Novel benzofurans with 99mTc complexes as probes for imaging cerebral β-amyloid plaques

Article abstract of DOI:10.1021/ml100140d

Two novel benzofuran derivatives coupled with ^99mTc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, ^99mTc-BAT-BF

Full text of DOI:10.1021/ml100140d

pubs.acs.org/acsmedchemlett
Novel Benzofurans with 99mTc Complexes as Probes for
Imaging Cerebral β-Amyloid Plaques
Masahiro Ono,*,†,‡ Yasufumi Fuchi,† Takeshi Fuchigami,† Nobuya Kobashi,†
Hiroyuki Kimura,‡ Mamoru Haratake,† Hideo Saji,‡ and Morio Nakayama*,†
†Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, and ‡Graduate
School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
ABSTRACT Two novel benzofuran derivatives coupled with 99mTc complexes
were tested as probes for imaging cerebral β-amyloid plaques using single photon
emission tomography. Although both derivatives bound to Aβ(1-42) aggregates,
99mTc-BAT-BF showed higher affinity than 99mTc-MAMA-BF. In sections of brain
tissue from an animal model of AD, 99mTc-BAT-BF clearly labeled β-amyloid
plaques. In biodistribution experiments using normal mice, 99mTc-BAT-BF dis-
played high uptake soon after its injection and washed out from the brain rapidly,
a highly desirable feature for an imaging agent. 99mTc-BAT-BF may be a potential
probe for imaging β-amyloid plaques in Alzheimer's brains.
KEYWORDS Alzheimer's disease, β-amyloid plaque, Tc-99m, single photon
emission computed tomography (SPECT), imaging
lzheimer's disease (AD) is a neurodegenerative dis-
ease of the brain associated with irreversible cognitive
decline, memory impairment, and behavioral changes.
for imaging. Its ready availability, essentially 24 h a day,
and easiness of use make it the radionuclide of choice.
Several 99mTc-labeled imaging probes have been developed
(Figure 1),24-28 but no clinical study of them has been
reported. New 99mTc-labeled imaging agents will provide
simple, convenient, and widespread SPECT-based imaging
methods for detecting and eventually quantifying β-amyloid
plaques in living brain tissue.
In the present study, we synthesized two benzofuran
derivatives with monoamine-monoamide dithiol (MAMA)
and bis-amino-bis-thiol (BAT). MAMA and BAT were selected
as a chelation ligand taking into consideration the perme-
ability of the blood-brain barrier, because they form an
electrically neutral complex with 99mTc.29 We then evaluated
their biological potential as probes by testing their affinity for
Aβ aggregates and β-amyloid plaques in sections of brain
tissue from Tg2576 mice and their uptake by and clearance
from the brain in biodistribution experiments using normal
mice. To our knowledge, this is the first time that benzofu-
rans coupled with 99mTc complexes have been proposed as
probes for the detection of β-amyloid plaques in the brain.
The synthesis of the 99mTc/Re benzofuran derivatives is
outlined in Scheme 1. The key step in the formation of the
benzofuran backbone was readily achieved by reacting
2-hydroxy-5-methoxybenzaldehyde with 4-nitrobenzylbromide
to produce compound 1 in a yield of 75%. The amino derivative
2was prepared from 1by reduction with SnCl2 in a yield of 95%.
A
The presence of β-amyloid (Aβ) aggregates in the brain is
generally accepted as a hallmark of AD.1,2 Currently, the only
definitive diagnosis of AD is by pathological examination of the
postmortem staining of affected brain tissue, and the early
appraisal of clinical symptoms for the diagnosis of AD is
often difficult and unreliable. Thus, the detection of individual
plaques in vivo by single photon emission tomography
(SPECT) or positron emission tomography (PET) has been
strongly desired to improve diagnosis and also accelerate
the discovery of effective therapeutic agents for AD.3-6
Many radiolabeled probes for imaging β-amyloid based on
Congo Red, thioflavin T, and DDNP have been reported.
Among them, [11 C]PIB,7,8 [11 C]SB-13,9,10
[
18F]BAY94-
9172,11 , 1 2 [11 C]BF-227,13 [18F]FDDNP,14-16
[
123I]IMPY,17-19
and [18F]AV-4520,21 have been tested clinically and demon-
strated potential utility.
We have recently reported that 125I-, 11 C-, and 18F-labeled
benzofuran derivatives showed high affinity for Aβ aggre-
gates and good uptake into and rapid clearance from the
brain, indicating that benzofuran can function as a promis-
ing scaffold for the development of β-amyloid imaging
probes.22,23 In this study, we planned the development of
novel benzofuran derivatives labeled with technetium-99 m
(
99mTc). 99mTc (T1/2 = 6.01 h, 141 keV) has become the most
commonly used radionuclide in diagnostic nuclear medi-
cine, because it is readily produced by an 99Mo/99mTc gen-
erator; the medium γ-ray energy that it emits is suitable for
detection, and its physical half-life is compatible with
the biological localization and residence time required
Received Date: June 16, 2010
Accepted Date: July 26, 2010
Published on Web Date: August 02, 2010
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Figure 1. Chemical structure of 99mTc-labeled Aβ imaging probes reported previously.
Scheme 1. Synthesis of Re- and 99mTc-benzofuran Derivativesa
a Reagents: (a) DMF, K2CO3, 4-nitrobenzylbromide. (b) EtOH, SnCl2. (c) CH3COOH, (CH2O)n, NaBH3CN. (d) CH2Cl2, BBr3. (e) CH3CN, K2CO3, 1,3-
dibromopropane. (f) CH3CN, DIPEA, PMB-BAT. (g) TFA, MeSO3H, anisole. (h) CH2Cl2/MeOH, (PPh3)2ReOCl3, AcONa. (i) CH3CN, 0.1 N HCl, 99mTc-GH.
( j) CH3CN, TRT-MAMA, DIPEA. (k) TFA, Et3SiH.
Conversion of 2 to the dimethylamino derivative 3 was achieved
by an efficient method with paraformaldehyde, sodium cyano-
borohydride, and acetic acid (78% yield). TheO-methyl group of
3 was removed by reacting with BBr3 to give 4 in a yield of 63%.
After a trimethylene group was introduced into 4 as a linker by
reacting with 1,3-dibromopropane, the chelation ligands were
conjugated with 5. The thiol-protected chelation ligands (PMB-
BAT and TRT-MAMA) were synthesized according to methods
reported previously with some slight modifications. Then, 5 was
joined to PMB-BAT or TRT-MAMA to generate the compounds 6
(PMB-BAT-BF) and 9 (TRT-MAMA-BF), respectively. After depro-
tection of the thiol group in 6and 9, theRecomplexes(7and 10)
were directly prepared by a reaction with (PPh3)2ReOCl3. The
corresponding 99mTc complex, 8 (99mTc-BAT-BF) or 11 (99mTc-
MAMA-BF), was prepared by a ligand exchange reaction employ-
ing the precursor 99mTc-glucoheptonate (GH). The resulting
mixture was analyzed by reversed-phase high-performance
liquid chromatography (HPLC), showing that a single radioactive
complex formed with radiochemical purity higher than 95%
after purification by HPLC. The identity of the complex was
established by comparative HPLC using the corresponding Re
complexes as a reference. The retention times for 99mTc-BAT-BF
and 99mTc-MAMA-BF on HPLC (radioactivity) were 13.2 and
10.3 min, respectively. The retention times of the corresponding
Re complexes (7 and 10) on HPLC (UV detection) were 11.4 and
9.4 min, respectively.
To evaluate the binding affinity of Re-BAT-BF (7) and Re-
MAMA-BF (10), inhibition assays with [125I]IMPY and Aβ-
(1-42) aggregates were performed (Figure 2).18 Both ligands
inhibited the binding of [125I]IMPY to Aβ(1-42) aggre-
gates in a dose-dependent manner, indicating an affinity for
Aβ aggregates. Their Ki values were 11.5 and 24.4 nM, res-
pectively, suggesting that Re-BAT-BF displayed higher affinity
than Re-MAMA-BF (Table 1). The results also indicated that
99mTc-BAT-BF and 99mTc-MAMA-BF would bind Aβ aggregates.
Indeed, in subsequent assays, 99mTc-BAT-BFand 99mTc-MAMA-BF
showed higher affinity than 99mTc-BAT and 99mTc-MAMA
(Figure S1 in the Supporting Information). These results
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stronglysupport our previous report that benzofuran derivatives
have considerable tolerance for structural modifications.22,23
Next, the affinity of 99mTc-BAT-BF for β-amyloid plaques
was investigated in vitro using sections of Tg2576 mouse
brain (Figure 3). Autoradiographic images showed many
radioactive spots in the brain tissue. Furthermore, the radio-
activity of 99mTc-BAT-BF corresponded with the areas of
staining with thioflavin-S, a pathological dye commonly used
for β-amyloid plaques. In contrast, normal mouse brain
displayed no remarkable accumulation of 99mTc-BAT-BF
(data not shown). The results suggest that 99mTc-BAT-BF
binds affinity for β-amyloid plaques in the mouse brain in
addition to binding synthetic Aβ aggregates.
Figure 2. Inhibition curves of Re-BAT-BF (7) (pink circle) and Re-
MAMA-BF (10) (green square) for the binding of [125I]IMPY to
Aβ(1-42) aggregates.
The biodistribution of 99mTc-BAT-BF and 99mTc-MAMA-BF
was examined in normal mice (Table 2). A biodistribution
experiment provides important information on uptake in the
brain. The ideal imaging probe should penetrate the blood-
-brain barrier to deliver a sufficient dose into the brain but
be rapidly cleared from normal regions so as to achieve in a
high signal-to-noise ratio. 99mTc-BAT-BF showed greater up-
take (1.34%ID/g) than 99mTc-MAMA-BF (0.74% ID/g) at
2 min postinjection. The uptake of 99mTc-BAT-BF peaked
at 10 min postinjection, reaching 1.37% ID/g, and about
60% of radioactivity accumulated at 2 min postinjection had
been washed out from the brain by 60 min. The uptake of
Table 1. Inhibition Constants for the Binding of [125I]IMPY to
Aβ(1-42) Aggregates
compound
Ki (nM)a
Re-BAT-BF (7)
11.5 ( 0.56
24.4 ( 0.77
Re-MAMA-BF (10)
a Values are the means ( standard errors of the mean of three
independent determinations.
Table 2. Biodistribution of Radioactivity after Injection of 99mTc-
Labeled Benzofuran Derivatives in Normal Micea
time after injection (min)
organ
2
10
30
60
99mTc-BAT-BF (8)
1.96 (0.06)
blood
4.40 (0.27)
1.93 (0.26)
2.15 (0.91)
liver
21.94 (5.94) 20.87 (1.28) 19.65 (1.31) 15.09 (3.83)
kidney
intestineb
spleen
lung
stomachb
pancreas
heart
10.28 (1.76)
1.45 (0.18)
5.20 (1.01)
26.70 (2.27)
1.33 (0.57)
4.14 (0.77)
17.60 (2.60)
1.34 (0.12)
7.90 (0.40)
3.68 (0.52)
3.09 (0.23)
6.48 (1.33)
1.90 (0.43)
4.57 (0.24)
8.29 (0.97)
1.37 (0.18)
4.27 (0.18)
7.42 (1.62)
1.69 (0.21)
3.51 (0.64)
4.09 (1.37)
2.98 (0.38)
3.28 (1.35)
0.94 (0.20)
2.70 (0.57)
9.02 (1.93)
1.16 (0.14)
2.36 (0.48)
4.17 (1.92)
1.42 (0.15)
1.51 (0.25)
0.56 (0.07)
brain
99mTc-MAMA-BF (11)
1.78 (0.25) 2.15 (0.12)
blood
4.13 (0.42)
2.24 (0.24)
liver
20.17 (3.81) 21.62 (2.62) 23.32 (1.59) 20.16 (2.13)
kidney
intestineb
spleen
lung
stomachb
pancreas
heart
7.37 (1.06)
0.95 (0.22)
4.48 (0.56)
24.04 (5.17)
0.73 (0.21)
2.70 (0.47)
8.09 (1.16)
2.13 (0.19)
3.69 (0.34)
7.59 (2.13)
2.35 (0.58)
4.00 (1.28)
5.11 (0.29)
4.75 (0.93)
3.49 (0.61)
4.24 (0.35)
4.94 (0.57)
5.48 (0.61)
5.05 (0.90)
1.23 (0.09)
3.28 (0.45)
5.73 (0.66)
2.59 (0.65)
3.54 (1.26)
2.81 (0.51)
3.76 (0.36)
2.16 (0.34)
0.89 (0.08)
12.28 (2.20) 10.48 (1.79)
0.74 (0.15) 0.99 (0.22)
brain
Figure 3. Autoradiography of 99mTc-BAT-BF in sections from Tg2576
mouse brain (A). Labeled plaques were confirmed by the staining of
the adjacent sections with thioflavin-S (B).
a Each value represents the mean (SD) for five mice. Expressed as %
injected dose per gram. b Expressed as % injected dose per organ.
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99mTc-MAMA-BF peaked 30 min after the injection at 1.23%
ID/g, and the washout from the brain was slower than that of
99mTc-BAT-BF throughout the time course, which is unsuita-
ble for imaging in vivo. The log P values of 99mTc-BAT-BF and
99mTc-MAMA-BF were 3.33 and 3.01, respectively. Although
lipophilicity is just one of the factors affecting the uptake of a
compound into the brain,4 it may explain the good uptake of
99mTc-BAT-BF.
In conclusion, we successfully designed and synthesized
novel benzofuran derivatives conjugated with 99mTc or Re
complexes for the detection of β-amyloid plaques in the
brain. In experiments in vitro, Re-BAT-BF bound to Aβ
aggregates with greater affinity than did Re-MAMA-BF, and
99mTc-BAT-BF clearly labeled β-amyloid plaques in sections
of brain tissue from Tg2576 mice. In addition, 99mTc-BAT-BF
displayed good uptake into and a rapid washout from the
brain after its injection in normal mice. The combination of
good affinity for β-amyloid plaques, uptake, and clearance
makes 99mTc-BAT-BF a promising probe for the detection of
β-amyloid plaques in the brain. The results of the present
study should provide useful information for the develop-
ment of 99mTc-labeled probes for the imaging of β-amyloid
plaques in the brain.
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SUPPORTING INFORMATION AVAILABLE Procedures for
the preparation of new ligands, analysis of data, experiments in
vitro, and biodistribution experiments. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: þ81-75-753-4608. Fax: þ81-75-753-4568. E-mail:
ono@pharm.kyoto-u.ac.jp (M.O.). Tel: þ81-95-819-2441. Fax: þ81-
95-819-2441. E-mail: morio@nagasaki-u.ac.jp (M.N.).
Funding Sources: This study was supported by Grants-in-Aid for
Scientific Research (B), Young Scientists (A), and Exploratory
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
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A.; Huang, S. C.; Barrio, J. R. Localization of neurofibrillary
tangles and β-amyloid plaques in the brains of living patients
with Alzheimer disease. Am. J. Geriatr. Psychiatry 2002, 10,
24–35.
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