Synthesis and biological evaluation of novel technetium-99m labeled phenylbenzoxazole derivatives as potential imaging probes for β-amyloid plaques in brain

Article abstract of DOI:10.1016/j.bmcl.2012.05.010

Two uncharged ^99mTc-labeled phenylbenzoxazole derivatives were biologically evaluated as potential imaging probes for β-amyloid plaques. The ^99mTc and corresponding rhenium complexes were synthesized by coupling monoamine-monoamide dithiol (MAMA) and bis(aminoethanethiol) (BAT) chelating ligand via a pentyloxy spacer to phenylbenzoxazole. The fluorescent rhenium complexes 6 and 9 selectively stainined the β-amyloid plaques on the sections of transgenic mouse, and showed high affinity for Aβ_(1-42) aggregates (K_i = 11.1 nM and 14.3 nM, respectively). Autoradiography in vitro indicated that [^99mTc]6 clearly labeled β-amyloid plaques on the sections of transgenic mouse. Biodistribution experiments in normal mice revealed that [^99mTc]6 displayed moderate initial brain uptake (0.81% ID/g at 2 min), and quickly washed out from the brain (0.25% ID/g at 60 min). The preliminary results indicate that the properties of [^99mTc]6 are promising, although additional refinements are needed to improve the ability to cross the blood-brain barrier.

Full text of DOI:10.1016/j.bmcl.2012.05.010

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4327–4331
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel technetium-99m labeled
phenylbenzoxazole derivatives as potential imaging probes for b-amyloid
plaques in brain
⇑
⇑
Xuedan Wang, Mengchao Cui , Pingrong Yu, Zijing Li, Yanping Yang, Hongmei Jia, Boli Liu
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China
a r t i c l e i n f o
a b s t r a c t
Two uncharged 99mTc-labeled phenylbenzoxazole derivatives were biologically evaluated as potential
imaging probes for b-amyloid plaques. The 99mTc and corresponding rhenium complexes were synthe-
sized by coupling monoamine–monoamide dithiol (MAMA) and bis(aminoethanethiol) (BAT) chelating
ligand via a pentyloxy spacer to phenylbenzoxazole. The fluorescent rhenium complexes 6 and 9 selec-
tively stainined the b-amyloid plaques on the sections of transgenic mouse, and showed high affinity
for Ab(1–42) aggregates (Ki = 11.1 nM and 14.3 nM, respectively). Autoradiography in vitro indicated that
Article history:
Received 3 April 2012
Revised 2 May 2012
Accepted 4 May 2012
Available online 11 May 2012
Keywords:
[
99mTc]6 clearly labeled b-amyloid plaques on the sections of transgenic mouse. Biodistribution experi-
Alzheimer’s disease
b-Amyloid plaque
Technetium-99m
Phenylbenzoxazole
Imaging probe
ments in normal mice revealed that [99mTc]6 displayed moderate initial brain uptake (0.81% ID/g at
2 min), and quickly washed out from the brain (0.25% ID/g at 60 min). The preliminary results indicate
that the properties of [99mTc]6 are promising, although additional refinements are needed to improve
the ability to cross the blood–brain barrier.
Ó 2012 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is the leading cause of neurodegener-
ative disorder of the brain, accounting for most dementia cases
after the age of 60. Histopathologically, the formation of extracel-
lular b-amyloid (Ab) plaques is one of the pathological hallmarks
of this disease.1 In clinic, it is very difficult to differentiate AD from
other dementia cases. Currently, diagnosis of AD relies on the re-
sults from neuropsychological tests. However, this method is often
complicated and unreliable, where the degree of accuracy ranges
from 50% to 90%. A definite diagnosis of AD can only be confirmed
by histopathological observation of Ab plaques in the cerebral cor-
tex of postmortem brain tissue. At present, the exact etiology of AD
is not completely understood, the most widely accepted theory
regarding to this disease is the amyloid cascade hypothesis.2–4
Therefore, Ab represents an important molecular target for AD,
and the detection of deposited Ab plaques with non-invasive tech-
niques such as positron emission tomography (PET) or single
photon emission computed tomography (SPECT) could achieve
the differential diagnosis of AD in its pre-symptomatic stages.5,6
Over the past decade, based on the scaffolds of thioflavin-T (ThT)
and Congo Red (CR), (commonly used dyes for detection of Ab pla-
ques), several specific radiotracers were synthesized and evaluated
as in vivo imaging probes for Ab plaques with PET and SPECT. Some
[ [
18F]BAY94-9172,13 18F]GE-06714 and [18F]AV-4515,16 have been
evaluated in clinical trials.
However, the development of SPECT tracers was lagging far be-
hind, to the best of our knowledge, a radioiodinated ligand
[
123I]IMPY, is the only SPECT tracer tested in humans. Some unde-
sirable properties including high lipophilicity, in vivo instability
together with insufficient target-to-background ratio may account
for the failure of [123I]IMPY in clinical trials.17–19 Furthermore,
some other radioiodinated ThT analogs for SPECT such as TZDM,20
IBOX,21 phenylbenzofuran derivatives22 and phenylindole deriva-
tives23 have shown high affinity for Ab aggregates in vitro and high
initial uptake, but their potential use was limited by the slow
washout rate from the brain and the lack of routine availability
of 123I radioisotope.
At present, the most widely used radionuclide in diagnostic nu-
clear medicine for SPECT imaging is technetium-99m (99mTc),
mainly due to its optimal nuclear properties (T1/2 = 6.01 h,
141 keV), easy availability (through commercial 99Mo/99mTc gener-
ators), and low cost. Accordingly, the development of 99mTc-la-
beled imaging probes targeting Ab plaques will provide simple,
convenient, and widespread method for the diagnosis of AD. In
the past few years, several 99mTc-labeled imaging probes have been
developed (Fig. 1). Such as the initially reported 99mTc-labeled Con-
go Red24,25 and Chrysamine G derivatives,26,27 which displayed
high affinity for Ab aggregates in vitro. However, due to the large
molecular weight and ionized character at physiological pH, they
cannot cross the blood–brain barrier (BBB). Attempts to prepare
PET tracers such as
[ [ [
11C]PIB,7,8 18F]FDDNP,9–11 11C]SB-13,12
⇑
Corresponding authors. Tel./fax: +86 10 58808891 (M.C.).
E-mail addresses: cmc@bnu.edu.cn (M. Cui), liuboli@bnu.edu.cn (B. Liu).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.010

4328
X. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4327–4331
tBu
N
tBu
tBu
N
N
N
N
N
HO
N
N
OH
Tc
HN
O
N
NaO3S
N
N
SO3Ns
HOOC
O
COOH
N
O
Tc
N
S
N
N
N
NH2
H2N
S
tBu
Congo Red derivative
O
Chrysamine G derivative
N
S
H
N
N
S
N
S
S
S
N
N
S
N
O
S
N
Tc
O
Tc
O
O
Tc
O
NH2
N
N
S
Benzothiazole aniline derivative
N
Benzothiazole aniline derivative
Biphenyl derivative
N
S
N
S
O
N
S
N
S
O
Tc
O
Tc
O
N
O
O
Benzofuran derivative
Chaclone derivative
O
O
O
N
O
N
S
N
S
O
N
N
S
O
N
Tc
O
Tc
O
N
S
Tc
O
S
O
S
N
NC
CN
Aurone derivative
DDNP derivative
Flavone derivative
N
Figure 1. Chemical structures of 99mTc-labeled Ab imaging probes reported previously.
99mTc-labeled nonpolar, neutral, small in size and more lipophilic
ligands have been reported. Kung and his co-workers reported
the 99mTc-labeled N2S2-biphenyl derivatives, which showed high
initial brain uptake (1.18% dose/organ at 2 min), but it failed to
bind to the Ab plaques in the postmortem human brain tissue of
patients with confirmed AD.28 Some other groups reported a series
of benzothiazole aniline (BTA),29–31 phenylbenzofuran,32 DDNP,33
chaclone,34 flavone and aurone35 derivatives conjugated with
bis(aminoethanethiol) (BAT) or monoamine–monoamide dithiol
(MAMA) ligands. Although it was demonstrated that these 99mTc-
labeled derivatives bind to Ab plaques in vitro, they still cannot
cross BBB to a sufficient degree for the in vivo imaging.
PMB-MAMA or N-Boc-Tr-BAT to generate the compounds 4 and
7, respectively. Compounds 5 and 8 (the precursors for 99mTc label-
ing) were obtained by deprotection of the thiol groups in 4 and 7.
The rhenium complexes (6 and 9) were prepared by the reaction of
4 and 7 with (PPh3)2ReOCl3 in CH2Cl2. The corresponding 99mTc
complexes [99mTc]6 and [99mTc]9 were prepared by a ligand
exchange reaction employing the precursor 99mTc-glucoheptonate
(GH) in boiling water, and the desired products were formed as
major radioactive products. After purification by reversed-phase
high-performance liquid chromatography (HPLC), the final prod-
ucts were obtained with radiochemical purity higher than 95%.
The identity of the complexes were established by comparative
HPLC using the corresponding Re complexes as reference. The
retention time of [99mTc]6 and [99mTc]9 on HPLC (radioactivity)
were 7.92 and 9.97 min, respectively. The retention times of the
corresponding rhenium complexes (6 and 9) on HPLC (UV detec-
tion) were 7.46 and 9.31 min, respectively (Fig. S1 in the Supple-
mentary data).
The specific binding of the rhenium complexes 6 and 9 to Ab
plaques were evaluated by neuropathological staining with the
brain sections from a transgenic mouse (C57BL6, APPswe/PSEN1,
12 months old), an animal model for AD. As shown in Figure 2A
and C, both Re complexes could clearly stain Ab plaques on the
brain sections with low background, and the similar stain pattern
of Ab plaques was consistent with that stained with thioflavin-S
using the adjacent sections (Fig. 2B and D). The results indicated
that these two Re complexes could bind specifically to Ab plaques.
Furthermore, the quantitative binding affinities of rhenium com-
plexes 6 and 9 for Ab1–42 aggregates were determined by competi-
tion binding assay using [125I]IMPY as radio-ligand, while IMPY
was also screened using the same system for comparison. As
shown in Table 1, complexes 6 and 9 displayed high affinity to
Ab1–42 aggregates (Ki = 11.1 nM and 14.3 nM, respectively), which
Recently, we have synthesized and evaluated a series of 18F-la-
beled phenylbenzoxazole derivatives as novel Ab imaging probes.
They showed high affinity for Ab aggregates and favorable pharma-
cokinetics in vivo, which suggests that this class of tracers has
potential applications for PET imaging.36 Building on the previous
results, we attempt to design novel 99mTc-labeled phenylbenzoxaz-
ole derivatives for SPECT imaging. In the present study, we report
the synthesis of two phenylbenzoxazole derivatives conjugated
to MAMA and BAT via a pentyloxy spacer as well as their complex-
ation to Re and 99mTc. We also report the biological evaluation of
these two probes as novel Ab imaging probes.
The synthetic route of the phenylbenzoxazole derivatives is
outlined in Scheme 1. The key step in the formation of the phenyl-
benzoxazole backbone was achieved by reacting 2-amino-4-
methoxyphenol with 4-(dimethylamino)benzoic acid in PPA,
compound 1 was obtained in a yield of 39.6%. Subsequent demeth-
ylation of the methoxyl group using BBr3 in CH2Cl2 afforded 2 in a
yield of 89.5%. The thiol-protected chelation ligands (PMB-MAMA
and N-Boc-Tr-BAT) were synthesized according to the methods re-
ported previously.37 After introduction of the pentyloxy linker into
2 by reacting with 1,5-dibromo pentane, 3 were conjugated to

X. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4327–4331
4329
OH
O
N
O
O
N
a
c
b
N
N
N
N
O
NH2
O
HO
Br
O
1
2
3
Boc
Boc
N
N
O
NH
N
O
N
HN
3
e
N
O
N
O
N
N
N
N
N
d
S
S
SH HS
S
S
Tr
Tr
4
5
Tr
Tr
g
f
N
S
N
S
O
N
S
N
O
N
N
O
Re
O
Tc
O
N
S
O
99m
6
6
Tc]
[
O
O
O
NH
N
S
O
NH
N
O
NH HN
3
d
N
O
h
N
O
N
S
SH HS
O
S
S
8
PMB PMB
7
PMB PMB
g
f
O
N
S
N
O
N
S
N
S
O
N
O
N
Re
O
Tc
O
N
S
O
99m
9
9
[
Tc]
Scheme 1. Synthesis of 99mTc-labeled phenyl benzoxazole and the corresponding rhenium derivatives. Reagents and conditions: (a) 4-(dimethylamino)benzoic acid, PPA,
140 °C; (b) BBr3, CH2Cl2; (c) K2CO3, CH3CN, 90 °C; (d) K2CO3, CH3CN, 90 °C; (e) TFA, Et3SiH; (f) 99mTc-GH, 100 °C; (g) ReOCl3(PPh3)2, CH2Cl2, CH3OH; (h) anisole, CH3SO3H, TFA.
Figure 2. Fluorescence staining of the rhenium complexes 6 and 9 on the sections from a transgenic model mouse (C57BL6, APPswe/PSEN1, 12 months old, 10
C). The presence and distribution of Ab plaques on the adjacent sections were confirmed with thioflavin-S (B, D).
lm thick) (A,
Table 1
Inhibition constants for the binding of [125I]IMPY to Ab1–
is comparable to the value of IMPY (Ki = 10.1 nM). Compared with
the 99mTc-labeled phenylbenzothiazole38 and phenylbenzofuran32
derivatives reported previously, these phenylbenzoxazole deriva-
tives also maintain high binding affinity to Ab aggregates.
To further characterize the binding to Ab plaques, in vitro auto-
radiography was performed by incubating [99mTc]6 with sections
of AD mouse brain. As shown in Figure 3A and C, [99mTc]6 dis-
played excellent labeling of Ab plaques in the cortex region and a
aggregatesa
Compounds
42
Ki (nM)
6
9
11.1 3.5
14.3 2.2
10.1 1.9
IMPY
a
Measured in triplicate with results given as the
mean SD.

4330
X. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4327–4331
Figure 3. Autoradiography of [99mTc]6 in vitro on the section from a transgenic model mouse (C57BL6, APPswe/PSEN1, 12 months old, 10
lm thick) (A). The presence and
distribution of plaques in the same section were confirmed with thioflavin-S (B). A magnification view of the Ab plaques labeled with [99mTc]6 (C) and confirmed with
thioflavin-S (D).
low background level in white matter in the AD mouse brain.
Furthermore, the hot spots of radioactivity were perfectly accorded
with the results of in vitro fluorescence staining in the same sec-
tions with thioflavin-S (Fig. 3B and D, red arrows). The results con-
firm the high binding affinity of [99mTc]6 to Ab1–42 aggregates.
The lipophilicity (logD) of [99mTc]6 and [99mTc]9 measured
under experimental conditions showed moderate partition coeffi-
cients (logD = 2.73 0.02 and 2.93 0.09, respectively), which are
in a good range for BBB penetration. High initial brain uptake
and fast washout kinetics from the normal brain are two important
properties for a promising Ab imaging probe. The biodistribution
experiments of [99mTc]6 and [99mTc]9 were performed in normal
mice (5 weeks, male). Biodistribution study in mice is often used
as a method to measure the brain uptake. As shown in Table 2,
[
99mTc]6 with a BAT chelation ligand displayed moderate initial
brain uptake (0.81% ID/g at 2 min), and quickly washout from the
brain (0.25% ID/g at 60 min). But [99mTc]9 with a MAMA chelation
ligand displayed lower initial brain uptake at 2 min postinjection
(0.43% ID/g), and was washed out from the brain relatively slowly
(0.30% ID/g at 60 min). Since the only difference between [99mTc]6
and [99mTc]9 is the chelation ligands, the carbonyl group in MAMA
moiety may form hydrogen bond with water and other
Table 2
Biodistribution of [99mTc]6 and [99mTc]9 in normal micea
Organ
99mTc]6 (LogD = 2.73 0.02)
2 min
10 min
30 min
60 min
120 min
[
Blood
Brain
Heart
Liver
Spleen
Lung
Kidney
Stomachb
Intestineb
3.68 0.67
0.81 0.01
10.09 2.15
23.23 1.89
5.43 0.55
9.38 1.92
9.98 2.09
1.13 0.20
2.86 0.74
1.75 0.17
0.49 0.06
4.40 0.84
21.34 5.61
3.02 0.51
3.63 0.98
6.08 0.82
1.68 0.27
11.34 2.45
1.29 0.09
0.40 0.03
2.13 0.30
18.34 2.54
2.34 0.20
3.04 0.49
3.42 0.46
3.34 0.95
21.99 3.16
1.45 0.45
0.25 0.05
1.44 0.32
15.29 3.36
1.65 0.24
2.32 0.60
2.99 0.48
3.30 0.51
27.19 2.64
1.14 0.20
0.20 0.02
0.98 0.15
13.89 3.37
1.06 0.22
1.57 0.37
2.24 0.42
2.28 0.35
21.43 3.94
[
99mTc]9 (LogD = 2.93 0.09)
Blood
Brain
Heart
Liver
Spleen
Lung
Kidney
Stomachb
Intestineb
5.50 0.30
0.43 0.06
7.94 0.44
21.08 1.85
5.66 0.22
12.83 0.98
7.56 0.32
1.44 0.16
2.66 0.29
3.27 0.12
0.30 0.01
5.12 0.11
19.88 0.67
3.49 0.31
5.28 0.41
6.15 0.35
1.17 0.09
4.59 3.05
2.04 0.66
0.23 0.01
2.41 0.50
9.01 1.32
2.01 0.11
3.45 0.04
3.68 0.14
2.05 0.45
11.01 0.80
3.13 0.30
0.30 0.04
2.76 0.05
22.75 2.99
2.97 0.26
3.20 0.30
5.29 0.26
1.65 0.06
12.07 5.58
2.34 0.16
0.28 0.05
1.87 0.08
14.54 0.56
1.82 0.21
2.56 0.17
3.26 0.27
4.38 0.39
13.77 0.49
a
All data are expressed as the mean percentage (n = 5) of the injected dose per gram of wet tissue (%ID/g) the standard deviation of the mean.
Expressed as % injected dose per organ.
b

X. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4327–4331
4331
9. Agdeppa, E. D.; Kepe, V.; Flores-Torres, S.; Liu, J.; Satyamurthy, N.; Petric, A.;
Small, G. W.; Huang, S. C.; Barrio, J. R. J. Nucl. Med. 2001, 42, 64.
10. Agdeppa, E. D.; Kepe, V.; Shoghi-Jadid, K.; Satyamurthy, N.; Small, G. W.; Petric,
A.; Vinters, H. V.; Huang, S. C.; Barrio, J. R. J. Nucl. Med. 2001, 42, 65.
11. Shoghi-Jadid, K.; Small, G. W.; Agdeppa, E. D.; Kepe, V.; Ercoli, L. M.; Siddarth,
P.; Read, S.; Satyamurthy, N.; Petric, A.; Huang, S. C.; Barrio, J. R. Am. J. Geriatr.
Psychiatry 2002, 10, 24.
12. Verhoeff, N. P. L. G.; Wilson, A. A.; Takeshita, S.; Trop, L.; Hussey, D.; Singh, K.;
Kung, H. F.; Kung, M. P.; Houle, S. Am. J. Geriatr. Psychiatry 2004, 12, 584.
13. Rowe, C. C.; Ackerman, U.; Browne, W.; Mulligan, R.; Pike, K. L.; O’Keefe, G.;
Tochon-Danguy, H.; Chan, G.; Berlangieri, S. U.; Jones, G.; Dickinson-Rowe, K.
L.; Kung, H. P.; Zhang, W.; Kung, M. P.; Skovronsky, D.; Dyrks, T.; Holl, G.;
Krause, S.; Friebe, M.; Lehman, L.; Lindemann, S.; Dinkelborg, L. M.; Masters, C.
L.; Villemagne, V. L. Lancet Neurol. 2008, 7, 129.
14. Koole, M.; Lewis, D. M.; Buckley, C.; Nelissen, N.; Vandenbulcke, M.; Brooks, D.
J.; Vandenberghe, R.; Van Laere, K. J. Nucl. Med. 2009, 50, 818.
15. Choi, S. R.; Golding, G.; Zhuang, Z.; Zhang, W.; Lim, N.; Hefti, F.; Benedum, T. E.;
Kilbourn, M. R.; Skovronsky, D.; Kung, H. F. J. Nucl. Med. 2009, 50, 1887.
16. Kung, H. F.; Choi, S. R.; Qu, W. C.; Zhang, W.; Skovronsky, D. J. Med. Chem. 2010,
53, 933.
biomoleculars in vivo which decrease the initial brain uptake of
99mTc]9. The ratio brain2min/brain60min is considered an important
[
index with which to select probes with appropriate kinetics in vivo.
The brain2min/brain60min ratio of [99mTc]6 was 3.24. As compared
with 99mTc-labeled phenylbenzothiazole (2.06)30 and phen-
ylbenzofuran (2.39),32 the 99mTc-labeled phenylbenzoxazole deriv-
ative 6 had superior brain2min/brain60min ratio. Furthermore, the
excretion of the 99mTc-labeled ligands was observed predomi-
nantly by the hepatobiliary and excretory systems. Liver uptake
dropped gradually with time, while the accumulation of radioac-
tivity was observed within the intestine at later time periods.
In conclusion, two novel uncharged 99mTc-labeled phenylbenz-
oxazole derivatives and their corresponding rhenium complexes
were successfully synthesized and biologically evaluated as poten-
tial imaging probes for b-amyloid plaques. In vitro competition
binding assay indicated that the rhenium complexes displayed
high affinity for Ab(1–42) aggregates, and the high binding affinity
was further confirmed by in vitro autoradiography, [99mTc]6 clearly
labeled Ab plaques in sections of brain tissue from AD mouse brain.
In addition, [99mTc]6 exhibited moderate initial penetration (0.81%
ID/g) of and fast clearance from the brain, with a brain2min/brain
60min ratio of 3.24. Taken together, the present results suggest that
the 99mTc-labeled phenylbenzoxazole derivatives 6 may be a useful
Ab imaging probe for SPECT. But additional chemical modifications
are required to further improve the diffusion through the BBB.
17. Kung, M. P.; Hou, C.; Zhuang, Z. P.; Zhang, B.; Skovronsky, D.; Trojanowski, J. Q.;
Lee, V. M.; Kung, H. F. Brain Res. 2002, 956, 202.
18. Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plossl, K.; Hou, C.; Holtzman,
D. M.; Kung, H. F. J. Med. Chem. 2003, 46, 237.
19. Newberg, A. B.; Wintering, N. A.; Plossl, K.; Hochold, J.; Stabin, M. G.; Watson,
M.; Skovronsky, D.; Clark, C. M.; Kung, M. P.; Kung, H. F. J. Nucl. Med. 2006, 47,
748.
20. Zhuang, Z. P.; Kung, M. P.; Hou, C.; Skovronsky, D. M.; Gur, T. L.; Plossl, K.;
Trojanowski, J. Q.; Lee, V. M. Y.; Kung, H. F. J. Med. Chem. 2001, 44, 1905.
21. Zhuang, Z. P.; Kung, M. P.; Hou, C.; Plossl, K.; Skovronsky, D.; Gur, T. L.;
Trojanowski, J. Q.; Lee, V. M. Y.; Kung, H. F. Nucl. Med. Biol. 2001, 28, 887.
22. Ono, M.; Kung, M. P.; Hou, C.; Kung, H. F. Nucl. Med. Biol. 2002, 29, 633.
23. Watanabe, H.; Ono, M.; Haratake, M.; Kobashi, N.; Saji, H.; Nakayama, M.
Bioorg. Med. Chem. 2010, 18, 4740.
24. Han, H.; Cho, C. G.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118, 4506.
25. Zhen, W.; Han, H.; Anguiano, M.; Lemere, C. A.; Cho, C. G.; Lansbury, P. T. J. Med.
Chem. 1999, 42, 2805.
26. Dezutter, N. A.; Dom, R. J.; de Groot, T. J.; Bormans, G. M.; Verbruggen, A. M.
Eur. J. Nucl. Med. Mol. Imaging 1999, 26, 1392.
Acknowledgment
This study was funded by NSFC (20871021).
27. Dezutter, N. A.; de Groot, T. J.; Busson, R. H.; Janssen, G. A.; Verbruggen, A. M. J.
Labelled Compd. Radiopharm. 1999, 42, 309.
Supplementary data
28. Zhuang, Z. P.; Kung, M. P.; Hou, C.; Ploessl, K.; Kung, H. F. Nucl. Med. Biol. 2005,
32, 171.
Supplementary data (procedure for the preparation of 99mTc/Re
labeled phenylbenzoxazole derivatives, in vitro binding assay, fluo-
rescent staining and biodistribution experiments) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2012.05.010.
29. Serdons, K.; Verduyckt, T.; Cleynhens, J.; Terwinghe, C.; Mortelmans, L.;
Bormans, G.; Verbruggen, A. Bioorg. Med. Chem. Lett. 2007, 17, 6086.
30. Chen, X. J.; Yu, P. R.; Zhang, L. F.; Liu, B. Bioorg. Med. Chem. Lett. 2008, 18, 1442.
31. Serdons, K.; Verduyckt, T.; Cleynhens, J.; Bormans, G.; Verbruggen, A. J. Labelled
Compd. Radiopharm. 2008, 51, 357.
32. Ono, M.; Fuchi, Y.; Fuchigami, T.; Kobashi, N.; Kimura, H.; Haratake, M.; Saji, H.;
Nakayama, M. ACS Med. Chem. Lett. 2010, 1, 443.
33. Cui, M. C.; Tang, R. K.; Li, Z. J.; Ren, H. Y.; Liu, B. L. Bioorg. Med. Chem. Lett. 2011,
21, 1064.
References and notes
34. Ono, M.; Ikeoka, R.; Watanbe, H.; Kimura, H.; Fuchigami, T.; Haratake, M.; Saji,
H.; Nakayama, M. ACS Chem. Neurosci. 2010, 1, 598.
35. Ono, M.; Ikeoka, R.; Watanabe, H.; Kimura, H.; Fuchigami, T.; Haratake, M.; Saji,
H.; Nakayama, M. Bioorg. Med. Chem. Lett. 2010, 20, 5743.
36. Cui, M. C.; Ono, M.; Kimura, H.; Ueda, M.; Nakamoto, Y.; Togashi, K.; Okamoto,
Y.; Ihara, M.; Takahashi, R.; Liu, B. L.; Saji, H. J. Med. Chem., submitted for
publication.
37. Oya, S.; Plossl, K.; Kung, M. P.; Stevenson, D. A.; Kung, H. F. Nucl. Med. Biol. 1998,
25, 135.
1. Selkoe, D. J. Physiol. Rev. 2001, 81, 741.
2. Hardy, J. A.; Higgins, G. A. Science 1992, 256, 184.
3. Selkoe, D. J. JAMA J. Am. Med. Assoc. 2000, 283, 1615.
4. Hardy, J. A.; Selkoe, D. J. Science 2002, 297, 353.
5. Mathis, C. A.; Wang, Y.; Klunk, W. E. Curr. Pharm. Des. 2004, 10, 1469.
6. Cai, L.; Innis, R. B.; Pike, V. W. Curr. Med. Chem. 2007, 14, 19.
7. Mathis, C. A.; Wang, Y. M.; Holt, D. P.; Huang, G. F.; Debnath, M. L.; Klunk, W. E.
J. Med. Chem. 2003, 46, 2740.
8. Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y. M.; Blomqvist, G.; Holt, D. P.;
Bergstrom, M.; Savitcheva, I.; Huang, G. F.; Estrada, S.; Ausen, B.; Debnath, M.
L.; Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni,
G.; Mathis, C. A.; Langstrom, B. Ann. Neurol. 2004, 55, 306.
38. Lin, K. S.; Debnath, M. L.; Mathis, C. A.; Klunk, W. E. Bioorg. Med. Chem. Lett.
2009, 19, 2258.