A novel 18F-labeled pyridyl benzofuran derivative for imaging of β-amyloid plaques in Alzheimer's brains

Article abstract of DOI:10.1016/j.bmcl.2010.08.016

A potential probe for PET targeting β-amyloid plaques in Alzheimer's disease (AD) brain, FPYBF-1 (5-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) benzofuran-2-yl)-N,N-dimethylpyridin-2-amine), was synthesized and evaluated. In experiments in vitro, FPYBF-1 displayed high affinity for Aβ(1-42) aggregates (K_i = 0.9 nM), and substantial labeling of β-amyloid plaques in sections of postmortem AD brains but not control brains. In experiments in vivo, [¹⁸F]FPYBF-1 displayed good initial uptake (5.16%ID/g at 2 min postinjection) and rapid washout from the brain (2.44%ID/g at 60 min postinjection) in normal mice, and excellent binding to β-amyloid plaques in a murine model of AD. Furthermore, the specific labeling of plaques labeling was observed in autoradiographs of autopsied AD brain sections. [ ¹⁸F]FPYBF-1 may be a useful probe for imaging β-amyloid plaques in living brain tissue.

Full text of DOI:10.1016/j.bmcl.2010.08.016

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6141–6144
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel 18F-labeled pyridyl benzofuran derivative for imaging of b-amyloid
plaques in Alzheimer’s brains
a
b
b
a,
Yan Cheng a, Masahiro Ono a, , Hiroyuki Kimura , Shinya Kagawa , Ryuichi Nishii , Hideo Saji
⇑
⇑
a Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
b Shiga Medical Center Research Institute, 5-4-30, Moriyama, Moriyama City, Shiga 524-8524, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A potential probe for PET targeting b-amyloid plaques in Alzheimer’s disease (AD) brain, FPYBF-1 (5-(5-
(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N,N-dimethylpyridin-2-amine), was synthesized
and evaluated. In experiments in vitro, FPYBF-1 displayed high affinity for Ab(1–42) aggregates
(Ki = 0.9 nM), and substantial labeling of b-amyloid plaques in sections of postmortem AD brains but
not control brains. In experiments in vivo, [18F]FPYBF-1 displayed good initial uptake (5.16%ID/g at
2 min postinjection) and rapid washout from the brain (2.44%ID/g at 60 min postinjection) in normal
mice, and excellent binding to b-amyloid plaques in a murine model of AD. Furthermore, the specific
labeling of plaques labeling was observed in autoradiographs of autopsied AD brain sections.
Received 20 May 2010
Revised 22 July 2010
Accepted 4 August 2010
Available online 8 August 2010
Keywords:
Alzheimer’s disease
b-Amyloid plaques
Positron emission tomography (PET)
Benzofuran
[
18F]FPYBF-1 may be a useful probe for imaging b-amyloid plaques in living brain tissue.
Ó 2010 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder characterized by cognitive decline, irreversible memory
loss, disorientation, and language impairment. The presence of
b-amyloid (Ab) aggregates in the brain is generally accepted as a
hallmark of AD.1,2 Since the only definitive diagnosis of AD is by
pathological examination of autopsied brain tissue, the develop-
ment of techniques which enable the imaging of b-amyloid plaques
in vivo has been strongly desired.3–5
ethyl)-N-methylamino)naphthalene-6-yl)ethylidene)malononitrile
(FDDNP)12,13 showed differential uptake and retention in the brain
of AD patients for the first time. More recently, a stilbene deriva-
tive, (E)-4-(N-methylamino)-40-(2-(2-(2-[18F]-fluoroethoxy)ethoxy)-
ethoxy)-stilbene (BAY94-9172),14,15 a styryl pyridine derivative,
(E)-4-(2-(6-(2-(2-(2-([18F]-fluoroethoxy)ethoxy)ethoxy)pyridyn-3-
ylvinyl)-N-methyl benzenamine (AV-45),16–18 and a PIB analogue,
2-(3-[18F]-fluoro-4-methyamino-phenyl)benzothiazol-6-ol (GE-
067),19 have been shown to be useful for the imaging of b-amyloid
plaques in living brain tissue in phase II or III clinical trials
(Fig. 1).20
Preliminary studies with positron emission tomography (PET)
suggested that
13),6,7 11C] 2-(40-(methylaminophenyl)-6-hydroxybenzothiazole
(PIB),8,9 11C]2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-
[fluoro]ethoxy)benzoxazole (BF-227),10 and 11C]-2-[6-(methyl-
[
11C]4-N-methylamino-40-hydroxystilbene (SB-
[
[
We have evaluated a series of fluorinated benzofuran deriva-
tives as potential 18F-labeled tracers for the imaging of b-amyloid
plaques by PET.21 These derivatives displayed excellent affinity
for Ab aggregates in vitro and in vivo. The penetration of brain tis-
sues by 4-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-
yl)-N,N-dimethylbenzenamine (FPHBF-1, Fig. 2) was particularly
encouraging. However, the slow washout of this probe from the
normal mouse brain made it unsuitable for imaging in vivo. There-
fore, a critical need to fine-tune the kinetics of the uptake and
washout of benzofuran derivatives exists. Previous results regard-
ing uptake into and clearance from the brain point to high lipophil-
icity as one of the reasons for a slow washout from the brain.8,22–24
We planned to develop a novel fluorinated pyridyl benzofuran
derivative with less lipophilicity by displacing of the phenyl group
in phenyl benzofuran with a pyridyl group. Kung and co-workers
exploited a novel approach, fluoro-pegylation (FPEG) of the core
structure, to label derivatives with 18F.25 Since this approach offers
[
amino)pyridin-3-yl]-1,3-benzothiazol-6-ol (AZD2184)11 differed
in their uptake and retention in the brain between AD patients
and controls (Fig. 1). Success in using 11C-labeled tracers to image
b-amyloid plaques in the brain in cases of suspected AD has pro-
vided considerable impetus for further refinement of this tech-
nique. However, the short half-life of 11C (t1/2: 20 min) limits its
potential as a diagnostic tool. Since 18F with a longer half-life iso-
tope (t1/2: 110 min) would be more useful for this purpose, recent
efforts have focused on the development of comparable agents la-
beled with 18F. Preliminary studies with [18F]-2-(1-(2-(N-(2-fluoro-
⇑
Corresponding authors. Tel.: +81 75 753 4608; fax: +81 75 753 4568 (M.O.);
tel.: +81 75 753 4556; fax: +81 75 753 4568 (H.S.).
E-mail addresses: ono@pharm.kyoto-u.ac.jp (M. Ono), hsaji@pharm.kyoto-u.ac.jp
(H. Saji).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.016

6142
Y. Cheng et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6141–6144
N
11CH3
NH
11CH3
NH
N
S
11CH3
F
HO
HN
N
O
NH
O
N
O
HO
HO
HO
11CH3
S
N
[
11C]PIB
[
11C]SB-13
[
11C]BF-227
[
11C]AZD2184
NC
N
S
18F
3
N
CN
18F
3
HN
NH
O
O
18F
N
18F
[
18F]FDDNP
[
18F]BAY94-9172
[
18F]AV-45
[
18F]GE-067
Figure 1. Chemical structure of PET imaging agents targeting b-amyloid plaques in AD patients.
HO
O
O
F
F
NH
3
3
N
N
O
N
O
O
N
F
FPHBF-1
FPYBF-1
AZD4694
Figure 2. Chemical structure of benzofuran derivatives, FPHBF-1, FPYBF-1, and AZD4694.
a simple and easy way to incorporate 18F into a target without an
appreciable increase in lipophilicity, we selected FPEG for the
labeling of pyridyl benzofuran derivatives. We designed a novel
fluorinated ligand, 5-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)ben-
zofuran-2-yl)-N,N-dimethylpyridin-2-amine (FPYBF-1, Fig. 2) with
a fluoropolyethylene glycol side chain and a dimethylamino pyri-
dyl group. Another group recently reported a different fluorinated
pyridyl benzofuran derivative, 2-(2-fluoro-6-(methylamino)pyri-
din-3-yl)benzofuran-5-ol (AZD4694, Fig. 2) to have potential for
the imaging of cerebral b-amyloid plaques in living brain tissue.26
However, they did not report the 18F-labeling or in vivo character-
istics of [18F]AZD4694. This is the first time that a pyridyl benzofu-
ran derivative has been successfully radiolabeled with 18F and
evaluated for the imaging of b-amyloid plaques in vivo.
The synthesis of 5 (FPYBF-1) is outlined in Scheme 1. The key step
in the formation of the pyridyl benzofuran backbone is accom-
plished by Suzuki coupling between 5-methoxybenzofuran-2-boro-
nic acid and 2-amino-5-iodopyridine.27 Suzuki coupling afforded
the desired compound 1 in a yield of 52.1%. Conversion of 1 to the
corresponding dimethylamino derivative 2 was achieved by dime-
thylation with paraformaldehyde and sodium cyanoborohydride
(yield 62%). A methoxy group of 2 was converted to a hydroxyl group
using BBr3/CH2Cl2, which afforded 3 in a yield of 98.9%. The synthesis
of 4–6 was achieved using conventional methods reported previ-
ously.28 The 18F-labeled 5 ([18F]FPYBF-1) was prepared from a tosyl
precursor (6) via a nucleophilic displacement reaction with a fluo-
ride anion as shown in Scheme 2. Radiolabeling of the precursor gen-
erated [18F]FPYBF-1 with an average radiochemical yield of 52% and
radiochemical purity of >99%, and a specific activity of 242 GBq/
l
mol. The identity of [18F]FPYBF-1 was verified by a comparison of
the retention time with the nonradioactive compound.
Experiments in vitro to evaluate the affinity of FPYBF-1 for Ab
aggregates were carried out in solutions with [125I]IMPY as the li-
gand according to conventional methods.29,30 FPYBF-1 inhibited
the binding of [125I]IMPY in a dose-dependent manner with a Ki va-
lue of 0.9 nM, indicating that it has excellent affinity for Ab(1–42)
aggregates (Fig. 3). This Ki value is similar to that of phenyl benzo-
furan derivatives (Ki = 2.0 nM) reported previously,21 and the affin-
ity of the pyridyl benzofuran derivative for Ab(1–42) aggregates
remained high despite displacement of the phenyl group with a
pyridyl group. This result also shows that the benzofuran scaffold
can tolerate extensive structural modification.21,22,31
To evaluate the uptake of [18F]FPYBF-1 in the brain, a biodistri-
bution experiment was performed in normal mice (Table 1).
MeO
MeO
(b)
MeO
OH
OH
(a)
I
NH2
(d)
NH2
N
N
B
+
N
O
O
O
N
N
1
4
2
HO
O
O
(e)
(c)
HO
F
3
3
N
N
O
O
O
N
N
N
3
5 (FPYBF-1)
(f)
O
TsO
3
N
O
N
6
Scheme 1. Reagents and conditions: (a) Pd(Ph3P)4, Na2CO3 (aq)/dioxane, reflux.; (b) paraformaldehyde, sodium cyanoborohydride, acetic acid, rt; (c)BBr3, CH2Cl2, rt; (d) 2-[2-
(2-chloroethoxy)ethoxy]ethanol, K2CO3, DMF, 100 °C; (e) DAST, DME, 0 °C; (f) tosyl chloride, pyridine, rt.
O
O
18F
(a)
TsO
3
3
N
N
O
N
O
N
18F]5 ([18F]FPYBF-1)
6
[
Scheme 2. Reagents and conditions: (a) Kryptofix222, K2CO3, acetonitrile, 120 °C.

Y. Cheng et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6141–6144
6143
Table 1
100
50
0
Biodistribution of radioactivity after injection of [18F]FPYBF-1 in normal micea
Organ
2 min
10 min
30 min
60 min
Blood
Brain
Bone
2.83 0.89
5.16 0.30
1.61 0.33
2.13 0.49
3.75 0.64
1.33 0.28
1.76 0.09
2.78 0.22
1.11 0.13
1.98 0.35
2.44 0.36
1.42 0.24
a
Expressed as % of injected dose per gram. Each value represents the mean SD
for five mice.
of [18F]FPYBF-1 from normal brain is appropriate for the detection of
b-amyloid plaques in the AD brain. One way to select a ligand with
appropriate kinetics in vivo is to use the brain2 min/brain60 min ratio
as an index to compare the washout rate.32 Although the brain2
-4
-2
0
2
4
6
Log[Inhibitor](nM)
min/brain60
ratio of [18F]FPYBF-1 (2.1) was lower than that of
Figure 3. Competition curve of FPYBF-1 against [125I]IMPY.
min
[
18F]BAY94-9172 (4.8)14 or [18F]AV-45 (3.8),16 it was improved as
compared to the values for [18F]FPHBF-1 (1.0) reported previously.21
The favorable in vivo pharmacokinetics of [18F]FPYBF-1 were
achieved by changing the phenyl group in [18F]FPHBF-1 to a pyridyl
group. In HPLC analyses, [18F]FPYBF-1 and [18F]FPHBF-1 showed
retention times of 14.8 and 36.5 min, respectively, indicating that
[
18F]FPYBF-1 displayed high uptake (5.16%ID/g) at 2 min postinjec-
tion, sufficient for PET, and the radioactivity in the brain cleared
with time (2.44%ID/g at 60 min postinjection). Since normal brain
tissue has no b-amyloid plaques to trap [18F]FPYBF-1, the radioac-
tivity should wash out quite rapidly. Therefore, the rapid clearance
[
18F]FPYBF-1 is less lipophilic than [18F]FPHBF-1. Although lipophil-
Figure 4. In vitro autoradiograms of sections of AD brain labeled with [18F]FPYBF-1. Intensive labeling of b-amyloid plaques in brain tissue from AD patients (A). The control
subject exhibits no labeling by this tracer (B).
Figure 5. The labeling of b-amyloid plaques in vivo was visualized by autoradiography ex vivo with [18F]FPYBF-1 in sections of Tg2576 mouse brain (A). The same section was
also stained with thioflavin-S (C). Wild-type mouse brain showed no b-amyloid plaques (B).

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Y. Cheng et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6141–6144
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the brain,4 it may explain the favorable pharmacokinetics of
[
(1.42%ID/g), suggesting little defluorination in vivo and interference
with the imaging is expected to be relatively minor.
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(5 l
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to b-amyloid plaques. Autoradiographic images revealed extensive
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aggregates.
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for imaging b-amyloid plaques in living brain tissue, we carried out
autoradiography ex vivo in Tg2576 mice (36 months, male) and in
wild-type mice (36 months, male) as age-matched controls.
Tg2576 transgenic mice show marked Ab deposition in the cingu-
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showed clear labeling of b-amyloid plaques in the Tg2576 mouse
brain (Fig. 5A). Wild-type mouse brain showed no such labeling
(Fig. 5B). b-Amyloid plaques were confirmed present by co-staining
the sections with thioflavin-S, a pathological dye commonly used
to stain b-amyloid plaques (Fig. 5C). This is consistent with the re-
sults in vitro, showing [18F]FPYBF-1 to be highly selective in bind-
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In conclusion, based on previous results, we designed a novel
fluorinated pyridyl benzofuran ligand, FPYBF-1, for the imaging
of b-amyloid plaques in the brain. FPYBF-1 showed high binding
affinity for Ab aggregates in vitro and for b-amyloid plaques in sec-
tions of autopsied AD brain. It also displayed good uptake in the
brain (5.16%ID/g at 2 min postinjection) and excellent binding to
b-amyloid plaques ex vivo in transgenic mice. [18F]FPYBF-1 is
now under preclinical evaluation for use as a probe in PET. Other
pyridyl benzofuran derivatives are also under investigation.
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Acknowledgments
The study was supported by a Grant-in-aid for Young Scientists
(A) and Exploratory Research from the Ministry of Education, Cul-
ture, Sports, Science and Technology.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.08.016.
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