Utilization of [11C]phosgene for radiosynthesis of N-(2-{3-[3,5-bis(trifluoromethyl)]phenyl[11C]ureido}ethyl) glycyrrhetinamide, an inhibitory agent for proteasome and kinase in tumors

Article abstract of DOI:10.1016/j.bmcl.2012.04.049

N-(2-{3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for proteasome and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea 2 using [¹¹C]phosgene ([¹¹C]COCl₂) as a labeling agent with the expectation that [¹¹C]2 could become a positron emission tomography ligand for the imaging of proteasome and kinase in tumors. The strategy for the radiosynthesis of [¹¹C]2 was to react hydrochloride of 3,5-bis(trifluoromethyl)aniline (4·HCl) with [ ¹¹C]COCl₂ to possibly give isocyanate [¹¹C]6, followed by the reaction of [¹¹C]6 with N-(2-aminoethyl) glycyrrhetinamide (3).

Full text of DOI:10.1016/j.bmcl.2012.04.049

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3594–3597
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Utilization of [11C]phosgene for radiosynthesis of N-(2-{3-[3,5-bis(trifluoro-
methyl)]phenyl[11C]ure2;ido}ethyl)glycyrrhetinamide, an inhibitory agent for
proteasome and kinase in tumors
Chiharu Asakawa a, Masanao Ogawa a,b, Masayuki Fujinaga a, Katsushi Kumata a, Lin Xie a,
Tomoteru Yamasaki a, Joji Yui a, Toshimitsu Fukumura a, Ming-Rong Zhang a,
⇑
a Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
b SHI Accelerator Service Co. Ltd, 5-9-11 Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
N-(2-{3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted
derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for protea-
some and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea
2 using [11C]phosgene ([11C]COCl2) as a labeling agent with the expectation that [11C]2 could become a
positron emission tomography ligand for the imaging of proteasome and kinase in tumors. The strategy
for the radiosynthesis of [11C]2 was to react hydrochloride of 3,5-bis(trifluoromethyl)aniline (4ꢀHCl) with
Received 8 March 2012
Revised 5 April 2012
Accepted 10 April 2012
Available online 18 April 2012
Keywords:
Proteasome
Kinase
[
11C]COCl2 to possibly give isocyanate [11C]6, followed by the reaction of [11C]6 with N-(2-amino-
ethyl)glycyrrhetinamide (3).
11C]urea
Ó 2012 Elsevier Ltd. All rights reserved.
[
[
11C]phosgene
PET
18-b-Glycyrrhetinic acid (GA, 1, Scheme 1) is the main constitu-
The promising and unique pharmacological profiles of 2 as an anti-
tumor agent promoted us to label this compound with positron-
emitting carbon-11 (11C; half life: 20.4 min) (Scheme 1), with the
expectation that [11C]2 may become the first positron emission
tomography (PET) ligand for the double imaging of kinase and pro-
teasome in tumors.
ent of Glycyrrhiza glabra, which has antitussive, antiulcer, antialler-
gic, anti-inflammatory, immunotrophic, and hypolipidemic
activity.1 In vitro inhibitory activity of 1 for animal and human
tumor cells was found 30 years ago.2 In vivo antitumor activity in-
duced by 1 was also reported for various tumors-bearing animals.3,4
The recent development of 1 derivatives has mainly focused on
compounds having both cytotoxic and cytostatic properties, which
can overcome multidrug resistance for chemotherapy.5–8
N-(2-{3-[3,5-Bis(trifluoromethyl)phenyl]ureido}ethyl)glycyr-
rhetinamide (2) is a new derivative of 1 with antitumor activity
that enables drug resistance to be overcome when administrated
with chemotherapeutic drugs.9 Compound 2 showed cytostatic
PET is a useful molecular imaging modality with high functional
sensitivity, which permits repeatable and non-invasive assessment
of biological and pharmacological processes.10,11 PET studies
with radioligands have been used to quantitatively measure and
elucidate the distribution and pharmacological action of receptors,
enzymes, and transporters etc., which contributes to disease diagno-
sis and determination of the most effective doses of therapeutic
drugs.10–12 We have already performed a number of 11C-labeling
of antitumor agents13–17 and used them as PET ligands for in vitro
and in vivo evaluations.
properties and high inhibitory activity (IC50: 4–12
cell lines, including A549, SKMEL, T98G, HS683, U373, PC3, MGF7
and B16F10. This compound at 1 M further inhibited the enzy-
lM) for 8 tumor
l
matic activity of 12 kinases, such as anaplastic lymphoma, B-
tyrosine, p-21 associated kinases family, enriched in tumors by
In the present study, we synthesized [11C]2 (Scheme 1) for the
first time. Regarding the chemical structure of 2 with hydroxy,
>50%. In addition, 2 at 7
lM bound with 3 catalytic units of protea-
amide, a,b-unsaturated ketone and urea functional groups, it is dif-
some and significantly inhibited the activation of proteasome.
Therefore, 2 was considered as a potent inhibitor of proteasome
and kinases which are overexpressed in many types of tumors.
ficult to envisage the labelling of this compound using the conven-
tional [11C]methyl iodide without changing its structure and
pharmacological activity. Fortunately, the presence of an unsym-
metrical urea moiety in 2 prompted us to label the molecule using
[
11C]phosgene ([11C]COCl2) as the labeling agent18,19 (Scheme 1).
⇑
Corresponding author. Tel.: +81 43 382 3708; fax: +81 43 206 3261.
E-mail address: zhang@nirs.go.jp (M.-R. Zhang).
The labeling approach included: (1) routine production of
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.049

C. Asakawa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3594–3597
3595
CF3
A
B
O
C
H
O
OH
O
N
N
H
N
H
CF3
H
H
O
H
O
H
H
H
HO
HO
1
2
CF3
O
H
H
N
O
N
11C
O
N
N
NH2
CF3
H
H
CF3
H
H
O
H
O
H
O
11C
Cl
+
+
H2N
Cl
CF3
H
H
HO
HO
[
11C]2
3
4
H
N
C
O
CF3
NHBoc
H
6
O
H
O
C
N
CF3
H2NCH2CH2NHBoc
a
CF3COOH
b
3
1
2
c
H
HO
5
Scheme 1. Reagents and conditions: (A) Chemical structures of 1 and 2; (B) retrosynthesis of [11C]2; (C) syntheses of 2 and 3: (a) N,N0-dicyclohexylcarbodiimide,
hydroxybenzotriazole, DMF, room temperature, 10 h, 90%; (b)CH2Cl2, room temperature, 2 h, 65%; (c) THF, room temperature, 10 h, 76%.
Entry 1
11C]COCl2
(2) synthesis and usefulness of two different
20–23
[
H2, Ni
a
Cl2
b
I2O5, H2SO4
c
11CO2
11CCl4
11COCl2
11CH4
amines: N-(2-aminoethyl)glycyrrhetinamide (3) and 3,5-bis(tri-
fluoromethyl)aniline (4), and (3) construction of an unsymmetrical
[
11C]urea moiety, as shown in the retro-synthetic route.
Entry 2
R-NH2
O
Before radiolabeling, we synthesized the non-radioactive com-
11C
pound 29 and 3 as a precursor of the present radiosynthesis, accord-
11COCl2
R'-NH2
R
N
N R'
H
H
ing to the synthetic route delineated in Scheme 1C. The coupling
reaction of
1 with N-(tert-butoxycarbonyl)-1,2-diaminoethane
Entry 3
was prepared in the presence of N,N0-dicylclohexylcarbodiimide
and hydroxybenzotriazole to give 5 in 90% yield. Removal of the
Boc group of 5 with trifluoroacetic acid gave 3 in 65% yield. Reaction
of 3 with commercially available isocyanate 6 in anhydrous THF at
room temperature for 10 h afforded 2 as an authentic sample in
76% yield. Compounds 5, 3 and 2 were identified by NMR and
high-resolution mass spectra.24
O
11C
HCl
.
11
C O
R'-NH2
11COCl2
R N
+
R
N
N
R'
R-NH2
H
H
Scheme 2. Reagents and conditions: Production of [11C]COCl2 and strategy for
constructing an unsymmetrical [11C]urea moiety: (a) 400 °C, 2 min; (b) 560 °C,
2 min; (c) room temperature, 2 min, 60–85% from
corrected).
[
11C]CO2 (n >50, decay-
The synthetic route for the preparation of of [11C]COCl2 as a
labeling agent is shown in entry 1 of Scheme 2. [11C]CH4 was pro-
duced by the reduction of cyclotron-produced [11C]CO2 with H2
using nickel metal as a catalyst. Chlorination of [11C]CH4 with
Cl2, followed by oxidation of [11C]CCl4, gave [11C]COCl2.20–23
In our facility, we have developed a convenient and reliable sys-
tem to achieve the automated production of [11C]COCl2 for routine
radiosynthesis.21,22 After irradiation by a cyclotron beam on the
target, [11C]CO2 was recovered from the target and concentrated
in the inner space of a stainless steel tube, which was cooled under
liquid N2 in advance. [11C]CO2 was released from the steel tube and
mixed with H2 gas. Passing this mixture with H2 of 10 mL/min
through a methanizer, which was coated with nickel catalyst and
heated at 400 °C, gave [11C]CH4. After mixing [11C]CH4 with Cl2
gas carefully, the gaseous mixture was flowed through a quartz
tube heated at 560 °C with N2 of 50 mL/min to produce [11C]CCl4.
Continuous passage of [11C]CCl4 through a glass tube filled with
oxidizing agents at room temperature produced [11C]COCl2. The
multi-step reaction afforded [11C]COCl2 with 60–85% radiochemi-
cal yield (n >50, decay-corrected) based on the total [11C]CO2,
which required about 10 min from the end of bombardment under
this online system. The routine production of [11C]COCl2 has en-
abled efficient synthesis of PET ligands containing [11C]urea and
[
11C]carbamate moieties.15,17,25
Reliable construction of an unsymmetrical [11C]urea moiety had
been a challenging task using the reaction of [11C]COCl2 with two
different amines.26–30 As shown in entry 2 of Scheme 2, formation
of symmetrical [11C]urea due to the reaction of [11C]COCl2 with
two molecules of the same amine was the main problem. To

3596
C. Asakawa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3594–3597
prevent the formation of symmetrical [11C]urea, we have set up a
reliable and convenient technique (entry 3). In place of the free
amine (RNH2), hydrochloride of the amine (RNH2ꢀHCl) was used
as the starting material for the first step-reaction with [11C]COCl2.
It was found that RNH2ꢀHCl had enough nucleophilicity to react
with [11C]COCl2, producing a [11C]isocyante as a possible interme-
diate.15 Due to decreased nucleophilicity, the excess RNH2ꢀHCl
could not further react with the [11C]isocyante to yield the unde-
sired symmetrical [11C]urea. After the first reaction step, another
amine R0NH2 was added to the reaction mixture and reacted with
the [11C]isocyante to produce the desired unsymmetrical [11C]urea.
In this present study, we thus applied this technique to synthesize
than utilization of 3ꢀHCl (Fig. 1B vs Fig. 2B). The difference between
the two results might be caused by different nucleophilicity of 3ꢀHCl
and 4ꢀHCl. Compared to the reactivity of alkylamine 3ꢀHCl with
[
11C]7, aniline 4ꢀHCl might be less reactive towards [11C]6. Subse-
quent addition of free 3 to the reaction mixture thus gave [11C]2
with more efficiency.
After optimizing the reaction conditions, such as the precursor
amount, reaction temperature and time, we carried out automated
synthesis of
[ a
11C]2 using home-made system32 to obtain
reliable and reproducible amount of radioactivity. Starting from
16.7–22.2 GBq of [11C]CO2, 0.70–1.01 GBq of [11C]2 was obtained
at the end of synthesis (n = 7) with a synthesis time of 34–
37 min from the end of bombardment. The identity of [11C]2 was
confirmed by co-injection with non-radioactive 2 on analytic HPLC.
In the solution of finally-formulated product, the radiochemical
purity of [11C]2 was higher than 97% and specific activity was
[
11C]2 using hydrochloride of 3 or 4 (3ꢀHCl or 4ꢀHCl) in place of free
amine 3 or 4.
[
11C]COCl2 gas was firstly trapped in a THF solution containing
3ꢀHCl (0.25 mg, 0.46
l
mol) at ꢁ15 °C for 1 min, possibly producing
[
11C]isocyanate [11C]7. Then, 4 (0.21 mg, 0.92
l
mol) was added to
32–48 GBq/lmol. No significant UV peaks corresponding to 3, 4
this mixture and the reaction mixture was heated at 60 °C for
3 min (Fig. 1A). After the two-step reactions, the reaction mixture
was analyzed and purified using a reversed-phase HPLC system.31
Figure 1B shows the HPLC chromatogram of this reaction mixture,
in which the desired [11C]2 was produced with 32.7% incorporation
yield of the total radioactivity.
and other chemical impurities were observed on the HPLC chart
of the product solution. Moreover, the radiochemical purity of
[
11C]2 remained >95% after standing for 90 min at room tempera-
ture, showing that this product was radiochemically stable within
the period of at least one PET scan. The analytical results were in
compliance with quality control/assurance specifications in our
institute.
In place of 3ꢀHCl, 4ꢀHCl was also used as the precursor for radio-
synthesis (Fig. 2). [11C]COCl2 gas was trapped in a THF solution
In conclusion, [11C]2 was synthesized using 4ꢀHCl as a precursor
and [11C]COCl2 as a labeling agent, followed by the reaction with 3.
The labeling route was reliable and reproducible, which produced
enough radioactivity of [11C]2 for evaluation experiment. We will
use several tumor cell lines to perform an in vitro cellular uptake
experiment and PET imaging of tumor-bearing rodents with
containing 4ꢀHCl (0.25 mg, 0.94
the 1-min [11C]COCl2 trapping step giving the possible [11C]isocya-
nate [11C]6 , 3 (0.96 mg, 1.88
mol) was added to the mixture and
lmol) at ꢁ15 °C for 1 min. After
l
this reaction mixture was heated at 60 °C for 3 min (Fig. 2A).
Figure 2B shows the HPLC chromatogram of the reaction mixture,
in which the desired [11C]2 was produced with 69.1% incorporation
yield of the total radioactivity.
[
11C]2. We hope that the results obtained by this study may be use-
ful for elucidating the relationship between kinase/proteasome
and chemotherapeutic resistance and studying the antitumor ef-
fects of 2 and its analogs.
By comparing the two synthetic routes of [11C]2, we found that
utilization of 4ꢀHCl gave a higher incorporation yield of radioactivity
A
H
H
11
C
O
N
O
N
NH2
HCl
N
O
.
H
H
O
11C
O
H
O
H
a
4
+
[
11C]2
Cl
Cl
b
H
H
HO
HO
[
11C]7
.
3 HCl
B
2000
1800
1600
1400
1200
1000
800
[
11C]2
UV
RI
600
400
200
0
0
2
4
6
8
10
12
14
Time / min
Figure 1. (A). Radiosynthesis from 3ꢀHCl: (a) THF, ꢁ15 °C, 1 min; (b) THF, 60 °C, 3 min, 32.7% (incorporation of total radioactivity in the final reaction mixture). (B) HPLC
chromatogram for the reaction mixture.

C. Asakawa et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3594–3597
3597
A
CF3
CF3
O
11C
a
3
b
[
11C]2
+
Cl
Cl
11
F3C
NH2
F3C
N C O
.
HCl
[
11C]6
.
4 HCl
B
4500
4000
3500
3000
2500
2000
1500
1000
500
[
11C]2
UV
RI
0
0
2
4
6
8
Time / min
10
12
14
Figure 2. (A). Radiosynthesis from 4ꢀHCl: (a) THF, ꢁ15 °C, 1 min; (b) THF, 60 °C, 3 min, 69.1% (incorporation of total radioactivity in the final reaction mixture). (B) HPLC
chromatogram for the reaction mixture.
18. Miller, P. M.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem., Int. Ed. 2008, 47,
Acknowledgements
8998.
19. Roeda, D.; Dollé, F. Curr. Top. Med. Chem. 2010, 10, 1680.
20. Nishijima, K.; Kuge, Y.; Seki, K.; Ohkura, K.; Motoki, N.; Nagatsu, K.; Tanaka, A.;
Tsukamoto, E.; Tamaki, N. Nucl. Med. Biol. 2003, 29, 345.
21. Ogawa, M.; Takada, Y.; Suzuki, H.; Nemoto, K.; Fukumura, T. Nucl. Med. Biol.
2010, 37, 73.
22. Takada, Y.; Ogawa, M.; Suzuki, H.; Nemoto, K.; Fukumura, T. Appl. Radiat. Isot.
2010, 68, 1715.
We are grateful to Mrs. Y. Yoshida and N. Nengaki (SHI Acceler-
ator Service Co., Ltd.) for technical support with radiosynthesis. We
also thank the staff of the National Institute of Radiological Sci-
ences for support with the cyclotron operation and radionuclide
production.
23. Yashio, K.; Katayama, Y.; Takashima, T.; Ishiguro, N.; Doi, H.; Suzuki, M.; Wada,
Y.; Tamai, I.; Watanabe, Y. Bioorg. Med. Chem. Lett. 2012, 1, 115.
24. Analytic data of compounds are listed as follows: Compound 5, white solid; mp:
220–222 °C (223 °C9). 1H NMR (300 MHz, DMSO-d6) d: 0.69 (8H, d,
J = 11.73 Hz), 1.01 (11H, d, J = 7.70 Hz), 1.16 (4H, t, J = 7.33 Hz), 1.33 (6H, s),
1.35 (9H, s), 1.49–1.84 (8H, m), 1.98 (2H, s), 2.30 (1H, s), 2.54 (1H, d,
J = 9.16 Hz), 2.98–3.15 (6H, m), 4.29 (1H, d, J = 5.13 Hz), 5.49 (1H, s), 6.68 (1H,
br), 7.57 (1H, br). HRMS (FAB) Calcd for C37H60N2O5, 612.450; Found: 613.455
([M+H]+).
References and notes
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Compound 3, white solid; mp: 153–155 °C. 1H NMR (300 MHz, DMSO–d6) d:
0.69 (8H, d, J = 9.90 Hz), 0.89 (5H, s), 1.01 (11H, d, J = 4.40 Hz), 1.10–1.15 (2H,
m), 1.27 (4H, s), 1.33 (6H, s), 1.40–2.07 (8H, m), 2.30 (1H, s), 2.97–3.16 (4H, m),
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for C32H52N2O3, 512.783; Found: 513.406([M+H]+).
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DMSO–d6) d: 0.64 (9H, d, J = 14.66 Hz), 0.81 (4H, s), 0.88 (4H, s), 0.94 (4H, s),
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s), 7.69 (1H, br), 8.04 (2H, s), 8.31 (1H, s), 9.44 (1H, s). HRMS(FAB) Calcd for
C
41H55N3O4F6, 767.900; Found: ([M+H]+).
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