESI) available: Experimental details
and HPLC traces. See DOI: 10.1039/c7md00425g
Scheme 1 A selection of organic molecules that can be prepared
using the thiocyanate ion.
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Scheme 3 Substitution reaction of benzyl bromide with [11C]NH4SCN
to generate benzyl [11C]thiocyanate.
[11C]SCN−. Carbon disulfide is known to react with ammonia
to give ammonium dithiocarbamate. On heating ammonium
dithiocarbamate to 90 °C, ammonium thiocyanate is gener-
ated along with one equivalent of H2S. We previously
reported a fast and easily accessible route to [11C]CS2 via the
reaction of sulfur vapour with [11C]CH3I. Unlike [11C]HCN,
[11C]CH3I is a much more commonly used carbon-11 label-
ling reagent that is prevalent in many PET centres. In our ini-
tial experiments to prepare [11C]SCN−, a stream of gaseous
[11C]CS2 was passed into an ammonia solution (0.1 M in
MeCN) and heated to 90 °C for 5 min. Analysis of the crude
reaction mixture confirmed [11C]NH4SCN formation, albeit in
low radiochemical yields (RCY) (<10%, Table 1). We
hypothesised that passing the [11C]CS2 gas stream directly
through the ammonia solution resulted in significant loss of
the volatile ammonia, hence greatly reducing its concentra-
tion and therefore limiting the reaction. To circumvent this,
the order of addition was changed to avoid ammonia loss;
first trapping the [11C]CS2 in acetonitrile (1 mL), then adding
the ammonia solution (50 μL, 2 M NH3 in CH3OH) and
heating to 90 °C for 5 min. Pleasingly, this resulted in near
quantitative radiochemical conversion of [11C]CS2 to
[11C]NH4SCN as observed by radio-HPLC (Table 1).
Given its ease of synthesis and potential utility as a nucle-
ophile, we aimed to explore the reactivity of the [11C]thiocya-
nate ion for substitution reactions. A simple model reaction
of [11C]NH4SCN with benzyl bromide was initially investi-
gated. In a typical labelling experiment, a solution of benzyl
bromide was injected into the reaction vial containing in situ
generated [11C]NH4SCN, and the mixture heated for 5 min at
90 °C (Scheme 3).
The crude product mixture was analysed by radio-HPLC
and the product identity confirmed by comparison of the ra-
dioactive sample with unlabelled reference material.
[11C]NH4SCN was found to react cleanly and quickly with ben-
zyl bromide showing virtually quantitative conversion to ben-
zyl [11C]thiocyanate (Chart 1). Encouraged by this result, we
Scheme
2 Previously reported routes to [
11C]SCN− relying on
generating [11C]HCN first (top); this work, which reports the synthesis
of [11C]SCN− via [11C]CS2 (bottom).
sulfur atom. It has been widely use to prepare organic thio-
cyanates and a range of other sulfur containing compounds
(Scheme 1).21 The thiocyanate ion is attractive from a
radiolabelling perspective because of its reactivity and po-
tential to form a wide range of organosulfur derivatives.
[11C]Thiocyanate has been previously reported, however, its
synthesis relies on the production of [11C]HCN, which is
not readily accessible in most PET centres, thus limiting its
potential wider use. Typically, [11C]SCN− is prepared by first
producing [11C]HCN, followed by conversion to a salt and
then reaction with
a sulfur source. The first reported
method describes a two-step process where [11C]HCN is
passed through a phosphorous pentoxide trap into a solu-
tion of sodium or potassium hydroxide to generate
[11C]CN−, which is then reacted with elemental sulfur to
give [11C]SCN− (Scheme 2, top).22,23 In an alternative ap-
proach, [11C]HCN can be converted to [11C]NaSCN via bro-
mination in triglyme to give [11C]BrCN followed by distilla-
tion over antimony and reaction with sodium sulfide
(Scheme 2, top).24 In an effort to prepare a range of sulfur
based labelled compounds we sought to explore alternative
methods to synthesise [11C]SCN− that circumvent the need
for specialised [11C]HCN synthesis equipment (Scheme 2).
Our recent work on the development of [11C]CS2 led us to
investigate this reagent as an alternative approach to prepare
proceeded to explore this reaction with
a range of
α-ketobromides to generate their respective 11C-labelled
Table 1 Conversion of [11C]CS2 to [11C]NH4SCN via reaction with ammonia solution
11CS2 + 2NH3 → NH4S11CN + H2S
Synthesis methoda
RCYb [11C]CS2 (%)
RCYb [11C]NH4SCN (%)
A
B
90
1
10
99
a
Method A: [11C]CS2 gas stream bubbled through ammonia solution (50 μL, 2 M NH3 in CH3OH, acetonitrile 1 mL) followed by heating to 90
°C for 5 min. Method B: addition of ammonia solution (50 μL, 2 M NH3 in CH3OH) to [11C]CS2 in acetonitrile (1 mL) followed by heating to 90
b
°C for 5 min. Non-isolated radiochemical yield (RCY) determined by analytical radio HPLC of the crude product based on conversion from
[
11C]CH3I. Average of minimum n = 3.
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Chart
2
11C-Radiolabelled thiazolone molecules. Average of
minimum n = 2.
heterocyclic structures.25–27 Thiazole structures are prevalent
in a number of important naturally occurring compounds,
for example thiamine and penicillin, and in a wide range of
bioactive small molecules such as benzothiazoles, while the
related thiazolones have been investigated for anti-cancer
activity.28 Carbon-11 radiolabelling within the ring of such
sulfur based heterocyclic structures is challenging, and to
the best of our knowledge has not been achieved until now.
Since thiazolones can be accessed in high yield from
α-thiocyanatophenones via an acid mediated cyclisation reac-
tion (Scheme 4), we sought to explore this pathway using our
in situ generated α-[11C]thiocyanatophenones.29
To test this in the radiochemistry laboratory, a solution of
1-phenyl-2-[11C]thiocyanatoethanone (2) was added to a mix-
ture of sulfuric and acetic acid, and heated to 90 °C for 5
min. This resulted in complete conversion of 2 to the cyclised
thiazolone, 4-phenylthiazol-2-[11C]one (10) (Scheme 5,
Chart 2). This cyclisation reaction was then performed with
the remaining phenyl-substituted α-[11C]thiocyanatophenones,
producing the corresponding 4-phenylthiazol-2-[11C]ones in
high radiochemical purity (70–95%, Chart 2).
Chart 1 Radiolabelled thiocyanate molecules. Average of minimum n
= 2.
Scheme 4 Acid mediated cyclisation of α-thiocyanatophenone which
is hypothesised to proceed via the intermediate oxathiolium salt prior
to thiazolone formation and elimination of sulfuric acid.
In conclusion, we have developed a new synthetic route to
ammonium [11C]thiocyanate via the reaction of ammonia
with [11C]carbon disulfide. The speed and efficiency of this
synthesis has enabled us to exploit the [11C]thiocyanate ion
as a potent nucleophilic species for the preparation of a
range of radiolabelled thiocyanate compounds in high radio-
chemical yields. Furthermore, we have been able to rapidly
conduct cyclisation reactions with these α-[11C]thio-
cyanatophenones to generate unprecedented 11C-thiazolone
molecules. We anticipate that this labelling route will find
further applications for the preparation of carbon-11 based
organosulfur tracers. Given that [11C]CS2 can be easily pre-
pared from the widely available carbon-11 precursor
[11C]CH3I we also expect that this method could be easily
adopted by other PET centres with carbon-11 facilities.
We are grateful for financial support from the EPSRC
(grant no. EP/L025140/1) and the Royal Society (grant no.
RG110449).
Scheme 5 One pot radiolabelling of 4-phenylthiazol-2-[11C]one (10)
via acid mediated cyclisation of the intermediate 1-phenyl-2-
[
11C]thiocyanatoethanone (2), (*) denotes the 11C labelling position.
α-thiocyanatophenones. We discovered that excellent conver-
sions could be achieved for the C-11 thiocyanation of all
seven α-ketobromides we tested, within a 5 min reaction time
(Chart 1). Lower conversions were observed for the reaction
of the diphenyl substrate (Chart 1, entry 8), most likely due
to the greater steric hindrance of this substrate inhibiting nu-
cleophilic attack of the thiocyanate ion. [11C]NH4SCN was
also found to react cleanly with mannose triflate, the precur-
sor used for 2-([18F]fluoro)-2-deoxy-D-glucose synthesis, to give
the labelled sugar thiocyanate derivative (9).
Thiocyanate compounds are interesting intermediates be-
cause they can be converted into other organosulfur and
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Conflicts of interest
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The authors declare no competing interest.
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