Radiosynthesis of novel carbon-11-labeled triaryl ligands for cannabinoid-type 2 receptor

Article abstract of DOI:10.1016/j.bmcl.2010.01.074

Two novel triaryl ligands 2 and 5 with potent in vitro binding affinities for the cannabinoid subtype-2 (CB2) receptor were labeled with a positron-emitting radioactive nuclide ¹¹C. Radioligands [¹¹C]2, [¹¹C]5, and their analogs [¹¹C]3 and [¹¹C]4 were synthesized by O-[¹¹C]methylation of their corresponding phenol precursors with [¹¹C]CH₃I. [¹¹C]2-5 had relatively high uptakes (>1.2% injected dose/g tissue) in mouse brains.

Full text of DOI:10.1016/j.bmcl.2010.01.074

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1565–1568
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Radiosynthesis of novel carbon-11-labeled triaryl ligands for
cannabinoid-type 2 receptor
Masayuki Fujinaga a, Katsushi Kumata a, Kazuhiko Yanamoto a, Kazunori Kawamura a, Tomoteru Yamasaki a,
Joji Yui a, Akiko Hatori a, Masanao Ogawa a,b, Yuichiro Yoshida a,b, Nobuki Nengaki a,b, Jun Maeda a,
Ming-Rong Zhang a,
*
a 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:
Two novel triaryl ligands 2 and 5 with potent in vitro binding affinities for the cannabinoid subtype-2
(CB2) receptor were labeled with a positron-emitting radioactive nuclide 11C. Radioligands [11C]2,
Received 15 December 2009
Revised 9 January 2010
Accepted 13 January 2010
Available online 21 January 2010
[
11C]5, and their analogs [11C]3 and [11C]4 were synthesized by O-[11C]methylation of their corresponding
phenol precursors with [11C]CH3I. [11C]2–5 had relatively high uptakes (>1.2% injected dose/g tissue) in
mouse brains.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cannabinoid subtype-2
PET
Triaryl ligands
Brain uptake
Radiosynthesis
Two seven-transmembrane
G
protein-coupled cannabinoid
of cannabinoid receptors in the human brain.9–12 These PET ligands
belonged mostly to probes specific for the CB1 receptor. However, to
our knowledge, PET ligands that can be used for imaging of the CB2
receptor in animals and humans have not been developed.
receptors have been identified and divided into the cannabinoid-
type 1 (CB1) and -type 2 (CB2) receptors.1,2 The CB1 receptor is
one of the most abundant neuromodulatory receptors in the brain;
both CB1 and CB2 receptors are widely distributed in peripheral
tissues.3 The CB2 receptor is particularly enriched in immune tis-
sues, but is also present in the brain at a low concentration.4 The
protective effect of the CB2 receptor in activated microglial cells
due to inflammation-induced damage to the central nervous sys-
tem (CNS) has been demonstrated in mouse models of multiple
sclerosis.5 The CB2 receptor is therefore considered to be a power-
ful neuroprotective target for treating neurodegenerative disor-
ders.6 Administration of CB2-selective agonists to wild-type mice
subjected to excytotoxicity reduced neuroinflammation, brain ede-
ma, striatal neuronal loss, and motor symptoms.6,7 The precise dis-
tribution and physiological significance of events mediated by the
CB2 receptor are still controversial.8 The therapeutic potential of
CB2 ligands in the pathology and/or etiology of CNS disorders
needs to be elucidated more clearly.
Thus far, only three PET ligands for the CB2 receptor have been
reported. [11C]Sch225336 and 11C- and 18F-labeled 2-oxoquinoline
analogs ([11C]1a and [18F]1b) were synthesized and evaluated in
normal rodents by
a
same research group (Scheme 1).13,14
CH3
NHSO2CH3
O
H3CO
N
H
S
RO
C4H9O
N
H
O
O2
H311CO
SO2
[
[
11C]1a: R = O11CH3
[
11C]Sch225336
R1
18F]1b: R = CH2CH218F
Cl
Cl
R1
Cl
Cl
R2
S
R2
S
Positron emission tomography (PET) is an in vivo imaging modal-
ity that uses short-lived, positron-emitting radioligands to probe
biochemical processes in living humans and animals. PET studies
with 11C- or 18F-labeled ligands have been performed for imaging
OH
O
2: R1 = R2 = OCH3,
11C]2: R1 = O11CH3, R2 = OCH3,
3: R1 = OCH3, R2 = OH,
11C]3: R1 = O11CH3, R2 = OH
4: R1 = R2 = OCH3,
11C]4: R1 = O11CH3, R2 = OCH3,
5: R1 = OCH3, R2 = OH,
11C]5: R1 = O11CH3, R2 = OH
[
[
[
[
* Corresponding author. Tel.: +81 43 382 3708; fax: +81 43 206 3261.
E-mail address: zhang@nirs.go.jp (M.-R. Zhang).
Scheme 1. Chemical structures of PET ligands for the cannabinoid-type 2 receptor.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.074

1566
M. Fujinaga et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1565–1568
Sch225336, 1a and 1b had potent in vitro binding affinities for hu-
man CB2 receptor (Ki = 4.5, 9.6, and 35.8 nM) and low affinities for
CB1 receptor. However, [11C]Sch225336 did not pass through the
and 6 (33%). Reduction of the carbonyl group in 5 and 6 with NaBH4
afforded alcohols 3 and 7 at high yields of 91% and 90%, respectively.
Labeling of 2–5 with 11C was performed using a home-made
automated synthesis system17 (Scheme 2). The labeling reagent
blood–brain barrier (BBB) to enter the mouse brain.13 11C]1a and
[
[
18F]1b had much higher uptakes of radioactivity in the mouse
[
11C]methyl iodide ([11C]CH3I) for radiosynthesis was produced
brain when compared to [11C]Sch225336, and were characterized
to have some specific binding in the brain and peripheral systems.
Based on these results, it is indicated that [11C]1a and [18F]1b are
promising PET ligands for the CB2 receptor.14
by reduction of the cyclotron-produced [11C]CO2 with LiAlH4, fol-
lowed by iodination with 47% hydroiodic acid. [11C]CH3I was puri-
fied by distillation and trapped in a solution of DMF (300 mL)
containing desmethyl phenol precursor 3, 7, 5, or 6 (1 mg, 3–
The aim of the present study was to label two novel triaryl li-
gands 2 and 5 for the CB2 receptor with 11C. The two ligands exhib-
ited high in vitro binding affinities (2, Ki = 0.27 nM; 5, 2.32 nM) for
CB2 in the homogenate fractions of rat brains.15 Moreover, they
had low affinity (2, >1000 nM; 5, 503 nM) for CB1. For the first
time, we labeled them with 11C to obtain [11C]2 and [11C]5. We also
synthesized two novel analogs 3 and 4 and labeled them with 11C.
Analog 3 or 4 was derived by removing or adding one methyl group
in 2 or 5. Compound 3 is a bioister of 2 and is less lipophilic than 2,
which may decrease non-specific binding in vivo. By searching this
triaryl compound’s library,15 we assumed that 3 and 4 maintain
binding affinities with the CB2 receptor similar to those for 2 and
5. In this study, we report: (1) chemical synthesis of non-radioac-
tive ligands 2–5 and their corresponding desmethyl precursors, (2)
radiosynthesis of [11C]2–5, and (3) radioactivity concentrations of
these radioligands in whole brain and blood of mice.
The triaryl ligands 2–5 and their desmethyl precursors for radio-
synthesis were prepared according to reaction sequences delineated
inScheme2.16 Couplingof triflate9 withdichlorophenylboronicacid
was a challenging step. We attempted this coupling according to a
conventional procedure15 in which Pd(PPh3)4 was used as a catalyst,
but we obtained the biaryl 10 only at a low yield. LiCl addition to the
reaction mixture caused the coupling to proceed efficiently to pro-
duce 10. The desired triaryl 2 was prepared by treatment of 10 with
2-thienylmagnesium bromide. Oxidation of 2 readily afforded 4
with a yield of 96%. Cleavage of one or two methoxy groups in 4 at
the same time was carried out with 2 equiv of BBr3, which produced
a mixture of mono- (5) and bis- (6) desmethylated compounds. This
mixture was purified using column chromatography to give 5 (57%)
4 mmol) and aqueous NaOH (7
[
l
L, 0.5 N) at ꢀ15 °C. After
11C]CH3I trapping ceased, the radioactive mixture was warmed
to 50 °C and kept for 5 min. The O-[11C]methylation reaction was
terminated by adding CH3CN/H2O, and the radioactive mixture
was applied onto a reversed phase semi-preparative HPLC system.
Purification of the reaction mixtures using this system (CAP-
CELL PAK C18 column: 10 mm ID ꢁ 250 mm, CH3CN/H2O: 7/3 or
8/2) provided [11C]2–5 in 34 15%, 33 9%, 28 5%, and 19 3%
radiochemical yields (n = 3 for each ligand based on [11C]CO2, cor-
rected for decay), respectively. Starting from 13–21 GBq of
[
11C]CO2, [11C]2–5 was reliably obtained as an injectable solution
with 1.0–3.6 GBq. This amount of radioactivity is generally suffi-
cient for animal experiments. The identity of these radioactive
products was confirmed by co-injection of non-radioactive 2–5
on analytic HPLC (CAPCELL PAK C18 column: 4.6 mm ID ꢁ 250 mm,
CH3CN/H2O: 7/3 or 8/2). In the final product solution, no significant
peak of the corresponding desmethyl precursor was observed in
their HPLC charts. The radiochemical purity of [11C]2–5 was higher
than 98% and the specific activity was 48–103 GBq/lmol. The
radiochemical purity of [11C]2–5 remained >95% after being main-
tained at 25 °C for 180 min, indicating these radioligands were sta-
ble for the time of a PET scan.
We determined radioactivity concentrations of [11C]2–5 in the
brain and blood of mice. A solution of each [11C]ligand (mean of
8 MBq/200 mL) was injected into the tail vein of male Wister mice
(ꢂ30 g, 7 weeks). Three mice were sacrificed by cervical dislocation
at 1, 5, 15, 30, and 60 min after injection with each ligand. Whole
brain and blood samples were quickly removed. The radioactivity
present in these tissues was measured and expressed as
a
Cl
Cl
OCH3
OCH3
OCH3
OCH3
O
(c)
(a)
(b)
HO
TfO
Cl
Cl
H
S
H3CO
CHO
H3CO
CHO
H3CO
H3CO
OH
8
9
10
2
Cl
Cl
Cl
OCH3
OH
OH
(d)
(e)
(f)
Cl
Cl
Cl
S
S
S
H3CO
R
R
O
O
OH
5: R = OCH3
6: R = OH
3: R = OCH3
7: R = OH
4
3
(i)
[
11C]2
7
(i)
[
11C]3
(g)
(h)
11CH3I
11CO2
11CH3OH
5
[
[
11C]4
11C]5
(i)
6
(i)
Scheme 2. Chemical synthesis and radiosynthesis: Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, 0 °C to rt, 2 h, 80%; (b) 3,5-dichlorophenylboronic acid, LiCl, Pd(PPh3)4,
2 M Na2CO3, Toluene, 90 °C, 24 h, 69%; (c) 2-thienylmagnesium bromide, THF, ꢀ20 °C, 5 h, 66%; (d) pyridinium chlorochromate, CH2Cl2, rt, 4 h, 96%; (e) BBr3, CH2Cl2, ꢀ40 °C to
rt, 19 h, 57% (5), 33% (6); (f) NaBH4, EtOH, 0 °C to rt, 5 h; 91% (3), 90% (7); (g) LiAlH4, THF, ꢀ15 °C, 2 min; (h) HI, 180 °C, 2 min; (i) NaOH, DMF, 50 °C, 5 min; 34% ([11C]2,
corrected for decay from [11C]CO2), 33% ([11C]3), 28% ([11C]4), 17% ([11C]5).

M. Fujinaga et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1565–1568
1567
Table 1
Radioactivity (% of injected dose/g tissue: mean SD, n = 3) in the brain and blood of mice at 1, 5, 15, 30, and 60 min after injection
Tissue
Brain
Time (min)
[
11C]2
[
11C]3
[
11C]4
[
11C]5
1
5
15
30
60
1.93 0.15
1.87 0.24
1.50 0.14
1.09 0.05
0.65 0.05
1.94 0.29
2.07 0.13
1.77 0.12
0.96 0.08
0.45 0.05
1.20 0.13
1.29 0.10
1.10 0.09
0.85 0.15
0.62 0.12
1.54 0.04
1.63 0.26
1.01 0.10
0.56 0.04
0.18 0.02
Blood
1
5
15
30
60
3.90 0.14
2.12 0.10
2.25 0.51
2.38 0.13
2.27 0.13
2.20 0.33
1.18 0.24
0.70 0.03
0.35 0.03
0.37 0.28
2.71 0.32
2.93 0.17
3.45 0.24
3.42 0.35
3.38 0.04
1.56 0.12
1.00 0.03
0.63 0.15
0.36 0.04
0.21 0.05
percentage of the injected dose per gram of wet tissue (% ID/g).
Radioactivity measurements were corrected for decay.
[
11C]3 and [11C]5 may become promising PET ligands for in vivo
imaging of the CB2 receptor in the brain.
Table 1 shows uptakes of [11C]2–5 in the brain and blood of
mice after injection at different time points. These radioligands en-
tered the brain rapidly and their maximum radioactivity levels
reached >1.2% ID/g, indicating that they could pass through the
BBB. This is a prerequisite for a good PET ligand used in brain imag-
ing, and was probably due to their high lipophilicity (clog D >4;
Pallas 3.4 Software). Although the maximum brain uptakes of
Acknowledgements
This study was supported in part by Grants-in-Aid for Scientific
Research for the Molecular Imaging Program from the Ministry of
Education, Culture, Sports, Science and Technology, Government
of Japan.
[
11C]2–5 were half-fold lower than those of [11C]1a and [18F]1b,
their radioactivity levels in the brain were higher than those of
some useful PET probes17–19 developed by us for clinical brain
imaging. Uptakes of alcohols [11C]2 and [11C]3 in the brain were
higher than those of ketones [11C]4 and [11C]5. After initial uptakes,
the radioactivity levels of [11C]2–5 in the brain decreased over
time, and their brain washout expressed as 1 min/60 min ratio ID
was 2.9, 4.3, 1.9, and 8.6, respectively.
References and notes
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Neurochem. 2005, 95, 437.
In the blood, [11C]2–5 displayed a different pattern of uptake
over time and dimethoxy [11C]2 displayed a slow decrease of radio-
activity in the blood. Uptake of another dimethoxy [11C]4 did not
reduce and its uptake at 60 min even increased by 1.2-fold in com-
parison with that at 1 min after injection. This result may be re-
lated to the high lipophilicity (clog D = 5.7) of [11C]4. A high
lipophilic ligand could bind to plasma proteins, which would sig-
nificantly obstruct its penetration into the brain. Indeed, among
the radioligands in the present study, the maximum uptake of
6. Palazuelos, J.; Aguado, T.; Pazos, M. R.; Julien, B.; Carrasco, C.; Resel, E.; Sagreda,
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Alexander, M.; Kumar, A.; Rahmim, A.; Scheffel, U.; Wong, D. F.; Dannals, R. F. J.
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Hecken, A.; Dupont, P.; De Lepeleire, I.; Rothenberg, P.; Stoch, S. A.; Cote, J.;
Hagmann, W. K.; Jewell, J. P.; Lin, L. S.; Liu, P.; Goulet, M. T.; Gottesdiener, K.;
Wagner, J. A.; de Hoon, J.; Mortelmans, L.; Fong, T. M.; Hargreaves, R. J. Proc.
Natl. Acad. Sci. U.S.A. 2007, 104, 9800.
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L.; Busson, R.; Lambert, D. M.; Van Laere, K.; Verbruggen, A. M.; Bormans, G. M.
Nucl. Med. Biol. 2008, 35, 793.
[
11C]4 in the brain was the lowest.
11C]3 and [11C]5 displayed rapid decrease of radioactivity in the
[
blood in contrast to [11C]2 and [11C]4. Uptakes of [11C]3 and [11C]5
at 60 min reduced to 17% and 13% of their values at 1 min, respec-
tively. Their ID ratios of brain/blood increased over time after
injection. The maximum value was 2.7 for [11C]3 at 30 min, 1.7
for [11C]5 at 15 min, whereas that was 0.9 for [11C]2 at 5 min and
0.4 for [11C]4 at 5 min. These results suggest that [11C]3 and
[
[
11C]5 have more suitable in vivo properties in the brain than do
11C]2 and [11C]4.
14. Evens, N.; Muccioli, G. G.; Houbrechts, N.; Lambert, D. M.; Verbruggen, A. M.;
Van Laere, K.; Bormans, G. M. Nucl. Med. Biol. 2009, 36, 455.
15. Moore, B. M. II; Bhattacharjee, H.; Yates, C. R.; Stuart, L. WO 2008/109027.
We did not measure the radioactivity concentrations of [11C]2–
16. Compound
2
(30,50-dichloro-2,6-dimethoxybiphenyl-4-yl)(thiophen-2-yl)metha-
5 in the mouse brain regions because of the possible low density
and unclear distribution of the CB2 receptor in the brain.4 It has
been reported that the CB2 receptor was increased in microglia
activated by brain injury and neuroinflammation.5,6 Based on the
brain kinetics of [11C]5, it is worth characterizing whether [11C]5
has in vivo specific binding with the CB2 receptor in the brain.
Due to its similar structure and brain kinetics with [11C]5, [11C]3
derived from the reduction of [11C]5 may also be a promising radi-
oligand for brain imaging, although the affinity of 3 for the CB2
receptor still needs to be measured. We are currently using inflam-
matory animal models to evaluate the potential of [11C]3 and
nol): White powder; mp: 158–160 °C; 1H NMR (300 MHz, DMSO-d6) d: 3.68
(s, 6H), 5.96 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 4.8 Hz, 1H), 6.85 (s, 2H), 6.93–6.97
(m, 2H), 7.23 (d, J = 1.8 Hz, 2H), 7.41 (dd, J = 1.5, 3.3 Hz, 1H), 7.50 (t, J = 2.0 Hz,
1H); GC–MS (EI), m/z: 394.
Compound 3 (30,50-dichloro-2-hydroxy-6-methoxybiphenyl-4-yl)(thiophen-2-yl)-
methanol): White powder; mp: 124–126 °C; 1H NMR (300 MHz, DMSO-d6) d:
3.67 (s, 3H), 5.86 (d, J = 4.0 Hz, 1H), 6.22 (d, J = 4.3 Hz, 1H), 6.67 (s, 2H), 6.93–
6.96 (m, 2H), 7.26 (d, J = 2.1 Hz, 2H), 7.39–7.41 (m, 1H), 7.47 (t, J = 2.0 Hz, 1H),
9.58 (s,1H); GC–MS (EI), m/z: 380.
Compound
4
(30,50-dichloro-2,6-dimethoxybiphenyl-4-yl)(thiophen-2-yl)metha-
none): White powder; mp: 203–205 °C; 1H NMR (300 MHz, CDCl3) d: 3.80 (s,
6H), 7.12 (s, 2H), 7.21 (t, J = 4.4 Hz, 1H), 7.25 (d, J = 1.8 Hz, 2H), 7.34 (t,
J = 1.8 Hz, 1H), 7.76–7.77 (m, 2H); High-resolution MS (FAB), m/z: 393.0084
(calculated for C19H15O3Cl2S, 393.0119).
[
11C]5 for the CB2 receptor in the brain.
Compound 5 (30,50-dichloro-2-hydroxy-6-methoxybiphenyl-4-yl)(thiophen-2-yl)-
methanone): Yellow powder; mp: 199–201 °C; 1H NMR (300 MHz, DMSO-d6) d:
3.76 (s, 3H), 6.98 (s, 1H), 7.10 (s, 1H), 7.32 (t, J = 4.2 Hz, 1H), 7.36 (d, J = 0.9 Hz,
In conclusion, four novel radioligands [11C]2–5 were synthe-
sized and they exhibited relatively high uptakes into mouse brains.

1568
M. Fujinaga et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1565–1568
2H), 7.56 (t, J = 1.3 Hz, 1H), 7.85 (d, J = 3.7 Hz, 1H), 8.14 (d, J = 5.1 Hz, 1H), 10.09
(s, 1H); High-resolution MS (FAB), m/z: 378.9929 (calculated for C18H13O3Cl2S,
Compound 9 (trifluoromethanesulfonic acid 4-formyl-2,6-dimethoxyphenyl ester):
1H NMR (300 MHz, CDCl3) d: 3.98 (s, 6H), 7.17 (s, 2H), 9.94 (s, 1H); GC–MS (EI),
m/z: 314.
378.9962).
Compound
6
(30,50-dichloro-2,6-dihydroxybiphenyl-4-yl)(thiophen-2-yl)metha-
Compound 10 (30,50-dichloro-2,6-dimethoxybiphenyl-4-carbaldehyde): 1H NMR
(300 MHz, CDCl3) d: 3.83 (s, 6H), 7.15 (s, 2H), 7.21 (d, J = 1.8 Hz, 2H), 7.35 (t,
J = 1.8 Hz, 1H), 9.98 (s, 1H); GC–MS (EI), m/z: 310.
none): White powder; mp: 187–189 °C; 1H NMR (300 MHz, DMSO-d6) d: 6.94
(s, 2H), 7.32 (t, J = 4.0 Hz, 1H), 7.40 (d, J = 1.8 Hz, 2H), 7.54 (t, J = 1.6 Hz, 1H),
7.80 (d, J = 3.3 Hz, 1H), 8.12 (d, J = 4.8 Hz, 1H), 9.96 (s, 2H); High-resolution MS
(FAB), m/z: 364.9848 (calculated for C17H11O3Cl2S, 364.9806).
17. Zhang, M.-R.; Kida, T.; Noguchi, J.; Furutsuka, K.; Maeda, J.; Suhara, T.; Suzuki,
K. Nucl. Med. Biol. 2003, 30, 513.
18. Zhang, M.-R.; Maeda, J.; Ogawa, M.; Noguchi, J.; Ito, T.; Yoshida, Y.; Okauchi, T.;
Obayashi, S.; Suhara, T.; Suzuki, K. J. Med. Chem. 2004, 47, 2228.
19. Zhang, M.-R.; Kumata, K.; Maeda, J.; Yanamoto, K.; Hatori, A.; Okada, M.;
Higuchi, M.; Obayashi, S.; Suhara, T.; Suzuki, K. J. Nucl. Med. 2007, 47, 43.
Compound
7
(30,50-dichloro-2,6-dihydroxybiphenyl-4-yl)(thiophen-2-yl)metha-
nol): White powder; mp: 58–61 °C; 1H NMR (300 MHz, DMSO-d6) d: 5.76 (d,
J = 3.7 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 6.50 (s, 2H), 6.93–6.96 (m, 2H), 7.31 (d,
J = 1.5 Hz, 2H), 7.40 (d, J = 4.9 Hz, 1H), 7.44 (t, J = 2.0 Hz, 1H), 9.45 (s, 2H); GC–
MS (EI), m/z: 350.