Synthesis and evaluation of 1-(4-[18F]fluoroethyl)-7-(4′- methyl)curcumin with improved brain permeability for β-amyloid plaque imaging

Article abstract of DOI:10.1016/j.bmcl.2011.08.003

Alzheimer's disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [¹⁸F]fluoropropylcurcumin ([¹⁸F]FP-curcumin), which demonstrated excellent bi

Full text of DOI:10.1016/j.bmcl.2011.08.003

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5765–5769
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of 1-(4-[18F]fluoroethyl)-7-(40-methyl)curcumin
with improved brain permeability for b-amyloid plaque imaging
Iljung Lee a, Jehoon Yang b, Jung Hee Lee b, Yearn Seong Choe a,
⇑
a Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
b Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Alzheimer’s disease is characterized by the accumulation of b-amyloid (Ab) plaques and neurofibrillary
tangles (NFTs) in the brain. We previously developed [18F]fluoropropylcurcumin ([18F]FP-curcumin),
which demonstrated excellent binding affinity (Ki = 0.07 nM) for Ab(1–40) aggregates and good pharma-
cokinetics in normal mouse brains. However, its initial brain uptake was poor (0.52% ID/g at 2 min post-
injection). Therefore, in the present study, fluorine-substituted 4,40-bissubstituted or pegylated curcumin
derivatives were synthesized and evaluated. Their binding affinities for Ab(1–42) aggregates were mea-
sured and 1-(4-fluoroethyl)-7-(40-methyl)curcumin (1) had the highest binding affinity (Ki = 2.12 nM).
Fluorescence staining of Tg APP/PS-1 mouse brain sections demonstrated high and specific labeling of
Ab plaques by 1 in the cortex region, which was confirmed with thioflavin-S staining of the same spots
in the adjacent brain sections. Radioligand [18F]1 was found to have an appropriate partition coefficient
(logPo/w = 2.40), and its tissue distribution in normal mice demonstrated improved brain permeability
(1.44% ID/g at 2 min post-injection) compared to that of [18F]FP-curcumin by a factor of 2.8 and fast
wash-out from mouse brains (0.45% ID/g at 30 min post-injection). These results suggest that [18F]1
may hold promise as a PET radioligand for Ab plaque imaging.
Received 29 June 2011
Revised 21 July 2011
Accepted 1 August 2011
Available online 10 August 2011
Keywords:
Alzheimer’s disease
b-Amyloid plaques
1-(4-[18F]Fluoroethyl)-7-(40-
methyl)curcumin
Brain permeability
Ó 2011 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is characterized by the accumulation
of b-amyloid (Ab) plaques and neurofibrillary tangles (NFTs) in
the brain.1–3 Although the causes of AD are still unknown, it is
the general consensus that Ab plaques and NFTs may play a major
role in the development of the disease. Therefore, in vivo imaging
of Ab plaques and/or NFTs may be beneficial for the diagnosis, stag-
ing, and treatment of AD.
widespread clinical application. As an alternative, 18F-labeled
ligands with longer half-lives may be beneficial for clinical use;
some of these are currently undergoing clinical trials or
have been conditionally approved by the FDA: a PIB derivative,
2-(3-[18F]fluoro-4-(methylamino)phenyl)benzo[d]thiazol-6-ol ([18F]
flutemetamol, 30-[18F]F-PIB, GE067),15–17 and pegylated stilbene
and styrylpyridine derivatives, {4-[2-(4-{2-[2-(2-[18F]fluoro-eth-
oxy)-ethoxy]-ethoxy}-phenyl)-vinyl]-phenyl}-methyl-amine ([18F]
florbetaben, BAY 94-9172)18,19 and (E)-4-(2-(6-(2-(2-(2-[18F]
fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methylaniline
([18F]florbetapir, AV-45) (Fig. 1).20,21 Preliminary results demon-
strated that these 18F-labeled ligands are potentially useful for
PET imaging of Ab plaques in AD patient brains.15–22 However,
these 18F-labeled radioligands have higher subcortical white
matter uptake than 11C-PIB, which may disturb distinguishing AD
patients from healthy subjects.
A highly conjugated dimeric ligand, (1E,3Z,6E)-1,7-bis(4-hydro-
xy-3-methoxyphenyl)-3-hydroxy-hepta-1,3,6-trien-5-one (curcu-
min) has been extensively studied for its anticancer, antioxidant,
and anti-inflammatory activities.23,24 It has also been found that
dietary curcumin lowered the Ab plaque burden in the hippocam-
pus and cortex regions of APPsw Tg2576 transgenic mouse brain
sections and stained Ab plaques in the hippocampus regions of
transgenic mouse brain sections and postmortem AD brains.25,26
In addition, it was recently reported that CRANAD-3, a curcumin
Most radioligands used for Ab plaque imaging are derived from
highly conjugated fluorescent dyes, such as Congo red (CR), Chrys-
amine G (CG), or thioflavin-T (Fig. 1), which have been used for
fluorescent staining of Ab plaques and NFTs in postmortem AD
brain sections.4–6 A neutral benzothiazole derivative, [11C]6-OH-
BTA-1 (PIB, Ki = 0.87 nM), is the most well characterized radioli-
gand, demonstrating minimal retention in the subcortical white
matter of AD patients compared to other benzothiazole-based
radioligands.7–13 Another 11C-labeled radioligand, 2-(6-([11C]methy
lamino)pyridin-3-yl)benzo[d]thiazol-6-ol (AZD2184, Ki = 1.70 nM),
is also
a
promising Ab plaque imaging agent because [3H]
AZD2184 demonstrated a higher pre-frontal cortex to subcortical
white matter uptake ratio compared to [3H]PIB in cortical brain
sections from transgenic mice and AD patients.14 However, the
short half-life (20 min) of 11C may limit its usefulness in
⇑
Corresponding author. Tel.: +82 2 3410 2623; fax: +82 2 3410 2667.
E-mail address: ysnm.choe@samsung.com (Y.S. Choe).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.003

5766
I. Lee et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5765–5769
N
N
N
N
N
N
HO
N
N
OH
-O3S
SO3-
HCOO
CHOO
Congo Red
Chrysamine G
CH3
N
11CH3
N
H
11CH3
N
H
N
S
N
CH3
N
CH3
S
N
HO
HO
S
H3C
[11C]AZD2184
Thioflavin-T
[11C]PIB
CH3
N
H
N
S
18F
18F
O
3
CH3
N
H
O
CH3
H
3
HO
N
N
18F
[18F]BAY94-9172
[18F]AV-45
3'-[18F]F-PIB
Figure 1. Chemical structures of Congo red, Crysamine G, thioflavin-T, [11C]PIB, [11C]AZD2184, 3-[18F]F-PIB, [18F]BAY94-9172, and [18F]AV-45.
derivative, detects Ab(1–42) species from monomer to plaques.27
Diagnosis of AD in its early stages will be very crucial given dis-
ease-modifying drugs that are available for clinical use; detection
of Ab(1–42) species prior to plaque formation may play a key role
in the early diagnosis of AD.
group. Synthetic pathways of curcumin derivatives, 1–5 (Fig. 2),
are shown in Schemes 1 and 2. The curcumin derivatives were syn-
thesized by aldol condensation of (1E,4Z)-5-hydroxy-1-phenyl-
hexa-1,4-dien-3-one compound (6 or 7) and the corresponding
vanillin derivatives, 8, 9, 15, or 16. In this reaction, the 1,3-diketone
of the 6 or 7-boron complex was formed, which was then reacted
with aldehyde 8, 9, 15, or 16 in the presence of amine. Dilute acid
treatment of the boron complex yielded curcumin derivatives 1–5
(Scheme 1). Compounds 8–12 were prepared in 57–88% yields
from vanillin and the corresponding fluoroalkyl tosylate, 2-bromo-
ethanol, 2-(2-chloroethoxy)ethanol, or 2-(2-(2-chloroethoxy)eth-
oxy)ethanol in the presence of K2CO3 (Scheme 2).
Fluoropegylated vanillin derivatives, 15 and 16, were prepared
from fluorination of the corresponding methanesulfonyl com-
pounds, 13 and 14, with CsF (Scheme 2). Compounds 13 and 14
were prepared from methanesulfonylation of 11 and 12. The nosy-
late precursor (19) for synthesis of [18F]1 was synthesized from 18
using 4-nitrobenzenesulfonyl chloride and Et3N in the presence of
B2O3 (Schemes 2 and 3). Compound 18 was synthesized from aldol
condensation of either 17 and 3,4-dimethylbenzaldehyde or 7 and
10 (Schemes 1 and 2). The former method was used because the
residual vanillin derivative (10) remained in the product based
on 1H NMR analysis in the latter method. Compound 17 was pre-
pared by aldol condensation of 10 and 2,4-pentanedione in the
presence of B2O3, (n-BuO)B, and n-butylamine and then purified
We previously developed a 18F-labeled curcumin derivative,
(1E,4Z,6E)-1-(4-(3-[18F]fluoropropoxy)-3-methoxyphenyl)-5-hy-
droxy-7-(4-hydroxy-3-methoxyphenyl)-hepta-1,4,6-trien-3-one (flu-
oropropylcurcumin; FP-curcumin).28 However, despite its
excellent binding affinity (Ki = 0.07 nM) for Ab(1–40) aggregates,
its initial brain uptake was relatively low (0.52% ID/g at 2 min
post-injection). This may be explained by its rapid metabolism in
the liver and in the intestinal wall, like curcumin.29 However,
[
18F]FP-curcumin has a high and specific binding to Ab plaques
once it is taken up by the brain. This is supported by reports that
this radioligand showed higher hippocampus (Ab plaque rich re-
gion) to cerebellum uptake ratio compared to that of [11C]PIB
(3.0–3.5 vs 1.5) in transgenic mouse (Tg2576) brain sections, and
that uptake by the hippocampus was decreased by 70% in the
presence of 10 l
M PIB.30 Thus, improving the brain permeability
of curcumin-based radioligands is a key element to consider for
such radioligands to be useful for Ab plaque imaging.
In order to improve the brain permeability of curcumin deriva-
tives, the lipophilicity was adjusted such that a para-OH group of a
phenyl ring was substituted with an alkoxy group or a polyethoxy
O
OH
O
OH
H3CO
H3CO
OCH3
O
H3CO
HO
OCH3
OH
F
Curcumin
1
O
OH
O
O
OH
H3CO
H3CO
OCH3
H3CO
OCH3
O
O
O
F
HO
O
F
F
2
3
5
OH
O
OH
H3CO
H3CO
OCH3
O
H3CO
HO
OCH3
O
O
F
O
4
Figure 2. Chemical structures of curcumin and fluorine-substituted curcumin derivatives.

I. Lee et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5765–5769
OH
5767
O
O
O
OH
H3CO
R
H3CO
R
H3CO
OCH3
a
b
H
F
H3CO
O
n
6: R = OH
7: R = OCH3
1: n = 2
2: n = 3
b
O
OH
H3CO
R
OCH3
O
O
F
n
3: R = OH, n = 1
4: R = OH, n = 2
5: R = OCH3, n = 1
Scheme 1. Reagents and conditions: (a) 2,4-pentanedione, B2O3, ethyl acetate, (n-BuO)3B, n-BuNH2, 100 °C, 1 h, 1 N HCl, 50 °C, 30 min; (b) vanillin derivative (8, 9, 15, or 16),
B2O3, ethyl acetate, (n-BuO)3B, piperidine, 80 °C, 30 min, 0.4 N HCl, 50°, 30 min.
O
O
O
O
OCH3
OH
OCH3
O
10: n = 1
11: n = 2
12: n = 3
OCH3
O
13: n = 1
14: n = 2
OCH3
O
15: n = 1
16: n = 2
b
c
d
H
H
H
H
O
O
O
H
OMs
F
n
n
n
a
e
O
O
OH
O
OH
OCH3
OCH3
O
H3CO
H3CO
OCH3
f
g
H
OH
OR
O
O
F
n
8: n = 2
9: n = 3
17
18: R = H
19: R = Ns
Scheme 2. Reagents and conditions: (a) fluoroalkyl tosylate, K2CO3, CH3CN, 110 °C, 1.5 h; (b) 2-bromoethanol, 2-(2-chloroethoxy)ethanol, or 2-(2-(2-chloroethoxy)eth-
oxy)ethanol, DMF, 100 °C, 5 h; (c) MsCl, Et3N, CH2Cl2, room temperature, 3 h; (d) CsF, CH3CN, 100 °C, 17 h; (e) 2,4-pentanedione, B2O3, ethyl acetate, (n-BuO)3B, n-butylamine,
100 °C, 1 h, 1 N HCl, 50 °C, 30 min; (f) 3,4-dimethylbenzaldehyde, B2O3, ethyl acetate, (n-BuO)3B, piperidine, 80 °C, 30 min, 0.4 N HCl, 50 °C, 30 min; (g) B2O3, CH2Cl2, Et3N,
NsCl, room temperature, 5 h, 0.4 N HCl, 50 °C, 30 min.
O
O
a
b
OCH3
O
OCH3
O
10
H
H
18F
ONs
c
O
[
OH
18F]6
20
[
H3CO
H3CO
OCH3
O
18F
O
OH
d
18F]1
H3CO
H3CO
OCH3
O
ONs
19
Scheme 3. Reagents and conditions: (a) Et3N, NsCl, CH2Cl2, room temperature, 1 h; (b) n-Bu4N[18F]F, CH3CN, 120 °C, 15 min; (c) 7, B2O3, (n-BuO)3B, piperidine, ethyl acetate,
120 °C, 20 min, 0.4 N HCl, 90 °C, 5 min; (d) n-Bu4N[18F]F, THF, 95 °C, 20 min.
by flash column chromatography followed by recrystallization
from ethanol (Scheme 2). Without the recrystallization step, 10 re-
mained in the product based on 1H NMR analysis.
(0.4 nM).19 Ki values of fluorine-substituted curcumin derivatives
were desirable, ranging from 2.12 to 4.65 nM (Table 1). Of the
derivatives, 1 exhibited the highest binding affinity (Ki = 2.12 nM).
Binding affinity was slightly decreased by pegylation (Ki = 3.01–
4.65 nM), and 7-(40-methyl) derivative 5 showed a higher binding
affinity (3.01 nM) than unmethylated derivatives 3 and 4, suggest-
ing that hydroxyl groups on phenyl rings are not required for avid
binding to Ab(1–42) aggregates. This result indicated that 1 had
similar binding affinity to those of the radiopharmceuticals
The binding affinity of curcumin derivatives, 1–5 was deter-
mined using Ab(1–42) aggregates and [125I]IMSB, and non-specific
binding was measured in the presence of 10 lM Chrysamine G
(CG). The Kd value of [125I]IMSB for binding to Ab(1–42) aggregates
was 1.19 nM, similar to the reported value of 0.73 nM.19 The Ki va-
lue of CG (0.43 nM) was also comparable to the reported value

5768
I. Lee et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5765–5769
Table 1
Table 2
Ki (nM) of ligands for Ab(1–42) aggregates
Tissue distribution of [18F]1 in normal mice
Ligand
Ki (nM)
Organ
% ID/g
60 min
2 min
30 min
120 min
Chrysamine G
Curcumin
0.43 0.068
3.57 0.025
2.12 0.097
2.69 0.033
4.65 0.267
4.44 0.313
3.01 0.087
Blood
Heart
Lung
9.76 0.59
7.18 0.58
23.78 2.92
38.83 2.88
16.41 2.92
10.95 0.58
0.89 0.34
1.86 0.13
1.44 0.09
1.26 0.08
1.68 0.33
3.94 0.64
43.02 3.33
20.80 12.3
4.01 1.24
0.76 0.29
1.08 0.08
0.45 0.04
0.89 0.15
1.30 0.19
2.27 0.56
26.83 0.43
10.59 1.25
2.25 0.90
0.47 0.05
1.00 0.16
0.43 0.05
0.67 0.13
1.54 0.45
2.19 0.46
12.51 1.45
8.08 1.90
1.42 0.15
0.37 0.07
1.62 0.12
0.29 0.03
1
2
3
4
5
Liver
Spleen
Kidney
Muscle
Femur
Brain
Values are means SD (n = 3).
Values are means SD (n = 4).
currently under clinical development (0.74–2.87 nM), although the
assays were done against Ab(1–42) aggregates in the former and
AD brain homogenates in the latter.18,21,22
in vivo, fluorescence staining of plaques by 1 and thioflavin-S were
compared using the brain sections from both a double transgenic
mouse (Tg APP/PS-1) and a wild-type mouse (Fig. 3). Many plaques
in the cortex region of the transgenic mouse brain were stained
with 1 (Fig. 3A and E), and the fluorescence staining pattern was
consistent with that observed with thioflavin-S, a dye used for
staining Ab plaques in vitro (Fig. 3B and F). In contrast, there were
no notable plaques stained with either 1 or thioflavin-S in wild-
type mouse brain sections (Fig. 3C–H). This result suggests that li-
gand 1 distinctively stains Ab plaques in transgenic mouse brains.
In order to investigate the in vivo pharmacokinetics of [18F]1,
tissue distribution in normal mice was performed. High radioactiv-
ity was accumulated in the lung, liver, and spleen at 2 min post-
injection and decreased over time. Brain uptake of [18F]1 was
1.44% ID/g at 2 min post-injection and was rapidly washed out
from the brain (2-min to 60-min uptake ratio, 3.35) (Table 2).
The initial brain uptake was improved compared to that of
Therefore, 1 was chosen for radiolabeling with 18F and further
evaluation as an Ab plaque imaging agent for PET, because of its
high binding affinity for Ab(1–42) aggregates and appropriate lipo-
philicity based on TLC analysis. Pegylated compounds 3–5 were
found to be more polar than FP-curcumin (logPo/w = 1.84) by TLC,
which may result in poor initial brain uptake. Radioligand [18F]1
was synthesized as shown in Scheme 3. The synthesis was carried
out using two methods: one-step and two-step radiolabeling. The
former was carried out by 18F-labeling of the nosylate precursor
(19); the decay-corrected radiochemical yield was 10–17% and to-
tal synthesis time was 60 min. Although [18F]1 was also synthe-
sized from 19 with n-Bu4N[18F]F in the presence of B2O3, the
decay-corrected radiochemical yield was in the same range with
the reaction performed in the absence of B2O3. However, the
two-step reaction using aldol condensation of [18F]6 and 7 gave
[
18F]1 in 15–25% yield and with higher specific activity. The use
[
18F]FP-curcumin by a factor of 2.8,24 probably because of the in-
of tosylate precursor in place of the nosylate precursor (19) affor-
ded [18F]1 in a 5–10% yield with lower specific activity. Therefore,
the two-step method was used in this study. The radiochemical
yield of [18F]6 from 20 and n-Bu4N[18F]F based on TLC analysis
was 70% or greater. The subsequent aldol condensation of [18F]6
and 7 in the presence of B2O3, (n-BuO)3B, and piperidine followed
by HPLC purification gave the product a decay-corrected overall
radiochemical yield of 15–25% and a specific activity of 37.6 GBq/
creased lipophilicity. This is a notable improvement in brain per-
meability, considering unique properties of curcumin derivatives.
In addition, [18F]1 did not appear to undergo metabolic defluorina-
tion due to a constant level of femur uptake with time (1.00–1.86%
ID/g). These results indicated that [18F]1 had favorable pharmaco-
kinetics in normal mouse brains. The recent studies demonstrated
that the radiopharmceuticals currently under clinical development
(BAY 94-9172, and AV-45) had high initial brain uptake (7.33–
7.77% ID/g) in normal mice and fast wash-out from mouse brains
(2-min to 60-min uptake ratios, 3.90–4.82).18,21 However, further
studies with 18F-labeled curcumin-based ligands are clearly war-
ranted if their brain permeability could be improved, because they
l
mol. The total synthesis time including HPLC purification was
90–100 min. The partition coefficient of [18F]1 (logPo/w = 2.4) was
found to be higher than that of [18F]FP-curcumin (logPo/w = 1.84).28
Curcumin has strong fluorescence based on its highly conju-
gated structure. To confirm whether 1 could label Ab plaques
Figure 3. (Left) A double transgenic mouse brain section stained with 1 (ꢀ40) (A), the adjacent section stained with thioflavin-S (ꢀ40) (B), an age-matched wild-type mouse
brain section stained with 1 (ꢀ40) (C), and the adjacent section stained with thioflavin-S (ꢀ40) (D). (Right) Magnification of the cortex regions in red boxes of left panels
(ꢀ100). A double transgenic mouse brain section stained with 1 (E), the adjacent section stained with thioflavin-S (F), an age-matched wild-type mouse brain section stained
with 1 (G), and the adjacent section stained with thioflavin-S (H).

I. Lee et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5765–5769
5769
10. Mathis, C. A.; Wang, Y.; Holt, D. P.; Huang, G. F.; Debnath, M. L.; Klunk, W. E. J.
Med. Chem. 2003, 46, 2740.
11. Klunk, W. E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D. P.;
Bergström, M.; Savitcheva, I.; Huang, G.; Estrada, S.; Ausén, B.; Debnath, M. L.;
Barletta, J.; Price, J. C.; Sandell, J.; Lopresti, B. J.; Wall, A.; Koivisto, P.; Antoni, G.;
Mathis, C. A.; Långström, B. Ann. Neurol. 2004, 55, 306.
12. Lopresti, B. J.; Klunk, W. E.; Mathis, C. A.; Hoge, J. A.; Ziolko, S. K.; Lu, X.;
Meltzer, C. C.; Schimmel, K.; Tsopelas, N. D.; DeKosky, S. T.; Price, J. C. J. Nucl.
Med. 2005, 46, 1959.
13. Rowe, C. C.; Ng, S.; Ackermann, U.; Gong, S. J.; Pike, K.; Savage, G.; Cowie, T. F.;
Dickinson, K. L.; Maruff, P.; Darby, D.; Smith, C.; Woodward, M.; Merory, J.;
Tochon-Danguy, H.; O’Keefe, G.; Klunk, W. E.; Mathis, C. A.; Price, J. C.; Masters,
C. L.; Villemage, V. L. Neurology 2007, 68, 1718.
have different in vivo binding sites from thioflavin-T based radioli-
gands for Ab plaques and thus may have different in vivo proper-
ties, such as low subcortical white matter uptake or detection of
Ab(1–42) species prior to plaque formation.
In conclusion, five curcumin derivatives were synthesized and
evaluated in vitro and in vivo. Of the derivatives, [18F]1 demon-
strated a high binding affinity for Ab(1–42) aggregates, suitable
lipophilicity, specific binding to Ab plaques in Tg APP/PS-1 mouse
brain sections, improved brain permeability compared to that of
[
18F]FP-curcumin, and fast wash-out from normal mouse brains.
These results suggest that [18F]1 may be a potential radioligand
for Ab plaque imaging.
14. Johnson, A. E.; Jeppsson, F.; Sandell, J.; Wensbo, D.; Neelissen, J. A. M.; Juréus,
A.; Ström, P.; Norman, H.; Farde, L.; Svensson, S. P. S. J. Neurochem. 2009, 108,
1177.
15. Mathis, C. A.; Ikonomovicb, M. D.; Debnath, M. L.; Hamilton, R. L.; DeKosky, S.
T.; Klunk, W. E. Neuroimage 2008, 41, T113.
Acknowledgments
16. Koole, M.; Lewis, D. M.; Buckley, C.; Nelissen, N.; Vandenbulcke, M.; Brooks, D.
J.; Bandenbeghe, R.; Van Laere, K. J. Nucl. Med. 2009, 50, 818.
17. Nelissen, N.; Laere, K. V.; Thurfjell, L.; Owenius, R.; Vandenbulcke, M.; Koole,
M.; Bormans, G.; Brooks, D. J.; Vandenberghe, R. J. Nucl. Med. 2009, 50, 1251.
18. Zhang, W.; Oya, S.; Kung, M. P.; Hou, C.; Marier, D. L.; Kung, H. F. Nucl. Med. Biol.
2005, 32, 799.
19. 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. F.; 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.
This study was supported in part by the Samsung Biomedical
Research Institute grant (C-A6-228-3) and by the Nuclear Research
Development Program of the Korea Science and Engineering Foun-
dation (KOSEF) grant funded by the Korean government (MEST)
(Grant code: 2010-0018315).
Supplementary data
20. Zhang, W.; Kung, M. P.; Oya, S.; Hou, C.; Kung, H. F. Nucl. Med. Biol. 2007, 34, 89.
21. 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.
22. Kung, H. F.; Choi, S. R.; Qu, W.; Zhang, W.; Skovronsky, D. J. Med. Chem. 2010,
53, 933.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.003.
23. Cheng, A. L.; Hsu, C. H.; Lin, J. K.; Hsu, M. M.; Ho, Y. F.; Shen, T. S.; Ko, J. Y.; Lin, J.
T.; Lin, B. R.; Ming-Shiang, W.; Yu, H. S.; Jee, S. H.; Chen, G. S.; Chen, T. M.; Chen,
C. A.; Lai, M. K.; Pu, Y. S.; Pan, M. H.; Wang, Y. J.; Tsai, C. C.; Hsieh, C. Y.
Anticancer Res. 2001, 21, 2895.
24. Lin, J. K.; Shih, C. A. Carcinogenesis 1994, 15, 1717.
25. Lim, G. P.; Chu, T.; Yang, F.; Beech, W.; Frautschy, S. A.; Cole, G. M. J. Neurosci.
2001, 21, 8370.
26. Yang, F.; Lim, G. P.; Befum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S.
S.; Chen, P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. J. Biol. Chem.
2005, 280, 5892.
27. Ran, C.; Moore, A. World Molecular Imaging Congress. Kyoto, Japan, 2010;
Abstract.
28. Ryu, E. K.; Choe, Y. S.; Lee, K. H.; Choi, Y.; Kim, B. T. J. Med. Chem. 2006, 49, 6111.
29. Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P. S. Planta
Med. 1998, 64, 353.
30. Patel, P. C.; Sarsoza, F.; Vasilevko, V.; Pan, M. L.; Tsu, W.; Constantinescu, C.;
Coleman, R.; Head, E.; Mukherjee, J. NeuroImage 2008, 41S, T115.
References and notes
1. Ginsberg, S. D.; Schmidt, M. L.; Crino, P. B.; Eberwine, J. H.; Lee, V. M. Y.;
Trojanowski, J. Q. Cerebral Cortex: Neurodegenerative Age-related Changes in
Structure Function of Cerebral Cortex In Peters, A., Morrison, J. H., Eds.; Kluwer
Academic/Plenum Publishers: New York, 1999; pp 603–654.
2. Lee, V. M.; Trojanowski, J. Q. Neuron 1999, 24, 507.
3. Selkoe, D. J. JAMA 2000, 283, 1615.
4. Mathis, C. A.; Wang, Y.; Klunk, W. E. Curr. Pharm. Design 2004, 10, 1469.
5. Ashburn, T. T.; Han, H.; McGuinness, B. F.; Lansbury, P. T., Jr. Chem. Biol. 1996, 3,
351.
6. Klunk, W. E.; Pettegrew, J. W.; Abraham, D. J. J. Histochem. Cytochem. 1989, 37,
1273.
7. Mathis, C. A.; Mahmood, K.; Debnath, M. L.; Klunk, W. E. J. Labelled Compd.
Radiopharm. 1997, 39, 594.
8. Klunk, W. E.; Wang, Y.; Huang, G.; Debnath, M. L.; Holt, D. P.; Mathis, C. A. Life
Sci. 2001, 69, 1471.
9. Mathis, C. A.; Bacskai, B. J.; Kajdasz, S. T.; McLellan, M. E.; Frosch, M. P.; Hyman,
B. T.; Holt, D. P.; Wang, Y.; Huang, G. F.; Debnath, M. L.; Klunk, W. E. Bioorg. Med.
Chem. Lett. 2002, 12, 295.