Design and synthesis of phenoxypyridyl acetamide or aryl-oxodihydropurine derivatives for the development of novel pet ligands targeting the translocator protein 18 kDa (TSPO)

Full text of DOI:10.1002/bkcs.10979

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DOI: 10.1002/bkcs.10979
BULLETIN OF THE
J. Lee et al.
KOREAN CHEMICAL SOCIETY
Design and Synthesis of Phenoxypyridyl Acetamide or
Aryl-oxodihydropurine Derivatives for the Development of Novel PET
Ligands Targeting the Translocator Protein 18 kDa (TSPO)
Jihye Lee,† Jae Ho Jung,‡ Byung Chul Lee,‡,§ and Sang-Yoon Lee†,¶,
*
†Neuroscience Research Institute, Gachon University, Incheon 21565, Korea.
*E-mail: rchemist@gachon.ac.kr
‡Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National
University Bundang Hospital, Seongnam 13620, Korea
§Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of
Convergence Technology, Suwon 16229, Korea
¶Department of Neuroscience, College of Medicine, Gachon University, Incheon 21936, Korea
Received July 8, 2016, Accepted September 3, 2016, Published online October 13, 2016
Keywords: Translocator protein 18 kDa, Positron emission tomography radioligand,
Neurodegenerative disease, Neuroinflammation
Since last decades, the neuroinflammation has been eluci-
dated to develop the methods of therapy or diagnosis for
neurodegenerative disease including Alzheimer’s disease,
Parkinson’s disease, multiple sclerosis and so on.1 The
translocator protein 18 kDa (TSPO) is mainly found on the
outer mitochondrial membrane as intramitochondrial cho-
lesterol transporter. In central nervous system, the overex-
pression of TSPO represents the activation of microglia,
which involves initial stage of the neuroinflammation.2
Development of TSPO ligands with high-binding affinity
and specificity emerged in the mid-1980s, and the first
generation TSPO ligands, Ro5-48643 and PK111954 were
investigated as a positron emission tomography (PET)
ligand (Figure 1(a)).
Because PET ligands are very useful for sensitive, non-
invasive, and pathological diagnosis, many researchers
have developed the various structures of TSPO ligands as
PET tracers. [11C]PK11195 is the first generation of TSPO
PET ligand showing high-binding affinity (Ki = 3–5 nM)
and widely used in clinical study, but non-specific binding
and slow pharmacokinetic properties are the limitation for
in vivo quantification of inflammatory process in brain.2b
Later, C-11 labeled phenoxyphenyl acetamide [11C]
PBR285 was introduced in 2007 and showed higher con-
trast between inflammatory region and normal region,
which is derived from its relatively lower lipophilicity (c
log P = 2.98).5a In the same year, another C-11 labeled
TSPO PET ligand [11C]AC-5216 was reported, which has
aryl-oxodihydropurine as a core structure.6
PET images resolution compared to F-18. Consequently,
several groups have put their efforts on the development
of F-18 labeled TSPO PET ligands (Figure 1(b) and
(c)).7–10 Among them, 6-[18F]fluoro-PBR28 showed the
enhanced binding affinity compared to PK11195 (2.3–5.9
times in rat and human) and PBR28 (1.6 times in rat).11
The introduction of fluorine into the 6 position on pyri-
dine ring of PBR28 is much beneficial to obtain higher
binding affinity against TSPO.
In this paper, as a continuing effort to search novel
TSPO PET ligands, we designed and prepared phenoxypyr-
idyl acetamide and aryl-oxodihydropurine derivatives, and
also evaluated their binding affinity. To examine the chemi-
cal and biological properties, we prepared non-radioactive
compounds (Figure 1(b) and (c)).
As shown in Figure 1(b), the synthesis and evaluation of
O-[18F]fluoroethyl derivatives of [11C]methyl compounds
have been continuously studied and reported. And in sev-
eral reports, O-[18F]fluoroethyl derivatives showed
improved properties than [11C]methyl compounds, espe-
cially in binding affinity to TSPO.7,8,10 These results led us
to design 6b, which is the direct derivative of 6-F-PBR28
having F-18 on O-[18F]fluoroethyl moiety instead of 6-
[18F]fluoropyridyl. And also we designed 6a having pheno-
lic OH without any alkyl substituent, as there is no prece-
dent report on this specific compound. The synthetic
methods for 6a and 6b are described in Scheme 1.11a
Through the linear six-step reaction, 6a and 6b were pre-
pared in 2.8 and 4.7% overall yield from the commercially
available 4-chloro-3-nitropyridine. Compound 6a will be
able to be used as a precursor for the synthesis of [18F]6b
in further study.
But still these PET ligands have limitations for clinical
use, because they have short-lived radioisotope C-11
(half-life, 20 min), which is not suitable for multi-dose
production or remote supply to PET center. In addition,
C-11 has higher positron energy, which might lower the
Next, we designed fluorophenyl derivatives of AC-5216
(14a–c), as aromatic [18F]fluorination is one of the well-
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NO2
O
NO2
O
NO2
O
N
N
N
NO2
Cl
N
(1)
(2)
(3)
HO
F
1
2
3
O
H
N
NH2
N
O
N
N
N
OR
OR
F
O
(4)
(5)
(6)
F
O
F
4
5a R=H
5b R=CH2CH2F
6a R=H
6b R=CH2CH2F
Scheme 1. Synthesis of 6a and 6b. Reagents and conditions:
(1) PhOH, K2CO3, DMF, 70ꢀC, 5 h, 78%; (2) t-BuOOH, t-BuOK,
DMF, −40ꢀC, 1.5 h, 19%; (3) DAST, MeCN, 90ꢀC, 6 h, 46%;
(4) Fe powder, AcOH, 90ꢀC, 40 min, 86%; (5) (a) salicylaldehyde ,
CH2Cl2, reflux, 1 h; (b) NaBH4, MeOH, rt, 2 h, 68% (5a), 86%
(5b); (6) Ac2O, AcOH, 75ꢀC, 1 h, 71% (6a), 93% (6b). DMF,
dimethylformamide; DAST, diethylaminosulfur trifluoride.
(6a–b and 14a–c) with compound 19, which has a reported
value for Ki and log D.12b
As shown in Table 1, 6a (24.85 Æ 6.55 nM) and 6b
(29.14 Æ 7.12 nM) showed the better affinity than 19
(47.72 Æ 4.60 nM). The obtained IC50 value itself was not
very impressive, but when we compare our experimental
data with the reported Ki for 19 (0.51 Æ 0.06 nM),12b we
postulated both 6a and 6b might be the quite promising
candidate for TSPO imaging. More interestingly, less lipo-
philic 6a (c log P = 3.13 Æ 0.58) showed better affinity
than 6b, which has somewhat higher c log P (4.01 Æ 0.60)
considered as exceeding lipophilicity for brain imaging.14
AC-5216 derivatives 14a–c, which have the fluoro-aryl
moiety, did not show any good binding affinity. meta-
Fluoro derivative 14b showed moderate affinity
(289 Æ 35.55 nM), but not sufficient to pursue a following
study.
In summary, we designed and successfully prepared
novel phenoxypyridyl acetamide and aryl-oxodihydropurine
derivatives, which are the current lead compounds for
TSPO PET imaging. The 6-F-PBR28 derivatives, 6a and
6b, showed promising binding affinity compared with the
AC-5216 derivatives, 14a–c. Especially, the less lipophilic
compound 6a showed the best binding affinity in our new
series compound. Based on these results, further investiga-
tion such as F-18 labeling on 6a and 6b is currently
underway.
Figure 1. Selected TSPO radioligands and the design of new deri-
vatives: (a) pioneer TSPO PET ligands, (b) phenoxyaryl acetamide
(DAA1106 and PBR28) derivatives, (c) aryl-oxodihydropurine
(AC-5216) derivatives.
known approach for F-18 radioligands. As shown in
Figure 1(c),6,12 several [18F]fluoroethyl derivatives of AC-
5216 ([18F]FEAC, [18F]FEDAC, and [18F]FAC) were
reported, but there is no approach to prepare any [18F]fluor-
ophenyl derivatives up to date. The AC-5216 derivatives,
14a–c, were prepared from benzamidine hydrochloride in
8.8, 17.1, and 16.8% overall yield for linear eight steps,
respectively (Scheme 2).12b And also we obtained the
enough amount of compound 13 as a precursor for several
F-18-labeled compounds for further study.
Last, we prepared the known compound 19 (FAC) as an
internal standard for binding assay (Scheme 3).12b We used
the common intermediate 9 and followed same synthetic
strategy for 14a–c to give the compound 19 in 22.4% over-
all yield. We also obtained the enough amount of com-
pound 18 as a precursor for further study.
Experimental
The binding affinity (IC50) was measured by competition
with [3H]PK11195 in a membrane of human leukocytes,9,13
and c log P of each compound was calculated using ACD/
ChemSketch software (ACD, Inc., Toronto, Canada). As men-
tioned above, we compared the newly prepared derivatives
N-(6-Fluoro-4-phenoxypyridin-3-yl)-N-(2-hydroxyben-
zyl)acetamide (6a). 1H NMR (300 MHz, CDCl3) δ (ppm):
9.12 (s, 1H), 7.38–7.44 (m, 2H), 7.23–7.32 (m, 2H),
6.92–6.96 (m, 1H), 6.67–6.79 (m, 4H), 6.17 (d, J = 1.2 Hz,
1H), 4.79 (dd, J = 16.3 Hz, 4.7 Hz, 2H), 2.03 (s, 3H); 13C
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
O
O
O
Cl
N-(6-Fluoro-4-phenoxypyridin-3-yl)-N-(2-(2-fluor-
NH
oethoxy)benzyl)acetamide (6b). 1H NMR (300 MHz,
CDCl3) δ (ppm): 7.78 (s, 1H), 7.19–7.46 (m, 5H),
6.89–6.94 (m, 3H), 6.73–6.76 (m, 1H), 6.10 (d, J = 1.2 Hz,
1H), 5.23 (d, J = 14.1 Hz), 1H), 4.82 (d, J = 14.1, 1H),
4.43–4.73 (m, 1H), 3.90–4.16 (m, 2H), 2.44 (s, minor, 3H),
1.98 (s, major, 3H); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 170.1, 164.1, 163.1 (d, J = 235 Hz, 1C), 156.6,
153.0, 149.1, 148.9, 131.1, 130.9, 129.4, 126.9, 125.2,
121.2, 120.9, 112.3, 96.3 (d, J = 45 Hz, 1C), 82.5 (d,
J = 166 Hz, 1C), 67.7 (d, J = 19 Hz, 1C), 45.8, 22.4; 19F
NMR (282 MHz, CDCl3) δ (ppm): −62.11; ESI-MS m/z:
EtO
NH
EtO
N
(1)
(2)
(3)
HCl H2N
N
N
7
8
O
OH
O
NH
O
NH
O
HN
O
HN
O
HN
(4)
(5)
(6)
N
EtO
N
N
EtO
HO
N
N
N
9
10
11
H
H
N
N
N
F
calculated
for
C22H21F2N2O3
([M+H]):
399.2.
O
O
O
N
N
N
N
O
Found: 399.1.
O
O
N
HN
(7)
(8)
N
N
N
N-Ethyl-N-(2-fluorobenzyl)-2-(7-methyl-8-oxo-2-phenyl-
7,8-dihydro-9H-purin-9-yl)acetamide (14a). 1H NMR
(300 MHz, DMSO-d6) δ (ppm): 8.45 (s, 1H), 8.23–8.28
(m, 2H), 7.40–7.49 (m, 4H), 6.93–7.30 (m, 3H), 4.86–4.91
(m, 2H), 4.54–4.75 (m, 2H), 3.23–3.55 (m, 5H), 0.93–1.27
(m, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 198.7,
166.1, 165.8, 153.4, 150.0, 133.2, 133.1, 130.3, 129.7,
129.5, 129.0, 127.6, 124.7, 122.6, 116.2, 115.7, 41.4, 41.2,
27.8, 14.3, 12.9; ESI-MS m/z: calculated for C23H23FN5O2
([M+H]): 420.2. Found: 420.1.
N-Ethyl-N-(3-fluorobenzyl)-2-(7-methyl-8-oxo-2-phenyl-
7,8-dihydro-9H-purin-9-yl)acetamide (14b). 1H NMR
(300 MHz, CDCl3) δ (ppm): 8.33–8.37 (m, 2H), 8.23–8.27
(m, 1H), 7.41–7.47 (m, 3H), 6.91–7.24 (m, 4H), 4.92–4.82
(m, 2H), 4.61–4.66 (m, 2H), 3.44–3.52 (m, 5H), 1.12–1.38
(m, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 166.2,
165.8, 156.6, 153.4, 150.0, 137.9, 137.8, 131.2, 130.7,
130.3, 128.9, 127.5, 123.7, 122.5, 114.5, 113.8, 41.9, 41.1,
27.8, 14.3, 13.0; ESI-MS m/z: calculated for C23H23FN5O2
([M+H]): 420.2. Found: 420.1.
N
N
N
12
13
14a : 2-F Ph
14b : 3-F Ph
14c : 4-F Ph
Scheme 2. Synthesis of 14a-c. Reagents and conditions: (1) -
2-ethoxy-methylene malonate, Na, abs EtOH, 80ꢀC, 6 h, 75%;
(2) POCl3, 90ꢀC, 4 h, 93%; (3) glycine, TEA, abs EtOH, 80ꢀC,
4 h, 96%; (4) EtNH2 HCl, BOP, TEA, DMF, rt, 1 h, 93%;
(5) 1 M NaOH, EtOH, 80ꢀC, 2 h, 93%; (6) DPPA, TEA, DMF,
100ꢀC, 2 h, 66%; (7) MeI, K2CO3, DMF, rt, 1 h, 72%; (8) o,m,p-
F-C4H4Br, NaH, DMF, rt, 1 h, 32% (14a), 62% (14b), 61% (14c).
BOP,
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate; TEA, triethylamine; DPPA, diphenylpho-
sphoryl azide.
NMR (100 MHz, DMSO-d6) δ (ppm): 170.6, 164.3, 163.2
(d, J = 249 Hz, 1C), 155.9, 153.0, 149.2, 149.0, 131.2,
131.1, 129.2, 126.9, 123.0, 121.1, 119.3, 115.5, 96.1 (d,
J = 44 Hz, 1C), 46.1, 22.4; 19F NMR (282 MHz, CDCl3) δ
(ppm): −62.11; ESI-MS m/z: calculated for C20H18FN2O3
([M+H]): 353.1. Found: 353.1.
N-Ethyl-N-(4-fluorobenzyl)-2-(7-methyl-8-oxo-2-phenyl-
7,8-dihydro-9H-purin-9-yl)acetamide (14c). 1H NMR
(300 MHz, CDCl3) δ (ppm): 8.33–8.35 (m, 2H), 8.24–8.27
(m, 1H), 7.44–7.50 (m, 3H), 7.34–7.38 (m, 1H), 7.11–7.24
(m, 2H), 6.91–6.97 (m, 1H), 4.83–4.90 (m, 2H), 4.58–4.64
O
OH
O
NH
O
NH
O
HN
O
HN
O
HN
(1)
(2)
(3)
EtO
N
Table 1. In vitro binding affinity and lipophilicity of new
derivatives.
EtO
N
HO
N
N
9
N
N
IC50 (nM)a
c log Pb
15
16
Ligand
F
6a
24.85 Æ 6.55
29.14 Æ 7.12
>10 000
289 Æ 35.55
>10 000
47.72 Æ 4.60c
3.13 Æ 0.58
4.01 Æ 0.60
3.19 Æ 0.95
3.19 Æ 0.95
3.19 Æ 0.95
3.01 Æ 0.95d
H
N
H
6b
14a
14b
14c
19
N
N
O
O
O
N
N
N
N
O
O
O
HN
N
(4)
(5)
N
N
N
N
N
N
a
Affinity of compounds determined by displacement of [3H]PK11195
from isolated human leukocytes. The data are expressed as the mean
values and standard deviations in duplicate.
The c log P was calculated with ACD/ChemSketch software.
The reported Ki value of FAC for PBR was 0.51 Æ 0.06 nM.12b
The reported log D value was 3.12b
17
18
19
FAC
Scheme 3. Synthesis of 19 (FAC). Reagents and conditions:
(1) BnNH2, BOP, TEA, DMF, rt, 1 h, 91%; (2) 1 M NaOH,
EtOH, 80ꢀC, 2 h, 72%; (3) DPPA, TEA, DMF, 100ꢀC, 2 h, 72%;
(4) MeI, K2CO3, DMF, rt, 1 h, 71%; (5) 1-bromo-2-fluoro-ethane,
NaH, DMF, 1 h, 67% (19).
b
c
d
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
(m, 2H), 3.41–3.52 (m, 5H), 1.11–1.37 (m, 3H); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 166.0, 165.7, 156.6, 153.5,
150.0, 127.9, 133.2, 129.8, 129.0, 127.5, 122.6, 116.1,
115.6, 110.0, 41.7, 41.2, 27.8, 14.3, 13.0; ESI-MS m/z: cal-
culated for C23H23FN5O2 ([M+H]): 420.2. Found: 420.1.
5. (a) M. Imaizumi, H.-J. Kim, S. S. Zoghbi, E. Briard, J. Hong,
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N-Benzyl-N-(2-fluoroethyl)-2-(7-methyl-8-oxo-2-phenyl-
7,8-dihydro-9H-purin-9-yl)acetamide (19).
1H NMR
(300 MHz, CDCl3) δ (ppm): 8.34–8.38 (m, 2H), 8.23–8.26
(m, 1H), 7.45–7.50 (m, 5H), 7.36–7.41 (m, 2H), 7.26–7.27
(m, 1H), 4.91–4.97 (m, 2H), 4.76–4.82 (m, 2H), 4.62 (dt,
J = 47.5 Hz, 4.9 Hz, 2H), 3.63–3.79 (m, 2H), 3.49–3.52
(m, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 166.8,
156.6, 153.4, 150.0, 137.7, 137.3, 133.1, 130.3, 129.3,
128.9, 128.0, 127.5, 126.8, 122.6, 82.7, 50.8, 48.7, 41.7,
27.8; ESI-MS m/z: calculated for C23H23FN5O2 ([M+H]):
420.2. Found: 420.2.
In Vitro TSPO Binding Assay. The prepared TSPO-
targeted compounds, 6a and b and 14a–c, were assayed for
their binding affinity to TSPO using isolated human leuko-
cytes and the standard [3H]PK11195. These experiments
were carried out by the previously reported method.9,15
Acknowledgments. This work was supported by a grant
from the Korea Health Technology R&D Project through
the Korea Health Industry Development Institute (KHIDI),
funded by the Ministry for Health and Welfare, Korea
(HI14C1135) and the Gachon University research fund of
2014 (GCU-2014-0136).
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Supporting Information. Additional supporting informa-
tion (experimental procedure and spectra for all com-
pounds) is available in the online version of this article.
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