Fluorinated benzofuran derivatives for PET imaging of β-amyloid plaques in alzheimer's disease brains

Article abstract of DOI:10.1021/ml100082x

A series of fluorinated benzofuran derivatives as potential tracers for positron emission tomography (PET) targeting β-amyloid plaques in the brains of patients with Alzheimer's disease (AD) were synthesized and evaluated. The derivatives were produced using an intramolecular Wittig reaction. In experiments in vitro, all displayed high affinity for Aβ(1-42) aggregates with K_i values in the nanomolar range. Radiofluorinated 17, [ ¹⁸F]17, in particular labeled β-amyloid plaques in sections of Tg2576 mouse brain and displayed high uptake (5.66% ID/g) at 10 min postinjection, sufficient for PET imaging. In addition, in vivo β-amyloid plaque labeling can be clearly demonstrated with [¹⁸F]17 in Tg2576 mice. In conclusion, [¹⁸F]17 may be useful for detecting β-amyloid plaques in patients with AD.

Full text of DOI:10.1021/ml100082x

pubs.acs.org/acsmedchemlett
Fluorinated Benzofuran Derivatives for PET Imaging of
β-Amyloid Plaques in Alzheimer's Disease Brains
Yan Cheng,† Masahiro Ono,*,† Hiroyuki Kimura,† Shinya Kagawa,‡ Ryuichi Nishii,‡
Hidekazu Kawashima,† and Hideo Saji*,†
†Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan, and ‡Shiga Medical Center Research Institute, 5-4-30,
Moriyama, Moriyama City, Shiga, 524-8524, Japan
ABSTRACT A series of fluorinated benzofuran derivatives as potential tracers for
positron emission tomography (PET) targeting β-amyloid plaques in the brains of
patients with Alzheimer's disease (AD) were synthesized and evaluated. The deriva-
tives were produced using an intramolecular Wittig reaction. In experiments in vitro,
all displayed high affinity for Aβ(1-42) aggregates with Ki values in the nanomolar
range. Radiofluorinated 17, [18F]17, in particular labeled β-amyloid plaques in sections
of Tg2576 mouse brain and displayed high uptake (5.66% ID/g) at 10 min postinjec-
tion, sufficient for PET imaging. In addition, in vivo β-amyloid plaque labeling can be
clearly demonstrated with [18F]17 in Tg2576 mice. In conclusion, [18F]17 may be
useful for detecting β-amyloid plaques in patients with AD.
KEYWORDS Alzheimer's disease, fluorine-18, benzofuran, positron emission
tomography (PET)
lzheimer's disease (AD) is a neurodegenerative dis-
order characterized by dementia, cognitive impair-
ment, and memory loss. Autopsied brains of AD
[18F]BAY94-9172,12,13 and a styrylpyridine derivative, [18F]AV-
45,14,15 and a fluorinated PIB analogue, [18F]GE-067,16 have
proven useful in the imaging of β-amyloid plaques in living
human brain tissue in clinical trials (Figure 1).
A
patients show neuropathological features such as the presence
of senile plaques and neurofibrillary tangles, which contain
β-amyloid peptides (Aβ) and highly phosphorylated τ proteins.
Aβ aggregates in the brain are a hallmark of AD.1,2 The quan-
titative evaluation of Aβ aggregates in the brain with noninva-
sive techniques such as positron emission tomography (PET)
and single photon emission computed tomography (SPECT)
would allow a presymptomatic diagnosis and the monitoring of
putative effects of neuroprotective treatments. Thus, great
efforts have been made to develop radiotracers that bind to
β-amyloid plaques in vivo.3-5
To search for more candidates for 18F-labeled tracers for
PET, we planned to evaluate a new series of benzofuran
derivatives previously reported as useful radioiodinated or
11 C-labeled probes for imaging β-amyloid plaques.17,18 The
derivatives showed good affinity for Aβ aggregates in vitro in
binding experiments using synthetic Aβ aggregates and
neuropathological staining of AD brain sections. We report
here the in vitro and in vivo evaluation of a series of
fluorinated benzofuran derivatives as probes for imaging
β-amyloid plaques by PET.
The synthesis of the fluorinated benzofuran derivatives is
outlined in Schemes 1-3. The key step in the formation of
the benzofuran backbone is accomplished by an intramole-
cular Wittig reaction between triphenyl phosphonium salt
and 4-nitrobenzoyl chloride or 4-dimethylaminobenzoyl
chloride.17 The desired Wittig reagent, 3, was readily pre-
pared from 5-fluoro-2-hydroxybenzyl alcohol and triphenyl-
phosphine hydrobromide (yield 71%). Another Wittig
reagent, 13, was readily prepared from 2-hydroxy-5-meth-
oxybenzyl alcohol and triphenylphosphine hydrobromide
(yield 84%). Wittig reactions afforded the desired benzofu-
rans (4, 7, and 14) in yields of 31, 55, and 27%, respectively.
Recent success in developing radiolabeled agents targeting
Aβ aggregates has provided a window of opportunity to im-
prove the diagnosis of AD. Preliminary reports of PET imaging
suggested that [11 C]4-N-methylamino-40-hydroxystilbene (SB-
13),6 [11 C]2-(40-(methylaminophenyl)-6-hydroxybenzothiazole
(PIB),7,8 and [11 C]2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-
6-(2-[fluoro]ethoxy)benzoxazole (BF-227)9 showed differential
uptake and retention in the brain of AD patients as compared to
controls. However, 11 C is a positron-emitting isotope with a short
t1/2 (20 min), which limits its clinical application. Recent efforts
have focused on the development of comparable agents labeled
with a longer half-life isotope, 18F (t1/2, 110 min). Preliminary
studies with [18F]-2-(1-(2-(N-(2-fluoroethyl)-N-methylamino)-
naphthalene-6-yl)ethylidene)malononitrile ([18F]FDDNP)10,11
showed differential uptake and retention in the brain of AD
patients for the first time. More recently, a stilbene derivative,
Received Date: April 19, 2010
Accepted Date: June 30, 2010
Published on Web Date: July 11, 2010
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Figure 1. Chemical structures of PET imaging agents targeting β-amyloid plaques in AD patients.
Scheme 1a
a Reagents and conditions: (a) NaBH4, ethanol. (b) Triphenylphosphine hydrobromide, acetonitrile, reflux. (c) 4-Nitrobenzoyl chloride, toluene/NEt3,
reflux. (d) SnCl2, ethanol, reflux. (e) (CH2O)n, NaOMe, methanol, reflux. NaBH4, reflux. (f) 4-Dimethylaminobenzoyl chloride, toluene/NEt3, reflux.
Scheme 2a
for Aβ aggregates, 17 was tested further because of the ease
with which it could be labeled with 18F.
The 18F-labeled 17 ([18F]17) was prepared from a tosyl
precursor (22) via a nucleophilic displacement reaction with
the fluoride anion (Scheme 4).23 A solution of 22 (1.0 mg) in
acetonitrile (200 μL) was added to a reaction vessel containing
a Reagents and conditions: (a) (CH3O)2C(CH3)2, TsOH. (b) CBr4, PPh3,
18F. The mixturewas heated at 120 °Cfor10min. Radiolabeling
of the precursor generated [18F]17 with an average radio-
pyridine, DCM.
chemical yield of 10.0% and radiochemical purity of >99%.
The specific activity of [18F]17 was 242 GBq/μmol. The identity
To prepare the amine compound 5, the nitro group was
of [18F]17 was verified by a comparison of the retention time
reduced with SnCl2 in ethanol (yield 93%). Conversion of 5
with the nonradioactive compound. Initially, 21 was expected
to show similar radiolabeling to 17. However, the radiolabeling
of 21 under the various reaction conditions normally used for
18F radiolabeling gave a radiochemical yield (<0.1%) too low
to conduct a subsequent distribution experiment.
to the corresponding monomethylamino derivative 6 was
achieved by monomethylation with paraformaldehyde and
NaOMe (yield 30%). The synthesis outlined in Schemes 2
and 3 was achieved using methods reported previously.18-22
The binding experiments were carried out as described
previously.17,23 Assays using Aβ(1-42) aggregates demon-
strated that these fluorinated benzofuran derivatives com-
peted with [125I]IMPY to bind β-amyloid plaques with
excellent affinity (Ta bl e 1 ).24,25 Compound 7 with a dimethyl-
aminophenyl moiety in the phenylbenzofuran molecule
displayed slightly lower values (higher affinity) than 5 with
an aminophenyl moiety or 6 with a monomethylaminophe-
nyl moiety. However, all of the derivatives maintained good
binding affinity with Ki values in the nanomolar range. The
results strongly support our previous finding that benzofuran
derivatives have considerable tolerance for structural
modification.17,18 Among the derivatives with high affinity
To evaluate the uptake of [18F]17 in the brain, a biodistribu-
tion experiment was performed in normal mice (Tabl e 2 ).
[18F]17 displayed high uptake (5.66% ID/g) at 10 min post-
injection, sufficient for PET imaging, and the radioactivity in the
brain cleared with time. At 60 min postinjection, the uptake
was 2.80% ID/g, indicating a relatively slow washout from the
brain. One way to select a ligand with appropriate kinetics in
vivo is to use the brain2min/brain60 min ratio as an index to
compare the washout rate. Although the brain2min/brain60 min
ratio of [18F]17 (1.0) was still lower than that of [11 C]PIB
(12.0)7,8 or [18F]AV-45 (3.80),14,15 it was much improved as
compared to the values for iodinated benzofuran derivatives
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Scheme 3a
a Reagents and conditions: (a) NaBH4, ethanol. (b) Triphenylphosphine hydrobromide, acetonitrile, reflux. (c) 4-Dimethylaminobenzoyl chloride,
toluene/NEt3, reflux. (d) BBr3/CH2Cl2. (e) 2-[2-(2-Chloroethoxy)ethoxy]ethanol, K2CO3, DMF, reflux. (f) DAST, DME. (g) 5-(Bromomethyl)-2,2-
dimethyl-1,3-dioxane (10), K2CO3, DMF, 100 °C. (h) HCl, acetone. (i) Tosyl chloride, pyridine, 0 °C. (j) TBAF, THF, reflux.
Scheme 4a
a Reagents and conditions: (a) Tosyl chloride, pyridine. (b) Kryptofix222, K2CO3, acetonitrile, 120 °C.
Table 1. Chemical Structures and Inhibition Constants of Fluori-
nated Benzofuran Derivatives
Table 2. Biodistribution of Radioactivity after Injection of [18F]17
in Normal Micea
organ
2 min
10 min
30 min
60 min
blood
brain
bone
1.64 ( 0.07
2.88 ( 0.46
1.19 ( 0.18
2.48 ( 0.18
5.66 ( 0.31
1.76 ( 0.13
2.68 ( 0.26
3.14 ( 0.26
3.63 ( 1.11
3.41 ( 0.56
2.80 ( 0.06
2.74 ( 0.59
a Expressed as % of injected dose per gram. Each value represents
the mean ( SD for five mice.
defluorinationinvivo.13,19,26 However, thefreefluoridewasnot
taken up by brain tissue, and so, interference with the imaging
is expected to be relatively minor.
a Inhibition constants (Ki, nM) of compounds for the binding of
Next, to confirm the specific binding of radiofluorinated
ligands to β-amyloid plaques, we performed autoradiographic
imaging of [18F]17 with sections (10 μm) of Tg2576 mouse
brain. Tg2576 transgenic mice express human APP695 with the
K670N, M671L Swedish double mutation.27 They show marked
Aβ deposition in the cingulated cortex, entorhinal cortex,
dentate gyrus, and CA1 hippocampal subfield by 11-13 months
of age and have been frequently used to evaluate the specific
binding of β-amyloid plaques in experiments in vitro and in
vivo.15,18,19,23 Autoradiographic images of [18F]17 showed
high levels of radioactivity in the brain sections (Figure 2A).
Furthermore, the hot spots of [18F]17 corresponded with those
of thioflavin-S, a pathological dye commonly used to stain
[
125I]IMPY to Aβ(1-42) aggregates. Values are the means ( standard
errors of the mean for 3-6 independent experiments.
(0.47-0.48) reported previously.17 Furthermore, among these
benzofuran derivatives, the washout rate improved as the
lipophilicity decreased (log P values of [18F]17 and the iodi-
nated benzofuran derivatives were 1.20 and 2.12-2.35,
respectively).17 Thus, lipophilicity is important to improving
washout from the brain. To further enhance the washout rate,
the synthesis of less lipophilic benzofuran derivatives, for
example, by replacing the dimethylamino group with another
hydrophilic group, is now under investigation. Uptake in the
bone at 60 min was measurable (2.74% ID/g), suggesting little
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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: 81-75-753-4608. Fax: 81-75-753-4568. E-mail:
ono@pharm.kyoto-u.ac.jp (M.O.). Tel: 81-75-753-4556. Fax: 81-
75-753-4568. E-mail: hsaji@pharm.kyoto-u.ac.jp (H.S.).
Figure 2. Autoradiography of a section (10 μm) of Tg2576
mouse brain with [18F]17. [18F]17 showed excellent binding to
β-amyloid plaques (A). β-Amyloid plaques were confirmed pre-
sent by staining of the section with thioflavin-S (B).
Funding Sources: This study was supported by the Program for
Promotion of Fundamental Studies in Health Sciences of the
National Institute of Biomedical Innovation (NIBIO), a Health La-
bour Sciences Research Grant, and a Grant-in-Aid for Young Scien-
tists (A) and Exploratory Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
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