Development of alkoxy styrylchromone derivatives for imaging of cerebral amyloid-β plaques with SPECT

Article abstract of DOI:10.1016/j.bmcl.2015.05.048

Abstract We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as single photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-β (Aβ) plaques. Among the derivatives, the methoxy derivative

Full text of DOI:10.1016/j.bmcl.2015.05.048

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3363–3367
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of alkoxy styrylchromone derivatives for imaging
of cerebral amyloid-b plaques with SPECT
Takeshi Fuchigami , Ayaka Ogawa , Yuki Yamashita , Mamoru Haratake a,b, Hiroyuki Watanabe c,
a,
⇑
a
a
c
a
a
a,
⇑
Masahiro Ono , Masao Kawasaki , Sakura Yoshida , Morio Nakayama
a
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the development of radioiodinated styrylchromone derivatives with alkoxy groups as sin-
gle photon emission computed tomography (SPECT) imaging probes for cerebral amyloid-b (Ab) plaques.
Among the derivatives, the methoxy derivative 14 and the dimethoxy derivative 15 displayed relatively
Received 14 March 2015
Revised 15 May 2015
Accepted 18 May 2015
Available online 27 May 2015
high affinity for the Ab(1–42) aggregates with K
i
values of 22 and 46 nM, respectively. Fluorescent imag-
ing demonstrated that 14 and 15 clearly labeled thioflavin-S positive Ab plaques in the brain sections of
Tg2576 transgenic mice. In the in vivo studies, [1 I]14 and [ I]15 showed high initial brain uptake
expressed as the percentage of the injected dose per gram (2.25% and 2.49% ID/g at 2 min, respectively)
with favorable clearance (0.12% and 0.20% ID/g at 180 min, respectively) from the brain tissue of normal
mice. Furthermore, in vitro autoradiography confirmed that [1 I]15 binds thioflavin-S positive regions in
Tg2576 mouse brain sections. The derivative 15 may be a potential scaffold for the development of in vivo
imaging probes targeting Ab plaques in the brain. In particular, further structural modifications are
required to improve the compounds binding affinity for Ab.
25
125
Keywords:
Alzheimer’s disease
Amyloid-b plaque
Styrylchromone
Single photon emission computed
tomography (SPECT)
25
Ó 2015 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD), which is the most common cause of
dementia in the elderly, is characterized by the progressive decline
of cognition including learning and memory.1 It is estimated that
the number of patients with AD will increase to over 100 million
by the year 2050 and, for this reason, effective therapies need to
be developed to prevent the collapse of global health-care sys-
tems.2 Ab plaques have been detected in patients prior to the
appearance of the clinical symptoms of AD. This implies that the
detection and early initiation of treatment targeting Ab deposits
could be an effective therapeutic option to improve the symptoms
of AD patients in the early disease stage.2 Nuclear medicine imag-
ing techniques have been accepted as useful tools for the early
Recently, these PET tracers were approved by the US Food and
Drug Administration (FDA) for the specific detection of Ab plaques
8–10
in clinical practice.
In contrast, there are currently no effective
SPECT probes for detecting Ab plaques despite their convenience
and widespread utilization. SPECT is widely available in most hos-
pitals, and is generally less expensive, as compared to PET.1
Accordingly, the development of clinically useful SPECT imaging
probes for Ab can facilitate and encourage the initial diagnosis of
AD in elderly people. Previously, we have developed flavonoid
derivatives such as flavones, chalcones, aurones, and styrylchro-
1,12
,3
mones as prospective Ab imaging probes (Fig. 1), although clini-
cally available compounds have not yet been developed.1
3–22
We
4
detection of cerebral Ab plaque deposits. Numerous studies have
reported the development of positron emission tomography
found that radioiodinated styrylchromones (SCs) with amino
groups (NH , NHMe, and NMe ) bind to Ab aggregates with high
2
2
(
PET) and SPECT imaging probes of Ab plaques in the living
binding affinities. However, their initial uptake and washout from
normal mice brain tissue were inadequate for in vivo imaging.
5
–7
18
18
22
brain.
In particular,
F-flutemetamol,
F-florbetapir and
1
8
F-florbetaben have demonstrated highly correlated brain distri-
bution patterns with post-mortem existence of Ab plaques.
Therefore, we hypothesized that the structural modification of
SCs may improve the in vivo brain distribution and thereby, pro-
vide useful Ab imaging agents. Previously, we reported that
radioiodinated flavonoids such as flavone, chalcone, and aurone
derivatives with alkoxy groups at the p-position of the phenyl ring
showed good initial brain uptake and washout from the normal
brain without crucial decline in binding affinity for Ab.1
⇑
Corresponding authors. Tel./fax: +81 95 819 2443 (T.F.), +81 95 819 2441
M.N.).
E-mail addresses: t-fuchi@nagasaki-u.ac.jp (T. Fuchigami), morio@nagasaki-u.ac.
(
3,19,21
jp (M. Nakayama).
http://dx.doi.org/10.1016/j.bmcl.2015.05.048
0
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

3
364
T. Fuchigami et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3363–3367
R
R
R
O
O
O
O
I
I
R
I
I
O
O
O
Flavones
Chalcones
Aurones
Styrylchromones
R= NMe
2
, NHMe, NH
2
, OMe, OH
Figure 1. Chemical structures of flavonoid derivatives reported as Ab imaging probes.
Therefore, we considered that the introduction of alkoxy groups to
the structure of SCs could improve their in vivo brain distribution.
For this reason, we designed new radioiodinated SCs derivatives,
which have alkoxy groups introduced into the 2-phenyl ring of
the original structure. We envisaged that this structural modifica-
tion would enable their application in SPECT diagnosis.
carbonate resulted in oligoethyleneoxy derivatives 17, 18, and
19, respectively.
In vitro binding experiments to evaluate, the binding affinity of
the SC derivatives for Ab were performed. We used suspensions of
1
25
0
Ab(1–42) aggregates with
I-labeled 4-dimethylamino-4 -iodo-
styrylchromone (20), which showed high binding affinity for Ab
2
2
The synthesis of the alkoxy SC derivatives is presented in
aggregates (K
d
= 8.7 nM) in our previous studies. The inhibition
0
0
Scheme 1. O-acylation of the 5 -bromo-2 -hydroxyacetophenone
with the appropriate cinnamoyl chlorides provided phenyl cinna-
mates 1–3. The Baker–Venkataraman rearrangement of the phenyl
cinnamates using KOH gave the corresponding 1,3-diketones 4–6.
constant (K ) values of the SCs for the Ab aggregates ranged from
i
21.9 to 553 nM (Table 1). Derivative 13, which contained an unsub-
stituted 2-phenyl ring, displayed weak affinity for Ab aggregates
(K = 198 nM). In contrast, methoxy derivative 14 (K = 21 nM)
i i
The treatment of these 1,3-diketones with a mixture of H
2
SO
4
showed a 9-fold improvement in binding affinity versus 13, dis-
playing comparable affinity to dimethylamino derivative 20
and AcOH led to their cyclodehydration yielding (E)-2-styrylchro-
mones 7–9. These styrylchromones were converted to tributyltin
derivatives 10–12 using a bromo-to-tributyltin exchange reaction
catalyzed by Pd(0). The resulting tributyltin derivatives were
(K
may have a crucial role in binding interactions with Ab aggregates.
Dimethoxy derivative 15 had reasonable binding affinity
(K = 46 nM), suggesting that the introduction of a methoxy group
at the R position can retain binding affinity. However, introduc-
tion of a hydroxyl group at the R position did not improve the
binding affinity. Indeed, hydroxyl derivative 16 displayed
i 1
= 22 nM). Accordingly, the presence of a methoxy group at R
a
reacted with iodine in CHCl
1
1
3
to form the target iodo derivatives
3–15. Methoxy derivative 14 was converted to phenol derivative
6 by demethylation with BBr in CH Cl . Alkylation of 16
i
2
3
2
2
1
with ethylene chlorohydrin, ethylene glycol mono-2-chloroethyl
ether, or 2-[2-(2-chloroethoxy)ethoxy]ethanol using potassium
a
i
negligible Ab binding affinity (K = 121 nM). The oligoethyleneoxy
R
1
O
R
1
R
2
OH
R
1
a
O
b
c
HO
R
2
Br
R
2
O
Br
O
O
O
1
2
3
: R = H, R = H
4: R
5: R
6: R
1
1
1
= H, R
= OCH
= OCH
2
= H
, R
, R
1
2
: R
1
= OCH
3
, R
2
= H
3
2
= H
= OCH
3
: R = OCH , R = OCH
1
3
2
3
3
2
R
R
1
2
R
R
1
2
R
R
1
2
O
O
O
O
O
O
d
e
Br
Bu
3
Sn
I
7
8
9
: R = H, R = H
10: R = H, R = H
13: R
14: R
15: R
1
= H, R
= OCH
= OCH
2
= H
1
2
1
2
: R
1
= OCH
3
, R
2
= H
11: R = OCH , R = H
1
3
, R
, R
2
= H
= OCH
3
1
3
2
: R = OCH , R = OCH
1
3
2
3
12: R = OCH , R = OCH
1
3
2
1
3
2
3
OCH
3
OH
O
OH
n
O
O
O
O
O
f
g
I
I
I
O
14
16
17: n= 1
1
8: n= 2
9: n= 3
1
0
0
Scheme 1. Synthesis of styrylchromone derivatives. Reagents and conditions: (a) (1) SOCl
pyridine, KOH, reflux, 1 h; (c) H SO , AcOH, reflux, 1 h then rt, 1 h; (d) (SnBu , Pd(PPh
H(OCH CH Cl, K CO , DMF.
2
, DMF, reflux 1 h, (2) 5 -bromo-2 -hydroxyacetophenone, pyridine, reflux, 3 h; (b)
, Et N, dioxane, reflux, 7 h, (e) I , CHCl , rt, 30 min (f) CH Cl , BBr , rt, 24 h; (g)
2
4
)
3 2
)
3 4
3
2
3
2
2
3
2
)
2 n
2
3

T. Fuchigami et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3363–3367
3365
Table 1
Inhibition constant (K
derivatives
R
R
R
R
1
2
1
2
i
) for Ab(1–42) aggregates and logP values of styrylchromone
O
O
O
a
125I
R
1
Bu
3
Sn
O
O
R2
1
25
25
1
1: R = OCH , R = H
[
I]14: R
= OCH
= OCH
, R
, R
= H
2
= OCH
1
3
3
2
1
3
3
2
I
1
12: R
1
= OCH
, R
2
= OCH
3
[
I]15: R
1
3
O
Scheme 2. Radiosynthesis of 125I-labeled styrylchromone derivatives. Reagents and
conditions: (a) [ I]NaI, H O , HCl, EtOH, 3 min.
2 2
1
1
1
1
1
1
1
2
3: R = H, R = H
1
2
125
4: R
5: R
6: R
7: R
8: R
9: R
1
= OMe, R
= OMe, R
= OH, R
= OCH CH
= (OCH
= (OCH
2
= H
= OMe
= H
1
2
1
2
Based on the in vitro results, we selected 14 and 15 for further
biological evaluation. Fluorescence imaging experiments with the
SCs were performed using brain slices from a transgenic mouse
(Tg2576) model of Ab deposition. A number of fluorescence spots
denoting derivatives 14 and 15 were observed in the mouse brain
slices (Fig. 2A and B). The labeling patterns of these compounds
corresponded to the fluorescence signals obtained with thiofla-
vin-S staining (Fig. 2C and D). In contrast, there was no significant
fluorescence for 14 and 15 in the brain slices from wild-type mice
1
2
2
OH, R
2
= H
1
2
CH
CH
2
)
2
OH, R
OH, R
2
= H
1
2
2
)
3
2
= H
0: R = N(CH ) , R = H
1
3
2
2
a
logPb
Compounds
K
i
(nM)
Mw
13
14
15
16
17
18
19
20
198 ± 48.0
21.9 ± 5.10
45.5 ± 10.7
121 ± 20.8
446 ± 100
415 ± 64.5
553 ± 135
21.8 ± 3.35
374.1
404.2
434.2
390.2
434.2
478.3
522.3
417.3
—
2.15
2.14
1.87
—
(Fig. 2E and F). There was no marked autofluorescence detected in
any brain slices (data not shown). These results indicate that 14
and 15 have specific binding potential to Ab plaques in the mouse
brain.
—
—
2.65
c
a
For the biodistribution study and in vitro autoradiography,
Inhibition constant of styrylchromone derivatives were determined using
I]20 as the ligand in Ab aggregates. Each value (mean ± SEM) was determined by
1
25
125
125
[125
I-labeled SC derivatives ([ I]14, [ I]15) were synthesized by
an iododestannylation reaction of tributyltin derivatives (11 and
2) with hydrogen peroxide as an oxidant (Scheme 2). Using
3
–6 independent experiments.
b
The partition coefficient between n-octanol and sodium phosphate buffer at pH
1
7
.4 was determined by a conventional flask shaking method (n = 3).
c
22
HPLC systems, the radioligands were purified, and the radiochem-
ical qualities of these ligands were analyzed by co-injection of
non-radioactive compounds. The radioiodinated products were
obtained in radiochemical yields of 40–75% with a radiochemical
purity of >95%. Clinically available SPECT imaging probes for the
Ab plaque should show a high initial brain uptake and rapid clear-
ance from non-target regions in the brain. Therefore, biodistribu-
The logP values have been reported in our previous studies.
derivatives 17–19 exhibited reduced binding affinities
= 415–553 nM), which were over 20-fold lower than 14. In
(K
i
our previous study, the introduction of oligoethyleneoxy groups
to the phenyl ring of radioiodinated aurones did not considerably
alter Ab aggregate binding.21 In this study, we observed the
opposite effect, in that the presence of oligoethyleneoxy groups
on the 2-phenyl ring of the SCs clearly had a deleterious effect
on Ab aggregate binding affinity. These facts suggest that SCs and
aurones may exhibit different binding interactions with Ab
aggregates, although the mechanisms remain largely unclear.
1
25
125
tion studies of [ I]14 and [ I]15 were conducted in normal
mice and expressed as % of injected dose per gram (% ID/g)
1
25
125
(Table 2). The compounds [ I]14 and [ I]15 exhibited a high ini-
tial brain uptake (2.3% and 2.5% ID/g at 2 min, respectively) and a
favorable brain clearance (0.1% and 0.2% ID/g at 180 min,
Figure 2. Neuropathological staining of styrylchromone derivatives 14 (A) and 15 (B) in 10
lm sections of Tg2576 mice brain. Labeled plaques were confirmed by staining of
the adjacent sections with thioflavin-S (C and D). Fluorescence images of 14 (E) and 15 (F) in the age-matched control mouse brain sections. Scale bar = 50
l
m.

3
366
T. Fuchigami et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3363–3367
Table 2
Biodistribution of radioactivity after iv injection of 125I labeled styrylchromone derivatives in normal mice
Organ
Time after injection (min)
60
2
30
120
180
1
1
1
25
[
[
[
I]14
Blood
Liver
2.22 (0.31)
20.90 (3.32)
10.06 (1.94)
1.70 (0.67)
3.81 (1.11)
6.12 (1.61)
0.96 (0.26)
5.26 (0.84)
5.50 (1.08)
2.25 (0.38)
0.76 (0.09)
14.72 (3.73)
4.50 (1.55)
10.41 (3.60)
1.19 (0.20)
1.77 (0.33)
1.22 (0.88)
1.44 (0.22)
1.09 (0.08)
1.00 (0.12)
0.56 (0.13)
9.10 (2.58)
2.20 (0.41)
18.57 (7.07)
0.82 (0.17)
1.17 (0.28)
2.58 (2.09)
1.06 (0.44)
0.67 (0.15)
0.56 (0.11)
0.36 (0.08)
6.53 (3.63)
1.28 (0.40)
22.64 (6.14)
0.70 (0.26)
0.78 (0.18)
5.03 (4.15)
0.82 (0.74)
0.37 (0.10)
0.23 (0.06)
0.29 (0.04)
3.38 (0.59)
0.85 (0.12)
18.82 (3.81)
0.55 (0.32)
0.60 (0.19)
4.19 (1.37)
0.68 (0.72)
0.26 (0.08)
0.12 (0.02)
Kidney
Intestine
Spleen
Lung
Stomach
Pancreas
Heart
Brain
25
I]15
Blood
Liver
3.42 (0.32)
15.07 (1.39)
12.28 (1.43)
1.71 (0.47)
4.86 (0.69)
7.00 (0.99)
1.39 (0.18)
7.17 (1.62)
6.96 (0.93)
2.49 (0.39)
1.25 (0.16)
7.42 (1.46)
4.74 (0.70)
12.19 (4.91)
1.62 (0.31)
2.31 (0.31)
2.75 (2.17)
2.95 (0.90)
1.68 (0.23)
1.39 (0.16)
0.74 (0.10)
4.98 (1.39)
2.37 (0.33)
15.93 (8.64)
1.04 (0.16)
1.46 (0.18)
1.77 (0.53)
1.13 (0.17)
0.96 (0.13)
0.76 (0.12)
0.61 (0.14)
3.50 (0.82)
1.51 (0.18)
27.37 (4.85)
0.80 (0.49)
0.95 (0.11)
5.15 (3.29)
0.76 (0.34)
0.52 (0.08)
0.36 (0.05)
0.33 (0.05)
4.26 (0.80)
1.09 (0.20)
23.16 (3.95)
1.33 (1.19)
1.68 (2.48)
3.67 (2.82)
0.42 (0.20)
0.32 (0.08)
0.20 (0.12)
Kidney
Intestine
Spleen
Lung
Stomach
Pancreas
Heart
Brain
25
I]20
Blood
Liver
2.24 (0.43)
12.3 (2.65)
8.68 (2.05)
1.20 (0.48)
3.88 (1.94)
8.83 (2.51)
1.01 (0.31)
3.37 (0.59)
5.51 (1.33)
1.20 (0.23)
1.20 (0.17)
8.36 (2.01)
3.36 (1.25)
11.83 (2.26)
2.65 (0.45)
3.85 (0.69)
1.88 (0.79)
1.44 (0.58)
1.26 (0.31)
1.13 (0.21)
1.02 (0.16)
5.84 (1.18)
1.59 (0.66)
9.90 (5.68)
1.82 (0.45)
2.54 (0.82)
1.79 (0.66)
0.84 (0.14)
0.66 (0.13)
0.62 (0.10)
1.07 (0.19)
7.46 (2.61)
1.35 (0.55)
13.43 (5.52)
2.01 (0.89)
2.27 (0.55)
3.15 (1.46)
0.81 (0.31)
0.63 (0.14)
0.44 (0.11)
1.09 (0.29)
4.36 (1.29)
1.37 (0.41)
10.03 (2.58)
2.04 (0.29)
1.96 (0.89)
3.38 (2.68)
0.59 (0.21)
0.64 (0.17)
0.38 (0.11)
Kidney
Intestine
Spleen
Lung
Stomach
Pancreas
Heart
Brain
Each value represents mean (SD) for 5 or 6 mice at each interval.
respectively). The brain2min/brain60min ratio of 18F has been used as
are all within the specified range (Table 2), the most lipophilic
23,24
125
an index of brain washout.
The brain2min/brain60min ratio of
[
I]20 showed a relatively low blood–brain barrier permeability.
1
8
18
18
clinically used [ F]Florbetapir ([ F]AV-45) and [ F]Florbetaben
Taken together, these results indicate that the substitution of a
dimethylamino group with methoxy groups at the 2-phenyl ring
position of the SCs structure improves its brain distribution for
in vivo imaging.
1
8
25
(
[
F]BAY94-917218) was reported to be 3.823 and 4.8, respec-
tively. Since the brain2min/brain60min ratio of [1 I]14 and [ I]15
25
125
was calculated to be 4.5 and 3.3, respectively, the washout index
1
25
To further characterize [125I]14 and [125I]15 as possible imaging
probes for specifically targeting Ab plaques, in vitro autoradiogra-
phy was performed using brain sections from the Tg2576 mice.
of these [ I]SC derivatives seems to be comparable to the afore-
mentioned PET probes. Additionally, because the half-life of
1
23
radioactive iodine
I, used for SPECT, is much longer than that
1
8
125
of F (13.2 h vs 110 min), the brain2min/brain180min ratio can be
used as another index of brain washout in this study. The
Although some [ I]14 spots in the brain slices corresponded to
1
25
thioflavin-S stained regions, the overall [ I]14 image was incon-
sistent with the existence of Ab plaques (Fig. 3A and C). In contrast,
brain2min/brain180min ratios of [1 I]14 and [ I]15 were 18.8 and
25
125
2.5, respectively, indicating that these two 125I-labeled SC deriva-
tives have promising in vivo pharmacokinetics. Furthermore, the
clear [ I]15 autoradiographic images were observed in the thio-
125
1
flavin-S positive regions (Fig. 3B and D). The discrepancy between
the fluorescence and autoradiographic images of these SC deriva-
tives could have been caused by the different concentration of
1
25
collective in vivo results suggested that the washout of [ I]14
1
25
from the normal brain tissue was faster than that of [ I]15.
1
25
125
Both [ I]14 and [ I]15 demonstrated increased radioactivity in
the compounds. The concentration of the SCs was 100
fluorescence staining while only 0.3 nM of
l
M for the
I labeled SCs was
used in the autoradiography studies. It is unclear why only the
1
25
the stomach over time, and peaked at 5.0% and 5.2% ID/g at
6
0 min, respectively, suggesting that these SCs were gradually
1
25
deionidated in vivo. Since brain uptake of these tracers rapidly
declined with time, it is unlikely that the metabolites could easily
penetrate the blood brain barrier. Consistent with our previous
[
I]15 displayed a clear autoradiograph for Ab plaques, despite
the fact that derivative 15 possesses a lower binding affinity for
the Ab aggregates than 14 (Table 1). Several factors may have con-
tributed to these results, including the selectivity for Ab plaques
over other brain components, degree of nonspecific binding, and
conformation differences between the Ab aggregates and Ab pla-
2
2
study, relatively low initial brain uptake and high brain retention
125
of the dimethylamino derivative [ I]20 (1.20% ID/g at 2 min and
.38% ID/g at 180 min) was observed, compared with the methoxy
0
1
25
derivatives. It is reported that radiotracers with a low molecular
ques in the brain of Tg2576 mice. Regardless, the [ I]15 may be
a potential lead compound for the development of in vivo imaging
probes for Ab plaques in the brain. Further structural modification
of the SC derivatives can provide promising Ab imaging probes.
weight (<500 Da) and a moderate lipophilicity (logD7.4 values,
2
6,27
2
.0–3.5) show optimal passive brain entry in vivo.
Although
125
the molecular weights of the
I-labeled compounds in this study

T. Fuchigami et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3363–3367
3367
Figure 3. In vitro autoradiograms of styrylchromone derivatives [125I]14 (A) and [125I]15 (B) in the brain sections of Tg2576 mouse brain. Fluorescence images of thioflavin-S
in the adjacent section (C and D).
In conclusion, we demonstrated that radioiodinated styrylchro-
mone derivatives with methoxy groups had preferable pharma-
cokinetics for in vivo imaging without significant reduction in
binding affinity for the Ab aggregates. In particular, both fluores-
cent imaging and autoradiography showed that the dimethoxy
derivative [ I]15 labeled the thioflavin-S positive Ab plaques in
sections of the Tg2576 mouse brain. Further structural modifica-
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Acknowledgment
Financial support was provided by a Grant-in-Aid for Scientific
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Supplementary data
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