Synthesis and biological evaluation of novel oxindole derivatives for imaging neurofibrillary tangles in Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2012.06.086

This letter describes the synthesis and biological evaluation of a novel series of radioiodinated oxindole (OI) derivatives for detecting neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer's disease (AD). In binding experiments in vitro, 2-oxindole (2-OI) and 3-oxindole (3-OI) derivatives showed affinity for tau aggregates. The 3-OI derivative 14 showed the highest affinity of these derivatives. In biodistribution experiments using normal mice, the OI derivatives displayed good uptake (2.4-2.5% ID/g at 2 min) and clearance from the brain with time (0.6-1.4% ID/g at 30 min). In fluorescence staining experiments using AD brain sections, 14 clearly stained NFTs. 3-OI may serve as a new molecular scaffold for developing novel NFT imaging agents.

Full text of DOI:10.1016/j.bmcl.2012.06.086

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5700–5703
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel oxindole derivatives
for imaging neurofibrillary tangles in Alzheimer’s disease
Hiroyuki Watanabe a, Masahiro Ono a, , Hiroyuki Kimura a, Kenji Matsumura a, Masashi Yoshimura a,
⇑
Yoko Okamoto b, Masafumi Ihara b, Ryosuke Takahashi b, Hideo Saji a
a Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
b Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter describes the synthesis and biological evaluation of a novel series of radioiodinated oxindole
(OI) derivatives for detecting neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer’s dis-
ease (AD). In binding experiments in vitro, 2-oxindole (2-OI) and 3-oxindole (3-OI) derivatives showed
affinity for tau aggregates. The 3-OI derivative 14 showed the highest affinity of these derivatives. In bio-
distribution experiments using normal mice, the OI derivatives displayed good uptake (2.4–2.5% ID/g at
2 min) and clearance from the brain with time (0.6–1.4% ID/g at 30 min). In fluorescence staining exper-
iments using AD brain sections, 14 clearly stained NFTs. 3-OI may serve as a new molecular scaffold for
developing novel NFT imaging agents.
Received 2 May 2012
Revised 19 June 2012
Accepted 26 June 2012
Available online 1 July 2012
Keywords:
Oxindole
Neurofibirillary tangles
Tau protein
Ó 2012 Elsevier Ltd. All rights reserved.
Alzheimer’s disease
Alzheimer’s disease (AD) is the most common neurodegenera-
tive disorder of the elderly and is characterized clinically by
dementia, cognitive impairment, and memory loss. The number
of AD patients was estimated at 26.6 million worldwide in 2006.
Furthermore, the worldwide prevalence of AD is predicted to grow
four fold, to 106.8 million.1 Postmortem brains of AD patients re-
veal neuropathological features: the presence of senile plaques
(SPs) composed of b-amyloid (Ab) peptides and neurofibrillary tan-
gles (NFTs) composed of hyperphosphorylated tau protein.2,3 Cur-
rently, the clinical diagnosis of AD is based on cognitive tests,
which limit the diagnosis to a late stage of the disorder. There is
no simple and definitive diagnostic method to detect SPs and NFTs
in the brain without postmortem pathological staining of brain tis-
sue. Therefore, the quantitative evaluation of SPs and NFTs in the
living brain with non-invasive techniques such as positron emis-
sion tomography (PET) and single photon emission computed
tomography (SPECT) could lead to the presymptomatic detection
of AD and new anti-amyloid therapy.4–6
whereas SPs are found in the brains of both AD patients and cogni-
tively healthy individuals.21,22 Therefore, imaging of NFTs by PET/
SPECT is useful for presymptomatic diagnosis and monitoring of
the progression of AD. Some compounds such as quinoline deriva-
tives,23,24 thiohydantoin derivatives25 and phenyldiazenyl benzo-
thiazole derivatives26,27 have been reported as candidate probes
for the imaging of NFTs in AD brains. However, these probes have
not been tested clinically because of high affinity for both NFTs and
SPs or undesirable pharmacokinetics in normal mouse brain.
Therefore, there is no report regarding clinical trials in AD patients
using NFT imaging probes and more useful scaffolds for these
probes are strongly desired.
Recently, a library containing 72,455 small molecules was
screened to determine the feasibility of distinguishing tau aggre-
gates from Ab aggregates. Among them, a 2-oxindole (2-OI) scaf-
fold showed high affinity for tau aggregates with 1.5-fold
selectivity to bind Ab(1–42) aggregates in vitro.28,29 Therefore,
we designed and produced a novel series of derivatives of radioio-
dinated 2-OI and 3-oxindole (3-OI), a structural isomer of 2-OI, and
evaluated their potential as probes for imaging NFTs in vivo
(Fig. 1). To our knowledge, this is the first time that oxindole (OI)
derivatives have been proposed as NFT imaging agents for detect-
ing AD.
The formation and deposition of SPs is considered an initial event
in the progression of AD.7 Therefore, several PET/SPECT tracers such
as
[
11C]PIB,8,9
[ [ [
18F]FDDNP,10,11 18F]BAY94-0172,12,13 18F]AV-
45,14,15
[
18F]GE-067,16 18F]AZD4694,17,18 and [123I]IMPY19,20 have
[
been tested clinically and demonstrated utility for imaging of SPs
in vivo.
Previous studies show that NFTs in the hippocampus and
entorhinal cortex are positively correlated with cognitive decline,
The OI derivatives were prepared as shown in Schemes 1 and 2.
The synthesis of the 2-OI backbone was achieved by a Knoevenagel
condensation reaction30: 5-bromo-2-oxyindole was reacted with
4-monomethylaminobenzaldehyde31,32 or 4-dimethylaminobenz-
aldehyde in the presence of piperidine in toluene under reflux to
form 1 and 2 in yields of 90% and 56%, respectively. The tributyltin
⇑
Corresponding author. Tel.: +81 75 753 4608; fax: +81 75 753 4568.
E-mail address: ono@pharm.kyoto-u.ac.jp (M. Ono).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.086

H. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5700–5703
5701
Furthermore, these tributyltin derivatives can be also used as the
starting materials for radioiodination in the preparation of
[
R
H
N
125I]6, [125I]13, and [125I]14 (Scheme 3). Novel radioiodinated 2-
O
H
N
I
OI and 3-OI derivatives were obtained by an iododestannylation
reaction using NCS as an oxidant. It was anticipated that not add-
ing a carrier would result in a final product bearing a theoretical
specific activity similar to that of 125I (81.4 TBq/mmol). [125]13
I
R
O
2-OI
3-OI
Figure 1. Chemical structure of 2-OI and 3-OI derivatives reported in this study.
H
R = NHCH3, N(CH3)2.
H
N
N
O
O
a
125I
Bu3Sn
derivatives (3 and 4) were prepared from the corresponding bromo
compounds (1 and 2) using a halogen to tributyltin exchange reac-
tion catalyzed by Pd(0) in yields of 8% and 39%. These tributyltin
derivatives were readily reacted with iodine in chloroform at room
temperature to give iodo derivatives. 2-OI derivatives (5 and 6)
were obtained as mixtures of E/Z-isomers in a ratio of 58:42 and
84:16, respectively. We tried to purify the E/Z-isomers by HPLC.
However, the isomerization of 5 and 6 occurred too quickly to sep-
arate them. A previous report also suggested that E/Z mixtures of
oxindole were inseparable.33 Then, we used 5 and 6 as a mixture
of E/Z isomers in further experiments.
N
N
4
[
125I]6
R
R
Ac
N
H
N
a
b
125I
Bu3Sn
O
O
[
[
125I]13 (R = NHCH3)
9 (R = NHCH3)
10 (R = N(CH3)2)
125I]14 (R = N(CH3)2)
The synthesis of the 3-OI backbone was also achieved by a
Knoevenagel condensation reaction: 1-acetyl-5-bromo-3-hydrox-
yindole was reacted with 4-monomethylaminobenzaldehyde or
4-dimethylaminobenzaldehyde in the presence of piperidine in
toluene under reflux to form 7 and 8 in yields of 22% and 82%,
respectively. The tributyltin derivatives (9 and 10) were prepared
from the corresponding bromo compounds (7 and 8) using a halo-
gen to tributyltin exchange reaction catalyzed by Pd(0) in yields of
16% and 9%. These tributyltin derivatives were readily reacted with
iodine in chloroform at room temperature to give iodo derivatives.
Compounds 13 and 14 were obtained from 11 and 12 in the pres-
ence of K2CO3 to remove acetyl protected groups. 3-OI derivatives
(13 and 14) were obtained exclusively as Z-isomers. The configura-
tion of the exocyclic double bond was clearly evidenced by the
chemical shift in the 1H NMR spectrum of the ethylenic proton.34
Scheme 3. Reagents: (a) [125I]NaI, NCS. (b) K2CO3, methanol.
Table 1
Inhibition constants (Ki) for binding of OI derivatives determined using Thioflavin-S as
the ligand in tau and Ab(1–42) aggregates
Compound
Ki (nM)a
Ki ratio of Ab(1–42)/tau
tau
Ab(1–42)
5
6
13
14
1428 165
599 19
112 27
17 10
5057 158
4672 748
116 19
3.54
7.80
1.03
1.77
31
6
a
Values are the mean standard error of the mean for three independent
experiments.
H
N
H
N
H
N
H
N
R
O
O
a
b
c
O
+
Bu3Sn
O
I
H
Br
Br
R
O
R
R = NHCH3
R = N(CH3)2
3 (R = NHCH3)
4 (R = N(CH3)2)
5 (R = NHCH3)
6 (R = N(CH3)2)
1 (R = NHCH3)
2 (R = N(CH3)2)
Scheme 1. Reagents: (a) piperidine, ethanol; (b) Pd(PPh3)4, (Bu3Sn)2, toluene; (c) I2, CHCl3.
R
R
Ac
N
R
Ac
N
Ac
N
+
b
a
H
Br
OH
Bu3Sn
O
Br
O
O
R = NHCH3
R = N(CH3)2
7 (R = NHCH3)
8 (R = N(CH3)2)
9 (R = NHCH3)
10 (R = N(CH3)2)
R
R
Ac
N
H
N
d
c
I
I
O
O
11 (R = NHCH3)
12 (R = N(CH3)2)
13 (R = NHCH3)
14 (R = N(CH3)2)
Scheme 2. Reagents: (a) piperidine, ethanol; (b) Pd(PPh3)4, (Bu3Sn)2, toluene; (c) I2, CHCl3. (d) K2CO3, methanol.

5702
H. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5700–5703
and [125I]14 were obtained from [125I]11 and [125I]12 in the pres-
ence of K2CO3 to remove acetyl protected groups. The radiochem-
ical identity of the radioiodinated ligands was verified by
co-injection with non-radioiodinated compounds from HPLC
profiles. [125I]6, [125I]13, and [125I]14 were each obtained in a radio-
chemical yield of >17% with a radiochemical purity of >95% after
HPLC.
To quantify the affinity of 2-OI and 3-OI derivatives (5, 6, 13,
and 14) for tau aggregates, we carried out inhibition assays with
thioflavin-S (Th-S) as a competing ligand. The Ki values of the
derivatives (5, 6, 13, and 14) were 1428, 599, 112, and 17 nM,
respectively (Table 1). These results showed that the affinity of
the 3-OI derivatives for tau aggregates was higher than that of 2-
OI. The lower affinity of 2-OI may be attributable to the use of
the E/Z mixtures for the assay. Notably, the 3-OI derivative 14
had the highest affinity for tau aggregates among all OI derivatives.
To compare the affinity between tau and Ab aggregates, we also
carried out inhibition assays with Th-S as a competing ligand.
The Ki values of the derivatives (5, 6, 13, and 14) were 5057,
4672, 116, and 31 nM, respectively. The ratio of Ki values for tau
and Ab was 3.54, 7.80, 1.03, and 1.77 for 5, 6, 13, and 14, respec-
tively, indicating that these derivatives displayed higher binding
to tau aggregates than Ab aggregates. The 2-OI derivative 6 was
the most selective OI derivative. These results suggested that the
position of substituted groups in the OI scaffold plays an important
role in the affinity for tau and Ab(1–42) aggregates. Compound 6
showed more selective affinity for tau aggregates than BF-158,23
TH-2,25 and FPPDB,27 which displayed a ratio of EC50, Ki and Kd val-
ues for tau and Ab of 1.65, 7.33, and 1.54, respectively, while the
selectivity of OI derivatives was lower than that of THK-523
(12.4)24 and PDB-3 (17.2).26 Since a minor change to substituted
groups in the OI scaffold can affect the binding between tau and
Ab, the optimization of structural changes to the OI scaffold may
improve the selectivity for tau aggregates.
Table 2
Biodistribution of radioactivity after injection of [125I]OI derivatives in normal micea
Time after injection (min)
Tissue
2
10
30
125I]6
60
To evaluate the uptake into the brain of the OI derivatives, bio-
distribution experiments were performed in normal mice with
[
radioiodinated OI derivatives;
[ [ [
125I]6, 125I]13, and 125I]14
Blood
Liver
1.77 (0.10)
12.37 (1.10)
9.63 (0.61)
1.57 (0.21)
3.66 (0.40)
5.08 (0.34)
10.17 (1.14)
0.91 (0.08)
2.47 (0.30)
1.64 (0.17)
1.07 (0.18)
9.43 (2.16)
3.83 (0.76)
8.33 (3.86)
1.20 (0.19)
1.76 (0.17)
1.30 (0.16)
3.52 (0.35)
1.43 (0.09)
0.69 (0.10)
6.89 (0.87)
2.51 (0.57)
12.11 (2.23)
0.66 (0.15)
0.60 (0.13)
0.61 (0.11)
3.57 (0.85)
0.44 (0.09)
10.56 (1.96)
5.04 (0.58)
2.54 (0.84)
3.37 (0.99)
3.19 (0.46)
2.53 (0.33)
1.64 (0.61)
2.10 (0.21)
(Table 2). Radioactivity after injection of the OI derivatives pene-
trated the blood–brain barrier showing excellent uptake ranging
from 2.45% to 2.52% ID/g brain at 2 min postinjection. In addition,
they displayed good clearance from the normal brain with 1.43,
0.73, and 0.63% ID/g at 30 min postinjection for [125I]6, [125I]13,
and [125I]14, respectively. It is important to note that the ideal
imaging probe should have good penetration to deliver the in-
tended dose into the brain, while maintaining a fast washout from
normal tissues. Because the normal brain has no NFTs to trap the
probe, the washout should be fast. The brain2 min/brain30 min ratio
as an index to compare washout rates is used for determining
radioactivity pharmacokinetics in vivo.35 The brain2 min/brain30 min
ratio of [125I]6, [125I]13, and [125I]14 was 1.70, 3.31, and 4.00,
respectively, indicating that [125I]14 provided the best profile of
radioactivity in the brain among the three ligands. Furthermore,
the brain2 min/brain30 min ratio of [125I]14 (4.00) was higher than
Kidney
Intestine
Spleen
Pancreas
Heart
Stomachb
Brain
[
125I]13
Blood
Liver
7.50 (0.34)
9.51 (0.45)
13.48 (1.67)
2.29 (0.17)
6.97 (0.33)
5.43 (2.80)
8.52 (0.95)
0.77 (0.15)
2.45 (0.19)
4.97 (0.50)
3.30 (0.27)
11.59 (1.61)
19.35 (5.95)
7.55 (0.64)
14.05 (4.43)
2.25 (0.38)
6.32 (5.58)
2.96 (0.36)
0.74 (0.12)
1.95 (0.28)
6.26 (0.59)
10.01 (5.51)
9.86 (1.58)
7.75 (2.51)
1.40 (0.81)
2.65 (0.47)
2.92 (0.75)
0.23 (0.03)
12.40 (1.89)
18.16 (4.21)
4.24 (0.94)
9.67 (3.67)
2.95 (1.38)
5.36 (0.55)
1.70 (0.54)
1.75 (0.19)
Kidney
Intestine
Spleen
Pancreas
Heart
Stomachb
Brain
[
125I]14
Blood
Liver
4.70 (0.88)
9.81 (1.01)
11.93 (2.05)
2.13 (0.16)
3.20 (0.81)
4.40 (1.25)
7.94 (0.40)
0.96 (0.33)
2.52 (0.54)
3.76 (0.33)
2.06 (0.37)
9.85 (0.66)
11.38 (2.28)
7.05 (1.30)
4.08 (0.78)
1.39 (0.13)
2.23 (0.30)
2.10 (0.48)
0.63 (0.05)
2.23 (0.23)
8.90 (1.11)
7.55 (2.10)
10.70 (4.13)
2.17 (0.60)
0.94 (0.02)
2.11 (0.18)
3.80 (2.69)
0.36 (0.04)
that of
[ [ [
11C]BF-158 (3.65),23 18F]THK-523 (<2),24 18F]FPPDB
11.29 (1.30)
16.57 (2.87)
3.17 (0.75)
4.46 (0.79)
2.54 (0.26)
3.42 (0.19)
1.67 (0.23)
1.40 (0.13)
(1.23),27 and [125I]TH-2 (2.33).25 These results suggested [125I]14
to have more suitable pharmacokinetics for imaging NFTs than
any other compound reported previously.
Kidney
Intestine
Spleen
Pancreas
Heart
To confirm the affinity of the OI derivatives for NFTs in the AD
brain, fluorescent staining of sections of AD patient brain tissue
was carried out with 14 which showed the highest affinity for
tau aggregates among the OI derivatives (Fig. 2). Many fluores-
cence spots were observed in the entorhinal cortex of AD brain sec-
tions, as reflected by the high affinity for tau aggregates in the
Stomachb
Brain
a
Expressed as % injected dose per gram. Each value represents the mean (SD) for
five animals.
b
Expressed as % injected dose per organ.
Figure 2. Fluorescent staining with 14 (A) or thioflavin-S (B) in the entorhinal cortex of an AD brain section.

H. Watanabe et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5700–5703
5703
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In conclusion, we developed OI derivatives as novel ligands for
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in vitro binding assay, in vitro fluorescence staining using AD brain
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