18F-labeled phenyldiazenyl benzothiazole for in vivo imaging of neurofibrillary tangles in Alzheimer's disease brains

Article abstract of DOI:10.1021/ml200230e

We synthesized and evaluated (E)-4-((6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) benzo[d]thiazol-2-yl)diazenyl)-N,N-dimethylaniline (FPPDB) as a probe for the imaging of neurofibrillary tangles (NFTs) in patients with Alzheimer's disease (AD). In assays using thioflavin S (ThS) as a competitive ligand, FPPDB competed with ThS well and showed high affinity for both tau and Aβ_1-42 aggregates (K_i = 13.0 and 20.0 nM, respectively). The results of saturation binding assays also verified that FPPDB bound to both tau and Aβ_1-42 aggregates with high affinity (K_d = 44.8 nM and B_max = 45.8 pmol/nmol protein for tau aggregates and K _d = 45.4 nM and B_max = 38.9 pmol/nmol protein for Aβ_1-42 aggregates). Furthermore, [¹⁸F]FPPDB substantially labeled NFTs and senile plaques in AD brain sections but not control brain sections. In biodistribution experiments using normal mice, [ ¹⁸F]FPPDB displayed higher uptake (4.28% ID/g at 2 min postinjection) into and washout (2.53% ID/g at 60 min postinjection) from the brain with time. On the basis of the chemical structure of FPPDB, further increases in selective binding to tau aggregates may lead to the development of more useful probes for the imaging of NFTs in AD brains.

Full text of DOI:10.1021/ml200230e

Letter
pubs.acs.org/acsmedchemlett
18F-Labeled Phenyldiazenyl Benzothiazole for in Vivo Imaging of
Neurofibrillary Tangles in Alzheimer's Disease Brains
Kenji Matsumura,† Masahiro Ono,*,† Hiroyuki Kimura,† Masashi Ueda,† Yuji Nakamoto,‡
Kaori Togashi,‡ Yoko Okamoto,§ Masafumi Ihara,§ Ryosuke Takahashi,§ and Hideo Saji†
†Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida
Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
‡Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54
Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan
§Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507,
Japan
S
* Supporting Information
ABSTRACT: We synthesized and evaluated (E)-4-((6-(2-(2-
(2-fluoroethoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)-
diazenyl)-N,N-dimethylaniline (FPPDB) as a probe for the
imaging of neurofibrillary tangles (NFTs) in patients with
Alzheimer's disease (AD). In assays using thioflavin S (ThS) as
a competitive ligand, FPPDB competed with ThS well and
showed high affinity for both tau and Aβ1−42 aggregates (Ki =
13.0 and 20.0 nM, respectively). The results of saturation
binding assays also verified that FPPDB bound to both tau and
Aβ1−42 aggregates with high affinity (Kd = 44.8 nM and Bmax
=
45.8 pmol/nmol protein for tau aggregates and Kd = 45.4 nM and Bmax = 38.9 pmol/nmol protein for Aβ1−42 aggregates).
Furthermore, [18F]FPPDB substantially labeled NFTs and senile plaques in AD brain sections but not control brain sections. In
biodistribution experiments using normal mice, [18F]FPPDB displayed higher uptake (4.28% ID/g at 2 min postinjection) into
and washout (2.53% ID/g at 60 min postinjection) from the brain with time. On the basis of the chemical structure of FPPDB,
further increases in selective binding to tau aggregates may lead to the development of more useful probes for the imaging of
NFTs in AD brains.
KEYWORDS: Alzheimer's disease (AD), neurofibrillary tangles (NFTs), imaging, benzothiazole, PET
utility of the in vivo imaging of SPs in the brain. Many other
compounds with structural similarities have also been reported.
Since the accumulation of NFTs is highly correlated with
symptoms of AD10,11 and the detection of NFTs in the brain
should lead to the early diagnosis of AD and the evaluation of
severity and staging, the development of NFT-selective binding
probes is needed. However, there have been few reports on the
development of PET/SPECT imaging probes targeting NFTs.
A previous paper has reported quinoline and benzimidazole
derivatives as candidate probes for the imaging of NFTs in AD
brains.12,13 However, these derivatives showed affinity for both
NFTs and SPs, suggesting that they may not be NFT-selective
tracers. Therefore, to investigate the selective binding affinity
for both NFTs and SPs, we recently developed radioiodinated
compounds based on another chemical structure, a phenyl-
diazenyl benzothiazole (PDB) scaffold (Figure 1).14 All of the
PDB derivatives displayed high affinity for tau aggregates. PDB-
lzheimer's disease (AD) is a progressive neurodegener-
Aative brain disorder associated with cognitive decline,
disorientation, and language impairment and is characterized by
the presence of senile plaques (SPs) composed of β-amyloid
(Aβ) peptides and neurofibrillary tangles (NFTs) composed of
hyperphosphorylated tau protein.1 At present, the clinical
diagnosis of AD depends on medical history and neuro-
psychological findings, and the early cognitive and behavioral
symptoms of AD are often indistinguishable from normal signs
of aging. Because a definite diagnosis of AD is based on the
postmortem histopathological examination of SPs and NFTs,
useful methods of evaluating the histopathological changes in
vivo are strongly needed. The formation of SPs is considered an
initial manifestation of AD. Therefore, considerable effort has
focused on the development of imaging probes targeting SPs
for positron emission tomography (PET) and single photon
emission computed tomography (SPECT). Among them,
PET/SPECT probes such as IMPY,2 SB-13,3 PIB,4
AZD2184,5 FDDNP,6 BAY94-9172,7 AV-45,8 and GE-0679
have been tested clinically and demonstrated the potential
Received: September 23, 2011
Accepted: November 29, 2011
Published: December 1, 2011
© 2011 American Chemical Society
58
dx.doi.org/10.1021/ml200230e | ACS Med. Chem. Lett. 2012, 3, 58−62

ACS Medicinal Chemistry Letters
Letter
Figure 1. Chemical structure of iodinated and fluoro-pegylated PDB derivatives.
a
Scheme 1.
a
(A) Reagents and conditions: (a) HBr, reflux. (b) N,N-Dimethylaniline, NaNO2, 50% H2SO4, concentrated HCl, 0 °C. (c) 2-[2-(2-
Chloroethoxy)ethoxy]ethanol, K2CO3, DMF, 105 °C. (d) Tosyl chloride, pyridine. (e) Diethylamino sulfur trifluoride, 1,2-dimethoxyethane. (B)
Reagents and conditions: (a) 18F−, Kryptofix222, K2CO3, acetonitrile, 100 °C, 5 min.
Figure 2. Inhibition curves for the binding of ThS to tau (A) and Aβ1−42 (B) aggregates using FPPDB as a test compound.
3, with a dimethylamino group at position 4 of the phenyl
group, showed the highest affinity (17.2-fold that for Aβ1−42
aggregates), indicating it to be a tracer with greater selective
binding to tau aggregates than the quinoline and benzimidazole
derivatives reported previously. However, 125I-labeled PDB
derivatives showed a relatively low uptake into and slow
washout from the brain, suggesting high nonspecific binding,
which would contribute to a high level of background noise.
Since the slow washout of [125I]PDB derivatives in normal mice
prevents imaging in vivo, the improved property of the PDB
derivatives should make them better candidates for the study of
tau aggregates.
increases the lipophilicity of a compound, with fluorine for the
preparation of PET tracers. Recent reports have introduced a
new approach, fluoro-pegylation (FPEG) of the core structure,
to labeling with 18F.7,17,18 Because this approach offers a simple
and easy way to incorporate 18F without any increase in
lipophilicity, we selected FPEG for 18F-labeling of the PDB
scaffold. In the present study, we designed and synthesized a
novel fluorinated ligand, (E)-4-((6-(2-(2-(2-fluoroethoxy)-
ethoxy)ethoxy)benzo[d]thiazol-2-yl)diazenyl)-N,N-dimethyla-
niline (FPPDB, Figure 1) with a fluoro-polyethylene glycol side
chain instead of iodine at position 6 of PDB-3, and evaluated its
potential as a probe for the imaging NFTs in the brains in vivo.
A new ligand, FPPDB, was prepared as outlined in Scheme
1A. A methoxy group of 2-amino-6-methoxybenzothiazole was
converted to a hydroxy group using a HBr solution, which
afforded 1 in a yield of 71.0%. To obtain the backbone
Previous studies regarding uptake into and clearance from
the brain points to high lipophilicity as one of the reasons for a
slow washout.15,16 We then planned to develop a novel PDB
derivative with less lipophilicity by substituting iodine, which
59
dx.doi.org/10.1021/ml200230e | ACS Med. Chem. Lett. 2012, 3, 58−62

ACS Medicinal Chemistry Letters
Letter
Figure 3. Saturation curves of [18F]FPPDB for tau (A) and Aβ1−42 (B) aggregates.
structure of PDB, we used a diazo coupling reaction with N,N-
dimethylaniline to afford 2. Thereafter, 2-[2-(2-chloroethoxy)-
ethoxy]ethanol was coupled with the OH group of 2 to obtain
3. Fluorination of 3 to prepare 5 was achieved using
diethylamino sulfur trifluoride (DAST). 18F-labeling of 5 was
performed on a tosyl precursor (4) undergoing a nucleophilic
displacement reaction with the fluoride anion (Scheme 1B).
Radiolabeling with 18F was successfully performed on the
precursor to generate [18F]5 ([18F]FPPDB) with a radio-
chemical yield of 35% and radiochemical purity >99%. The
identity of [18F]FPPDB was verified by a comparison of
retention time with the nonradioactive compound.
aggregates, which was reflected the Ki values of FPPDB for
both aggregates in the competitive inhibition assays using ThS.
[18F]FPPDB was investigated for its affinity for NFTs in vitro
by autoradiography in human AD brain sections (Figure 4).
To evaluate the affinity of FPPDB for both tau aggregates
and Aβ1−42 aggregates, an assay using thioflavin-S (ThS) as a
competitive ligand was carried out. Similarly to iodinated PDB
derivatives reported previously, FPPDB competed well with
ThS to bind to tau aggregates (Figure 2A). The Ki value of
FPPDB for tau aggregates was estimated at 13.0 nM. Although
FPPDB exhibited significantly lower affinity than PDB-3 (Ki =
0.48 nM), it still maintained high enough affinity for tau
aggregates to image NFTs. Because both tau and Aβ1−42
aggregates possess a β-sheet structure, it would be important
to examine the selectivity of FPPDB. To this end, we
determined the affinity of FPPDB for Aβ1−42 aggregates using
a competitive inhibition assay with ThS. FPPDB also inhibited
the binding of ThS to Aβ1−42 aggregates (Figure 2B), the Ki
value being 20.0 nM. The ratio of the Ki values for tau and
Aβ1−42 aggregates was 1.54. As compared to PDB-3 (ratio of
17.2),14 FPPDB exhibited less selectivity between tau and
Aβ1−42 aggregates. The results suggest that the substituted
group at position 6 in the PDB scaffold plays an important role
in the binding to β-sheet structures in both tau and Aβ1−42
aggregates. The concentration of tau aggregates (∼150−300
pmol mg−1 of wet tissue) was reported to be higher than that of
Aβ aggregates (∼9 pmol mg−1 of wet tissue) in the frontal and
temporal cortices in late-stage AD,19,20 so it may be possible for
[18F]FPPDB to show contrast between NFTs and SPs in these
areas in vivo. However, to diagnose AD in the early stages,
probes with much higher NFT selectivity will be needed.
In competitive inhibition assays, FPPDB competed with ThS
to bind to both tau and Aβ1−42 aggregates. To verify that
FPPDB bound to these aggregates directly, saturation binding
assays of [18F]FPPDB to these aggregates were carried out
(Figure 3). A Scatchard analysis revealed the Kd value and Bmax
of FPPDB for both tau and Aβ1−42 aggregates to be almost
equal (Kd = 44.8 nM and Bmax = 45.8 pmol/nmol tau protein
for tau aggregates and Kd = 45.4 nM and Bmax = 38.9 pmol/
nmol Aβ1−42 protein for Aβ1−42 aggregates). This result showed
that FPPDB had almost equal affinity for tau and Aβ1−42
Figure 4. Autoradiogram of [18F]FPPDB (A) and immunohistochem-
ical staining with antibodies against hyperphosphorylated tau (B) and
Aβ1−42 (C) in brain sections from the same patient. Autoradiogram of
a control brain (D). Bars indicate 200 μm.
Autoradiographic images of [18F]FPPDB showed the accumu-
lation of radioactivity in the AD brain sections with little
nonspecific binding in white matter (Figure 4A). The
accumulation corresponded with the results of immunohisto-
chemical staining with both the anti phosphorylated tau
antibody (AT8) and the anti Aβ1−42 antibody (BC05) (Figure
4B,C, respectively). Conversely, [18F]FPPDB showed almost
no accumulation in normal human brain sections (Figure 4D).
These results suggested that [18F]FPPDB had enough affinity
to label NFTs in AD brain sections, although its affinity for tau
aggregates was lower than that of iodinated PDB derivatives.
However, the results also indicated that [18F]FPPDB did not
possess enough selectivity for NFTs to show high contrast
between NFTs and SPs in an autoradiographic study, similarly
to the iodinated PDB derivatives reported previously.
To further confirm the affinity of FPPDB for NFTs and SPs
in the AD brain, fluorescent staining was carried out using brain
sections from the same AD patient (Figure 5). Numerous
fluorescent spots were detected in the entorhinal cortex of AD
brain sections (Figure 5A,C) as reflected by the high affinity for
recombinant tau and Aβ1−42 aggregates in both competitive
inhibition and saturation binding assays in vitro. ThS stained
60
dx.doi.org/10.1021/ml200230e | ACS Med. Chem. Lett. 2012, 3, 58−62

ACS Medicinal Chemistry Letters
Letter
probes under clinical study such as [18F]BAY94-91727 and
[18F]AV-45,8 [18F]FPPDB's uptake into and washout from the
brain were not particularly satisfactory. The replacement of the
dimethylamino group of [18F]FPPDB with a less lipophilic
group may lead to the development of more promising probes
for diagnosing AD. Because defluorination, as reflected by the
uptake of [18F]FPPDB into bone, was low (1.82−1.92% ID/g),
interference with the imaging is expected to be relatively minor.
[18F]FPPDB was cleared from plasma by not only the
hepatobiliary system (20.2% ID/g in the liver at 2 min
postinjection) but the renal system (13.9% ID/g in the kidney
at 2 min postinjection). The hepatobiliary excretion to the
intestines was also rather fast, and radioactivity was observed to
accumulate within the intestine at later time points (22.9% ID/
g at 60 min postinjection).
In conclusion, we designed, synthesized, and evaluated a
PDB derivative, [18F]FPPDB, as a novel PET imaging agent for
diagnosing AD. In binding experiments in vitro, the derivative
displayed high affinity for both tau and Aβ1−42 aggregates.
NFTs and SPs were stained in experiments using auto-
radiography and fluorescent staining with AD brain sections,
reflecting the results of the in vitro assays. Although FPPDB
had lower selectivity for tau aggregates than PDB-3 in vitro, in
biodistribution experiments using normal mice, [18F]FPPDB
had improved pharmacokinetics as compared with [125I]PDB
derivatives. Replacement of iodine with fluorine in the PDB
scaffold was highly effective in improving the radioactive
pharmacokinetics of [18F]FPPDB in the brain. However, it
resulted in a decrease in selective binding for tau aggregates.
Further structural optimization based on the PDB scaffold, such
as changing the position substituted in the fluoro-pegylated
group or replacing the dimethylamino group with different
groups to improve the affinity for tau aggregates may lead to
the development of more useful probes for the in vivo imaging
of NFTs in AD brains.
Figure 5. Fluorescent staining with FPPDB (A and C) and ThS (B
and D) in the entorhinal cortex of AD brain sections. Many NFTs
were clearly stained with FPPDB (A) and ThS (B). SPs were also
stained with FPPDB (C) and ThS (D).
both NFTs (Figure 5B) and SPs (Figure 5D) clearly, and the
fluorescent spots corresponded to those obtained with FPPDB
(Figure 5A,C), suggesting that FPPDB bound to not only
NFTs but also SPs.
To determine the uptake of [18F]FPPDB in the brain, a
biodistribution experiment was performed in normal mice
(Table 1). [18F]FPPDB displayed high uptake (4.28% ID/g) at
2 min postinjection, sufficient for PET imaging, and the
radioactivity in the brain cleared with time. At 60 min
postinjection, the uptake was 2.53% ID/g, indicating a relatively
fast washout from the brain. Since normal brain tissue has
neither NFTs nor SPs to trap [18F]FPPDB, the radioactivity
should wash out quite rapidly. Therefore, [18F]FPPDB's rapid
clearance from normal brain makes it more appropriate as an
imaging agent for AD brain. [125I]PDB-3 displayed less uptake
into and a slower washout from the brain (0.94 and 2.89% ID/g
at 2 and 60 min postinjection, respectively) than [18F]-
FPPDB.14 The improved pharmacokinetics of [18F]FPPDB
were achieved by replacing iodine with a fluoro-pegylated group
at position 6. The log P value of [18F]FPPDB and [125I]PDB-3
was 2.05 and 3.84, respectively, suggesting that [18F]FPPDB is
less lipophilic than [125I]PDB-3. Although lipophilicity is just
one of the factors influencing the uptake of a compound into
the brain, it may explain in the favorable pharmacokinetics of
[18F]FPPDB. However, as compared with several Aβ imaging
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and characterization data for all
new compounds described in this study. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
Table 1. Biodistribution of Radioactivity after Injection of [18F]FPPDB in Normal Mice
time after injection (min)
tissue
blood
2
10
30
60
3.04 (0.40)
20.2 (1.19)
13.9 (1.50)
2.94 (0.38)
3.47 (0.80)
5.41 (0.69)
7.45 (0.84)
13.5 (3.51)
1.11 (0.07)
4.28 (0.45)
1.88 (0.47)
1.83 (0.82)
19.3 (1.00)
7.67 (3.42)
4.99 (0.95)
3.41 (0.80)
4.01 (1.03)
4.14 (1.87)
4.37 (4.60)
1.42 (0.35)
4.26 (0.37)
1.82 (0.50)
2.19 (0.75)
13.1 (1.45)
5.08 (3.67)
14.4 (1.44)
2.71 (0.80)
2.87 (0.63)
3.05 (1.64)
3.36 (3.70)
2.69 (0.44)
3.47 (0.54)
1.82 (0.49)
2.68 (0.63)
9.32 (1.51)
4.00 (3.75)
22.9 (1.38)
2.14 (0.76)
2.18 (0.67)
2.62 (1.45)
3.59 (3.18)
3.37 (1.26)
2.53 (0.54)
1.92 (0.33)
liver
kidney
intestine
spleen
pancreas
heart
lung
b
stomach
brain
bone
a
b
Each value represents the mean (SD) for five animals. Expressed as % injected dose per organ.
61
dx.doi.org/10.1021/ml200230e | ACS Med. Chem. Lett. 2012, 3, 58−62

ACS Medicinal Chemistry Letters
Letter
(12) Okamura, N.; Suemoto, T.; Furumoto, S.; Suzuki, M.;
Shimadzu, H.; Akatsu, H.; Yamamoto, T.; Fujiwara, H.; Nemoto,
M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.; Kudo, Y. Quinoline
and benzimidazole derivatives: candidate probes for in vivo imaging of
tau pathology in Alzheimer's disease. J. Neurosci. 2005, 25, 10857−
10862.
(13) Fodero-Tavoletti, M. T.; Okamura, N.; Furumoto, S.; Mulligan,
R. S.; Connor, A. R.; McLean, C. A.; Cao, D.; Rigopoulos, A.;
Cartwright, G. A.; O’Keefe, G.; Gong, S.; Adlard, P. A.; Barnham, K. J.;
Rowe, C. C.; Masters, C. L.; Kudo, Y.; Cappai, R.; Yanai, K.;
Villemagne, V. L. 18F-THK523: A novel in vivo tau imaging ligand for
Alzheimer's disease. Brain 2011, 134, 1089−1100.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +81-75-753-4608. Fax: +81-75-753-4568. E-mail: ono@
pharm.kyoto-u.ac.jp.
Funding
This study was supported by the Funding Program for Next
Generation World-Leading Researchers (NEXT Program) and
a Grant-in-aid for Young Scientists (A) and Exploratory
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
(14) Matsumura, K.; Ono, M.; Hayashi, S.; Kimura, H.; Okamoto, Y.;
Ihara, M.; Takahashi, R.; Mori, H.; Saji, H. Phenyldiazenyl
benzothiazole derivatives as probes for in vivo imaging of
neurofibrillary tangles in Alzheimer's disease brains. Med. Chem.
Commun. 2011, 2, 596−600.
(15) Cheng, Y.; Ono, M.; Kimura, H.; Kagawa, S.; Nishii, R.;
Kawashima, H.; Saji, H. Fluorinated benzofuran derivatives for PET
imaging of β-amyloid plaques in Alzheimer's disease brains. ACS Med.
Chem. Lett. 2010, 1, 321−325.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Hiroshi Mori for kindly providing human tau
cDNA for the in vitro binding assays.
(16) Ono, M.; Kawashima, H.; Nonaka, A.; Kawai, T.; Haratake, M.;
Mori, H.; Kung, M. P.; Kung, H. F.; Saji, H.; Nakayama, M. Novel
benzofuran derivatives for PET imaging of β-amyloid plaques in
Alzheimer's disease brains. J. Med. Chem. 2006, 49, 2725−2730.
(17) Chandra, R.; Oya, S.; Kung, M. P.; Hou, C.; Jin, L. W.; Kung, H.
F. New diphenylacetylenes as probes for positron emission
tomographic imaging of amyloid plaques. J. Med. Chem. 2007, 50,
2415−2423.
(18) Stephenson, K. A.; Chandra, R.; Zhuang, Z. P.; Hou, C.; Oya, S.;
Kung, M. P.; Kung, H. F. Fluoro-pegylated (FPEG) imaging agents
targeting Aβ aggregates. Bioconjug Chem 2007, 18, 238−246.
(19) Wang, J.; Dickson, D. W.; Trojanowski, J. Q.; Lee, V. M. The
levels of soluble versus insoluble brain Aβ distinguish Alzheimer’s
disease from normal and pathologic aging. Exp. Neurol. 1999, 158,
328−337.
REFERENCES
■
(1) Selkoe, D. J. Alzheimer's disease: Genes, proteins, and therapy.
Physiol. Rev. 2001, 81, 741−766.
(2) 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. Safety, biodistribution, and dosimetry of 123I-IMPY: a novel
amyloid plaque-imaging agent for the diagnosis of Alzheimer's disease.
J. Nucl. Med. 2006, 47, 748−754.
(3) Ono, M.; Wilson, A.; Nobrega, J.; Westaway, D.; Verhoeff, P.;
Zhuang, Z. P.; Kung, M. P.; Kung, H. F. 11C-labeled stilbene
derivatives as Aβ-aggregate-specific PET imaging agents for
Alzheimer’s disease. Nucl. Med. Biol. 2003, 30, 565−571.
(4) Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; 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.
Imaging brain amyloid in Alzheimer's disease with Pittsburgh
Compound-B. Ann. Neurol. 2004, 55, 306−319.
(5) Johnson, A. E.; Jeppsson, F.; Sandell, J.; Wensbo, D.; Neelissen, J.
A.; Jureus, A.; Strom, P.; Norman, H.; Farde, L.; Svensson, S. P.
AZD2184: A radioligand for sensitive detection of β-amyloid deposits.
J. Neurochem. 2009, 108, 1177−1186.
(20) Khatoon, S.; Grundke-Iqbal, I.; Iqbal, K. Brain levels of
microtubule-associated protein tau are elevated in Alzheimer's disease:
A radioimmuno-slot-blot assay for nanograms of the protein. J.
Neurochem. 1992, 59, 750−753.
(6) 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. 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.
(7) Zhang, W.; Oya, S.; Kung, M. P.; Hou, C.; Maier, D. L.; Kung, H.
F. F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting
Aβ aggregates in the brain. Nucl. Med. Biol. 2005, 32, 799−809.
(8) Wong, D. F.; Rosenberg, P. B.; Zhou, Y.; Kumar, A.; Raymont,
V.; Ravert, H. T.; Dannals, R. F.; Nandi, A.; Brasic, J. R.; Ye, W.;
Hilton, J.; Lyketsos, C.; Kung, H. F.; Joshi, A. D.; Skovronsky, D. M.;
Pontecorvo, M. J. In vivo imaging of amyloid deposition in Alzheimer
disease using the radioligand 18F-AV-45 (florbetapir F 18). J. Nucl.
Med. 2010, 51, 913−920.
(9) Koole, M.; Lewis, D. M.; Buckley, C.; Nelissen, N.;
Vandenbulcke, M.; Brooks, D. J.; Vandenberghe, R.; Van Laere, K.
Whole-body biodistribution and radiation dosimetry of 18F-GE067: A
radioligand for in vivo brain amyloid imaging. J. Nucl. Med. 2009, 50,
818−822.
(10) Gomez-Isla, T.; Hollister, R.; West, H.; Mui, S.; Growdon, J. H.;
Petersen, R. C.; Parisi, J. E.; Hyman, B. T. Neuronal loss correlates
with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann.
Neurol. 1997, 41, 17−24.
(11) Arriagada, P. V.; Growdon, J. H.; Hedley-Whyte, E. T.; Hyman,
B. T. Neurofibrillary tangles but not senile plaques parallel duration
and severity of Alzheimer's disease. Neurology 1992, 42, 631−639.
62
dx.doi.org/10.1021/ml200230e | ACS Med. Chem. Lett. 2012, 3, 58−62