11C-Labeling: Intracyclic Incorporation of Carbon-11 into Heterocycles

Article abstract of DOI:10.1002/ejoc.201901386

Labeling of heterocycles with carbon-11 is generally performed through peripheral functionalizations and more scarcely inside heterocyclic core. Such less common approach usually requires preliminary multi-step synthesis of reactive species. Herein, a cyclization reaction by direct use of cyclotron-produced [¹¹C]CO₂ is described to obtain various heterocycles intracyclically labeled in only 10 minutes.

Full text of DOI:10.1002/ejoc.201901386

A Journal of
Accepted Article
Title: 11C labeling: Intracyclic incorporation of carbon-11 into
heterocycles
Authors: François Liger, Florence Cadarossane, Thibaut Iecker,
Christian Tourvieille, Didier Le BARS, and Thierry Billard
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901386
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901386
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
11C labeling: Intracyclic incorporation of carbon-11 into
heterocycles.
François Liger,[a] Florence Cadarossanesaib,[a] Thibaut Iecker,[a] Christian Tourvieille,[a] Didier Le
Bars,[a],[b] and Thierry Billard*[a],[b]
Abstract: Labeling of heterocycles with carbon-11 is generally
performed through peripheral functionalizations and more scarcely
inside heterocyclic core. Such less common approach usually
requires preliminary multi-step synthesis of reactive species. Herein,
a cyclization reaction by direct use of cyclotron-produced [11C]CO2 is
described to obtain various heterocycles intracyclically labeled in only
10 minutes.
radiolabeled heterocycles. Nevertheless, because of low
reactivity of CO2, this approach has so far been little investigated.
A first approach has been described by an in situ formation of
isocyanates.[13] [11C]CO2 has been trapped by a diamine or an
amino-alcohol in a first step, followed by a dehydration in a
second step, mediated by POCl3. The resulting isocyanates were
then cyclized to provide corresponding imidazolones or
oxazolidinones. This method still requires two steps and appears
limited in term of substrates scope. More recently, cyclic ureas
were synthesized by cyclization of azidoamines with [11C]CO2,
mediated by phosphine.[14] However, this method is limited to urea
compounds. Furthermore, heteroaromatic compounds cannot be
directly obtained following these strategies.
Introduction
Positron emission tomography (PET) is a non-invasive medical
imaging technique used as diagnostic tool in several
pathologies.[1] PET is also more and more applied in drug design,
allowing in vivo quantitative biodistribution and pharmacokinetic
studies.[2] This method requires radiolabeling of molecules with a
positron emitting radioisotope.[3] Among the most useful isotopes,
fluorine-18 and carbon-11 are preferentially employed. Even if
fluorine-18 is preferred due to its superior radioactive half-life (109
min for fluorine-18 vs 20 min for carbone-11), 11C-molecules are
still predominantly used for research purposes. Indeed, it is easier
to obtain radiolabeled equivalent of existing drugs by “isotopic
replacement” of carbon atom.
Results and Discussion
We have previously described direct 11C-methylation of amines
through an in situ metal/carbene-mediated reduction of carbon
dioxide.[15] During this process, the intermediate formation of
formamides has been demonstrated. Consequently, we
supposed that a similar strategy applied to diamines could lead to
cyclic compounds.
This hypothesis has been evaluated with 1,2-phenylenediamine
(1a) as starting material to obtain the corresponding
benzimidazole (2a) (Table 1).
The main strategy for compounds labeling is generally peripheral
4]
introduction of 11C-subtituents.[3a,
Radiolabeling inside the
molecules core, in particular of heterocyclic structures, has been
scarcely described.
Starting from the described conditions for methylation of amines
(entry 1), we were delighted to observe the formation of the
expected benzimidazole 2a, with good radiochemical yields (entry
1). However, in this assay, 10 mg of diamine 1a have been used.
Generally, smaller amounts (ca. 20 µmol) of starting material are
engaged in radiolabeling reactions. Unfortunately, by decreasing
the diamine 1a quantity (1.1 mg), to match with a more traditional
amount, radiochemical yield also dramatically diminished (entry
2). By using a slight excess of ZnCl2 and IPr (1,3-Bis(2,6-
diisopropylphenyl)imidazol-2-ylidene), a satisfactory result was
reobtained (entry 3). However, an excess of silane appeared to
be necessary to observe the expected cyclization (entries 3-4).
Some similar cyclizations have also been described with non-
radioactive CO2.[16] Described conditions did not use any metal
catalysts with a reaction time of 24h. Nevertheless, in our case
the use of ZnCl2 appeared to be crucial to observe cyclization in
a reaction time of only 20 min, more consistent with carbon-11
half-life (entry 5). The metal certainly contributes to accelerate
reaction so fitting with the short time imposed by radioactive
decay.
Few intracyclic labelings with carbon-11 have been previously
performed with various 11C-reagents:[5] [11C]phosgene,[6]
[11C]formic
acid
or
derivatives,[7]
[11C]formaldehyde,[8]
[11]
[11C]cyanide,[9] [11C]thiocyanate,[10] [11C]CS2
or [11C]CO.[12]
However, all these reagents require their preliminary preparation,
often in tedious conditions, which is time consuming. The starting
material is generally [11C]CO2 produced with a cyclotron by 14N(p,
a)11C nuclear reaction. Consequently, direct use of cyclotron-
produced [11C]CO2 could be of interest to obtain intracyclic
[a]
F. Liger, F. Cadarossanesaib, T. Iecker, C. Tourvieille, Dr. D. Le
Bars, Prof. Dr. T. Billard
CERMEP-In vivo imaging
59 Bd Pinel, 69677 Lyon, France
E-mail: Thierry.billard@univ-lyon1.fr
www.fmi-lyon.fr
[b]
Dr. D. Le Bars, Prof. Dr. T. Billard
Institute of Chemistry and Biochemistry (UMR CNRS 5246),
Univ Lyon, Université Lyon 1, CNRS, CPE, INSA
43 Bd du 11 novembre 1918, 69622 Villeurbanne, France
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
associated with a decrease of reaction volume, brought positive
effects and excellent radiochemical yields were observed (entries
5-7). By switching from 200 µL to 100 µL, no significant
improvement was observed. An attempt to reduce reaction time
to 5 min led only to a medium result (entry 8). In view of these
results, a volume of 200 µL will be generally preferred for further
investigations, to avoid potential solubility problems.
Table 1. Cyclization reaction with 1a and [11C]CO2.
N
N
NH2
N
IPr
+ [11C]CO2 + silane
ZnCl2
Diglyme (400µL)
N
H
NH2
2a
1a
150°C, 20 min
Table 2. Effect of reaction time and solvent volume[a]
=
11C
Entry
Reaction time (min)
Diglyme volume (µL)
2a(%)[b]
83
Entry
1a
ZnCl2
IPr
Silane
2a(%)[a]
1
2
3
4
5
6
7
8
20
10
10[c]
10[d]
10
10
10
5
400
400
400
400
300
200
100
100
(mg)
(equiv.)
(equiv.)
(equiv.)
25
1
2
3
4
5
6
7
8
10
0.15
0.15
1.2
1.2
-
0.15
PhSiH3
(1.00)
68
27
52
-
1
ca. 1.1
ca. 1.1
ca. 1.1
ca. 1.1
ca. 1.1
ca. 1.1
ca. 1.1
0.15
1.2
1.2
1.2
1.2
1.2
1.2
PhSiH3
(8.50)
38
66
PhSiH3
(8.50)
87
PhSiH3
(1.60)
90
48
PhSiH3
(8.50)
-
[a] Conditions: 1a (1.1-2.2 mg), ZnCl2 (1.2 equiv.), IPr (1.2 equiv.), Ph2SiH2
(11 equiv.), diglyme, 150°C, 10 min). [b] Radiochemical yields (RCY) were
estimated from trapped [11C]CO2 within the reactor and are decay-corrected
from end of [11C]CO2 trapping inside reactor. [c] under microwave irradiation
(100 W). [d] ZnCl2 (2.4 equiv.), IPr (2.4 equiv.).
1.2
1.2
1.2[b]
PHMS
(28.90)
32
83
-
Ph2SiH2
(11.00)
Ph2SiH2
(11.00)
In these optimal conditions, molar activity of produced
benzimidazole 2a was around 18 GBq/µmol. To study the scope
of this radiolabeling, various aromatic diamines were then studied
(Scheme 1).
[a] Radiochemical yields (RCY) were estimated from trapped [11C]CO2 within
the reactor and are decay-corrected from end of [11C]CO2 trapping inside
reactor. [b] with FeCl3 instead of ZnCl2.
Various benzimidazoles were obtained with, in general,
satisfactory to good radiochemical yields. Substitution onto
nitrogen atom does not significantly influence the obtained results
(2a-c). Whatever the electronic character (electron withdrawing or
donor) of aromatic substituents, similar yields were observed (2a-
f). However, slightly lower yields were observed with 2g and 2h,
maybe due to a competitive coordination of ZnCl2 catalyst by the
carbonyl function (2g) or the nitrogen atom of the pyridine core
(2h). Interestingly, reaction is compatible with functional groups
such as ketone (2g), ester (2e) or bromine (2d). In particular, no
reduction side-products were detected.
To extend this radiolabeling methodology, 6-membered rings
have been also studied. Thus, perimidine 2i was obtained with
similar good yields compared to benzimidazoles. More
interestingly, quinazolinone 2j was also synthesized starting from
corresponding 2-aminobenzamide. Because of the weakest
nucleophilicity of amide group, the expected cyclic product was
formed with only a medium radiochemical yield. However, a good
result was achieved by doubling reaction time to 20 min. By
decreasing solvent volume to 100 µL, a better yield was also
observed in 10 min.
With PhSiH3 as reducing agent, the cyclization reaction is in
competition with methylation of amino groups which can proceed
in similar conditions.[15] Indeed, some side-products arising from
this methylation competitive reaction were also observed. To
circumvent this drawback, less reducing silanes have been
envisaged. If only low yields were obtained with PMHS
(Poly(methylhydrosiloxane)),
a
higher and very good
radiochemical yield was observed with Ph2SiH2 (entries 6-7). In
this case, no methylation of amines was detected. Finally, FeCl3
has also been envisaged as catalyst but without any success
(entry 8).
Even if a reaction time of 20 min is compatible with carbon-11
radiolabeling, shorter durations are generally expected.
Consequently, with optimal conditions (entry 7), reaction time was
reduced to 10 min. An important decrease of radiochemical yield
has been observed (Table 2, entries 1-2). Microwave activation
was deleterious for the reaction, as already observed in the
previously described radiomethylation reactions (entry 3).[15]
Doubling catalysts amounts did not bring significant improvement
(entry 4). In contrast, an increase of concentration of precursor 1a,
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
IPr (1.2 equiv.)
ZnCl2 (1.2 equiv.)
NH2
N
This one-step, late stage, intracyclic labeling has been applied to
the first 11C-labeling of theophylline drug[20] (2k), with intracyclic
incorporation of radioisotope (Scheme 3).
[
11C]CO2
+
+
Ph2SiH2
Diglyme (200 µL)
150°C, 10 min.
N
R
NHR
(11 equiv.)
2
1
=
11C
Br
N
N
N
N
N
IPr (1.2 equiv.)
ZnCl2 (1.2 equiv.)
Ph2SiH2 (11 equiv.)
O
N
O
N
N
H
N
Ph
N
H
NH2
NH2
N
N
N
[
11C]CO2
+
2a
2b
90% (n = 2)
2d
2c
Diglyme (200 µL)
150°C, 10 min.
N
H
86% (n = 13)
74% (n = 2)
O
70% (n = 2)
O
O
2k
MeO2C
MeO
MeO
N
N
14% (n = 2)
18% (n = 2)[a]
N
Ph
N
H
N
H
N
H
2f
2e
2g
Scheme 3. Intracyclic labelling of theophylline. Radiochemical yields are mean
values and were estimated from trapped [11C]CO2 within the reactor and are
decay-corrected from end of [11C]CO2 trapping inside reactor. [a] diglyme
volume = 100 µL
80% (n = 2)
89% (n = 2)
52% (n = 2)
O
N
N
NH
N
37% (n = 2)
81% (n = 2)[a]
66% (n = 3)[b]
NH
N
H
N
2h
[11C]Theophylline was obtained in a modest radiochemical yield.
However, in view of the low reactivity of the starting diamine, the
result remains quite satisfactory and demonstrates the usefulness
of this method to label elaborated molecules.
2i
83% (n = 3)
2j
54% (n = 3)
Scheme 1. Cyclizations of aromatic diamines with [11C]CO2. Radiochemical
yields are mean values and were estimated from trapped [11C]CO2 within the
reactor and are decay-corrected from end of [11C]CO2 trapping inside reactor.
[a] reaction time = 20 min. [b] diglyme volume = 100 µL.
During these previous investigations, some reproducibility issues
were observed with a batch of IPr. Despite various analyses of
the different batches of IPr, we have not succeeded to determine
the reasons of such issues. Consequently, to try to circumvent
If benzimidazoles represent privileged structure in medicinal
chemistry and drugs,[17] benzothiazoles are also important
heterocyclic compounds in drug design and pharmaceutical
agents.[18] This heterocycle is also used in radiotracers
development, as illustrated by β-amyloid radioligand [11C]PIB.[19]
Consequently, our method was extended to aminobenzenethiols
(3) to obtain, for the first time, intracyclically 11C-labeled
benzothiazoles 4 (Scheme 2).
With optimal conditions used for benzimidazoles, only modest
radiochemical yield was observed (4a). As demonstrated
previously (Scheme 1; 2j), by decreasing solvent volume (100 µL
instead of 200 µL), a better result is obtained. Nevertheless, in
general, radiochemical yields remain modest, but suitable for
workable radiolabelings.
such potential drawback,
a preliminary preparation of IPr
solutions in diglyme, just before use, was envisaged (Scheme 4).
In comparison to commercial IPr, similar results were observed
with benzimidazole or benzothiazole. This use of home-made
solution of IPr constitutes a valuable alternative to potential
reproducibility issue and we warmly recommend this simple to
implement solution to avoid some disappointments during
radiolabelings.
N+
N
Cl-
tBuOK
Diglyme
RT
3h
IPr (1.2 equiv.)
ZnCl2 (1.2 equiv.)
NH2
N
[
11C]CO2
IPr
+
+ Ph2SiH2
(11 equiv.)
NH2
YH
Diglyme (200 µL)
150°C, 10 min.
solution in diglyme
N
Y
S
SH
R
R
[
11C]CO2
+
4
3
ZnCl2 (1.2 equiv.)
Ph2SiH2 (11 equiv.)
150°C, 10 min.
=
11C
2, 4
1, 3
Cl
N
F3C
Y = NH, S
N
N
S
4a
S
N
S
2a
N
S
4a
36% (n = 2)
55% (n = 3)[a]
50% (n = 3)
4b
4c
85% (n = 3)
35% (n = 4)[a]
36% (n = 2)[a]
N
H
[IPr] = 0.24 M
V = 100 µL
[IPr] = 0.12 M
V = 200 µL
Scheme 2. Cyclizations of aminobenzenethiols with [11C]CO2. Radiochemical
yields are mean values and were estimated from trapped [11C]CO2 within the
reactor and are decay-corrected from end of [11C]CO2 trapping inside reactor.
[a] diglyme volume = 100 µL.
Scheme 4. Cyclization reactions with home-made solution of IPr.
Radiochemical yields are mean values and were estimated from trapped
[
11C]CO2 within the reactor and are decay-corrected from end of [11C]CO2
trapping inside reactor.
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
was 8 minutes. Radiochemical yields were ranging from 70 to 80% decay-
corrected.
Finally, in order to demonstrate the effective productivity of this
new radiolabeling approach, a full radiosynthesis, with HPLC
purification, was performed with perimidine 2i (Scheme 5).
Noteworthy, a home-made solution of IPr was preferred.
Acknowledgements ((optional))
N
NH
NH2 NH2
This work was supported by European Union (EU) through the
project Radiochemistry for Molecular Imaging (project number EU
IPr (200 µL, C = 0.12 M)
(solution in diglyme)
[
11C]CO2
+
FP7-PEOPLE-2012-ITN-RADIOMI).
Frédéric
Bonnefoi
ZnCl2 (1.2 equiv.)
Ph2SiH2 (11 equiv.)
150°C, 10 min.
1i
2i
(CERMEP - in vivo imaging) is acknowledged for his technical
assistance. The authors wish to thank the Centre National de la
Recherche Scientifique (CNRS), Institut national de la santé et de
la recherche médicale (INSERM) and University of Lyon 1 for
financial support.
140 mCi (5.2 GBq)
RCY = 75% (n = 3)
(overall time: 33 min)
Scheme 5. Production of perimidine 2i. The RCY value is mean value and was
estimated from trapped [11C]CO2 within the reactor and are decay-corrected
from end of [11C]CO2 trapping inside reactor.
Keywords: Carbon-11 • Heterocycles • Radiochemistry •
Radiolabeling • Positron emission tomography
A good radioactive quantity (140 mCi, 5.2 GBq) of [11C]perimidine
(2i) was produced with a high radiochemical yield (RCY = 75%)
and with a good radiochemical and chemical purity. This result is
very encouraging and demonstrates the usefulness of this original
radiolabeling method to produce radiotracers.
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Conclusions
To conclude, cyclization reactions by direct use of cyclotron-
produced [11C]CO2 were described to obtain in a late stage and
one-pot process, heterocyclic and heteroaromatic compounds
intracyclically labeled with carbon-11. This strategy constitutes a
proof of concept about direct use of [11C]CO2 in “radiocyclization”
reactions and should open the way to new developments
concerning radiolabeling of heterocyclic molecules.
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Synthesis of [11C]perimidine (2i): 200 µL of freshly prepared IPr solution
in diglyme (24 µmol, 1.2 eq) was added to a 1 mL vial containing 3.15 mg
of 1,8-diaminonaphtalene (20 µmol, 1eq). The resulting solution was
sonicated for 2 min and transferred to a 1.1 mL conical vial pre-charged
with 3.35 mg of zinc chloride (24.2 µmol, 1.21 eq). After addition of 40 µL
of diphenylsilane (0.215 mmol, 11 eq), the vial was sealed and placed into
the automated synthesis module 10 min before end of bombardment.
When the desired level of radioactivity was reached in cyclotron (nearly
3000 mCi – 111 GBq), reaction with [11C]CO2 proceeded according
previous general procedure (see SI). After 10 min of heating at 150°C, the
reaction vial was cooled at 20°C for 2.5 minutes. Then, 2 x 100 µL of MeOH
were sequentially added to the reaction mixture (30 seconds apart) and
after further 20 seconds, the whole content of the reaction vial was loaded
into a 3 mL HPLC loop. 700 µL of additional MeOH were used for rinsing
the reaction vial and loaded into the HPLC loop before injection on semi-
preparative HPLC column (Macherey-Nagel Nucleodur C18 HTec column
(10µm, 10 x 250mm). HPLC purification was conducted at 3 mL/min with
acetate buffer pH 5.2/MeCN (55/45) as mobile phase. Radioactive and UV
monitoring at 254 nm allowed the collection of 346-386 mCi (12.8-14.3
GBq, decay-corrected) of purified 1H-[11C]Perimidine 2i. Retention time
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
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10.1002/ejoc.201901386
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Labeling inside. Intracyclic labeling
with carbon-11 of heterocycles has
been performed directly from
cyclotron-produced [11C]CO2. Many
heterocycles have been obtained via a
de novo cyclization in only 10 min,
without the preliminary transformation
of [11C]CO2
Radiochemsitry*
François Liger, Florence
Cadarossanesaib, Thibaut Iecker,
Christian Tourvieille, Didier Le Bars,
Thierry Billard*
Page No. – Page No.
11C labeling: Intracyclic incorporation
of carbon-11 into heterocycles.
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.