Structure-activity relationships and in vivo evaluation of quinoxaline derivatives for PET imaging of β-amyloid plaques

Article abstract of DOI:10.1021/ml4000707

This letter describes the synthesis, structure-activity relationships, and in vivo evaluation of a new series of 2-phenylquinoxaline (PQ) derivatives for imaging β-amyloid (Aβ) plaques in Alzheimer's disease (AD). In experiments in vitro, the affinity of

Full text of DOI:10.1021/ml4000707

Letter
pubs.acs.org/acsmedchemlett
Structure−Activity Relationships and in Vivo Evaluation of
Quinoxaline Derivatives for PET Imaging of β‑Amyloid Plaques
Masashi Yoshimura,† Masahiro Ono,*,† Kenji Matsumura,† Hiroyuki Watanabe,† Hiroyuki Kimura,†
Mengchao Cui,† 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
Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
§Department of Neuroscience, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto
606-8507, Japan
S
* Supporting Information
ABSTRACT: This letter describes the synthesis, structure−
activity relationships, and in vivo evaluation of a new series of
2-phenylquinoxaline (PQ) derivatives for imaging β-amyloid
(Aβ) plaques in Alzheimer’s disease (AD). In experiments in
vitro, the affinity of the derivatives for Aβ aggregates varied,
with Ki values of 0.895 to 1180 nM. In brain sections from AD
patients, derivatives with a Ki of less than 111 nM intensely
labeled Aβ plaques, while those with values over 242 nM
showed no marked labeling. In biodistribution experiments
using normal mice, the derivatives showed good uptake into
(4.69−7.59 %ID/g at 2 or 10 min postinjection) and subsequent washout from (1.48−3.08 %ID/g at 60 min postinjection) the
brain. In addition, [18F]PQ-6 labeled Aβ plaques in vivo in APP transgenic mice, while it showed nonspecific binding in the white
matter. Further structural optimization based on [18F]PQ-6 may lead to more useful PET probes for imaging Aβ plaques.
KEYWORDS: Alzheimer’s disease (AD), β-amyloid (Aβ), PET, quinoxaline, structure−activity relationships
AD research because one can clearly distinguish between AD
lzheimer’s disease (AD) is a leading cause of dementia
Awith symptoms including progressive memory loss and an patients and healthy controls from the high signal-to-noise
ratio.5−7 More recently, a stilbene analogue with fluorinated
inability to carry out normal daily functions. As populations
continue to age rapidly all over the world, the increase in the
polyethylene glycol (PEG) units, [18F]-(E)-4-(2-(6-(2-(2-(2-
fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methylani-
line ([18F]AV-45, Florbetapir), has been approved by the US
Food and Drug Administration (FDA) for clinical AD diagnosis
by exclusion.8−10 Other 18F-labeled probes including [18F]-(E)-
4-(N-methylamino)-4′-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-
stilbene ([18F]BAY94−9172, Florbetaben)11−13 and 2-(3-
[18F]fluoro-4-methylaminophenyl)benzothiazol-6-ol ([18F]GE-
067, Flutemetamol)14,15 are expected to obtain FDA approval
in the near future.
Recently, we have developed a new type of probe based on
the quinoxaline pharmacophore.16,17 These derivatives dis-
played high affinity for Aβ aggregates with Ki values in the nM
range (4.1−10.7 nM) and showed specific labeling of Aβ
plaques in sections of brain tissue from AD patients and
transgenic mice. In biodistribution experiments, these probes
number of AD patients constitutes a serious social issue.
However, no diagnostic or therapeutic methods have been
established for AD.1 Post-mortem brains of AD patients reveal
senile plaques (SPs) composed of β-amyloid (Aβ) peptides and
neurofibrillary tangles (NFTs) formed by hyperphosphorylated
tau proteins.2 Although the precise molecular mechanisms
causing AD remain unknown, the amyloid cascade hypothesis,
that SPs play an important role in its development, is widely
accepted.3,4 Consequently, the in vivo imaging of SPs
composed of Aβ plaques with noninvasive techniques such as
positron emission tomography (PET) or single photon
emission computed tomography (SPECT) could be useful for
the presymptomatic diagnosis of AD and new antiamyloid
therapies.
Toward this end, great efforts have been made to develop
PET and SPECT probes that can image Aβ plaques in vivo.
Several PET probes have undergone clinical studies. [11C]PIB
([11C]-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole), a
neutral thioflavin T (ThT) analogue, has been widely used in
Received: February 19, 2013
Accepted: May 8, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ml4000707 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
a
showed high initial uptake into the brain (2.49−8.17 %ID/g at
2 min) and subsequently washed out from the brain with time.
These previous results suggested that quinoxaline may serve as
a new scaffold for the development of more useful PET probes.
In the present study, to further examine structure−activity
relationships on affinity for Aβ aggregates and pharmacoki-
netics in vivo, we designed and synthesized new fluorinated PQ
derivatives which have a fluoropegylated group at position 6 or
7 of the PQ structure.
Scheme 1
Figure 1. Chemical structure of fluoropegylated PQ derivatives.
The synthesis of 7-fluoropegylated and 6-fluoropegylated PQ
derivatives is outlined in Schemes 1 and 2, respectively. The
details of the synthesis are described in the Supporting
Information.
The desired 18F-labeled PQ derivatives were prepared via a
nucleophilic displacement reaction with a fluoride anion as
shown in Scheme 3. To prepare the desired 18F-labeled
dimethylated PQ derivatives, the tosylate precursors (16 and
34) were reacted with [18F]fluoride/potassium carbonate and
Kryptofix 222 in acetonitrile. Radiolabeling with 18F was
successfully performed on the precursor to generate [18F]PQ-3
and [18F]PQ-6 with radiochemical yields of 31.3 16.0% (n =
8) and 19.6
11.4% (n = 5), respectively. To prepare the
a
desired 18F-labeled nonmethylated and monomethylated PQ
derivatives, the N-Boc-protected tosylates 21, 22, 35, and 36
were employed as the precursors. Each of the tosylates was
reacted with [18F]fluoride/potassium carbonate and Kryptofix
222 in acetonitrile. The mixture was then treated with aqueous
HCl to remove the N-Boc-protected group. Radiolabeling with
18F was successfully performed on the precursor to generate
[18F]PQ-1, [18F]PQ-2, [18F]PQ-4, and [18F]PQ-5 with radio-
chemical yields of 25.9 12.5% (n = 3), 20.1 8.9% (n = 3),
34.0 9.5% (n = 3), and 22.7 5.5% (n = 3), respectively.
Each radiolabeling was accomplished with a radiochemical
purity greater than 95%. The identity of radioactive PQ
derivatives was verified by a comparison of the retention time
with that of the nonradioactive compound.
Reagents and conditions: (a) Br2, H2SO4, 0 °C to rt; (b) diethyl
phosphite, triethylamine, THF, 0 °C to rt; (c) TBSCl, imidazole, THF,
rt; (d) H2, Pd/C, MeOH, CH2Cl2, rt; (e) DMSO, rt; (f) TBAF, THF,
0 °C to rt; (g) 2-fluoroethyl 4-methylbenzenesulfonate, K2CO3, DMF,
105 °C; (h) (1) 2-fluoroethyl 4-methylbenzenesulfonate, K2CO3,
DMF, 105 °C, (2) H2, Pd/C, MeOH, CH2Cl2, rt; (i) (1)
paraformaldehyde, NaOMe, MeOH, 0 °C to reflux, (2) NaBH4,
reflux; (j) 2-bromoethanol, K2CO3, DMF, 105 °C; (k) (2-
bromoethoxy)-tert-butyldimethylsilane, K2CO3, DMF, 80 °C; (l)
TsCl, pyridine, 0 °C to rt; (m) Boc2O, DMAP, triethylamine, THF,
reflux; (o) TsCl, DMAP, pyridine, 0 °C to rt.
derivatives, PQ-6 showed the highest affinity for Aβ aggregates
with a Ki of 0.895 nM. The binding of [18F]PQ-6 with the
fluoroethyleneoxy group at position 6 in the PQ scaffold was
over 100-fold that of [18F]PQ-3 with the fluoroethyleneoxy
group at position 7. Furthermore, in comparison with AV-45,
the only such compound approved by the FDA, the affinity of
PQ-6 increased about 10-fold, suggesting the potential utility of
[18F]PQ-6 for imaging Aβ plaques in AD brain.
In vitro binding experiments to evaluate the affinity of the 6
PQ derivatives for Aβ1−42 aggregates were carried out in
solutions with [125I]6-iodo-2-(4′-N,N-dimethylamino)-
phenylimidazo[1,2-a]pyridine ([125I]IMPY) as the competing
ligand. AV-45 was also tested using the same system for
comparison. The results are listed in Table 1. The affinity of PQ
derivatives for Aβ aggregates varied, with Ki values of 0.895 to
1180 nM. The 6-fluoropegylated as well as 7-fluoropegylated
PQ derivatives had affinity for Aβ aggregates in the following
order: dimethylamino derivatives > monomethylamino deriv-
atives > primary amino derivatives. The results of the binding
experiments were consistent with those of some previous
studies.18−20 Furthermore, the affinity of 6-fluoropegylated PQ
derivatives (Ki = 0.895−242 nM) was much higher than that of
the corresponding 7-fluoropegylated PQ derivatives (Ki = 111−
1180 nM), indicating that the substituted site of the
fluoropegylated group in the PQ scaffold plays an important
role in the binding to Aβ aggregates. Among the 6 PQ
The binding of six [18F]PQ-1−6 derivatives or [18F]AV-45 as
a positive control to Aβ plaques in brain sections from AD
patients was evaluated by autoradiography in vitro. As shown in
Figure 2, [18F]PQ-5 and [18F]PQ-6 with a Ki of 15.7 and 0.895
nM, respectively, intensively labeled Aβ plaques showing a
strong signal in the cortex region and a low background level in
the white matter. [18F]PQ-3 with a Ki of 111 nM showed
moderate binding and labeled only a few Aβ plaques.
Conversely, [18F]PQ-1, [18F]PQ-2, and [18F]PQ-4 with Ki
values above 242 nM did not display marked binding to Aβ
plaques although they showed high nonspecific binding in the
white matter region. The results of autoradiography in vitro
were consistent with those of binding assays in vitro, and also
B
dx.doi.org/10.1021/ml4000707 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
a
Scheme 2
Table 1. Inhibition Constants (Ki, nM) for the Binding of
[
125I]IMPY to Aβ1‑42 Aggregates
a
compd
Ki (nM)
PQ-1
PQ-2
PQ-3
PQ-4
PQ-5
PQ-6
AV-45
IMPY
1180 370
758 83.8
111 13.2
242 29.0
15.7 1.28
0.895 0.141
12.8 2.10
7.21 1.23
a
Values are the means
standard errors of the mean of 6−13
independent determinations.
a
Reagents and conditions: (a) AlCl3, toluene, 0 to 80 °C; (b) 2-
fluoroethyl 4-methylbenzenesulfonate, K2CO3, DMF, 80 °C; (c) N,N-
dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd-
(PPh3)4, K2CO3 aq. (2 M), toluene, EtOH, reflux; (d) 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(PPh3)4, K2CO3 aq. (2
M), toluene, EtOH, reflux; (e) (1) paraformaldehyde, NaOMe,
MeOH, 0 °C to reflux, (2) NaBH4, reflux; (f) (2-bromoethoxy)-tert-
butyldimethylsilane, K2CO3, DMF, 80 °C; (g) Boc2O, DMAP,
triethylamine, THF, reflux; (h) (1) TBAF, THF, 0 °C to rt, (2)
TsCl, DMAP, pyridine, rt.
Figure 2. In vitro autoradiogram of AD brain sections (A−G) labeled
with [18F]PQ-1−6 and [18F]AV-45, respectively. In vitro autoradio-
gram of [18F]PQ-6 in a brain section from a healthy control (H). The
Aβ plaques were confirmed by immunostaining with an anti-Aβ1−42
antibody (I).
a
Scheme 3
a
Reagents and conditions: (a) 18F−, K2CO3, Kryptofix222, acetonitrile,
100 °C; (b) (1) 18F−, K2CO3, Kryptofix222, acetonitrile, 100 °C, (2)
HCl (1 M), 100 °C.
Figure 3. Comparison of brain uptake of [18F]PQ-1−6 and [18F]AV-
45 in normal mice.
suggested that the substituted site of the fluoroethylene group
in the PQ moiety may strongly affect the affinity of the PQ
derivatives for Aβ aggregates.
except [18F]PQ-1, show a higher initial brain uptake than
[18F]AV-45. Subsequently, the radioactivity in the brain cleared
with time (1.48−3.08 %ID/g at 60 min postinjection). Since
there are no Aβ plaques in normal mice, a high initial uptake
and rapid washout in normal brain are highly desirable
properties for the imaging of Aβ plaques in vivo. When we
caluculated the brain2min/brain60min ratio (see Supporting
Information, Table S8) to compare the washout rate,
Next, all of the 18F-labeled PQ derivatives were evaluated for
their biodistribution in normal mice. We carried out the
biodistribution study using [18F]AV-45 as a control under
similar experimental conditions. To compare the uptake into
and washout from the brain, a combined plot is presented in
Figure 3. All PQ derivatives displayed a high uptake, 4.69−7.59
%ID/g, at 2 or 10 min postinjection, indicating that they,
C
dx.doi.org/10.1021/ml4000707 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
[18F]PQ-3 (3.91) showed faster clearance than [18F]AV-45
(3.80). Conversely, a slightly slower clearance than [18F]AV-45
was observed for the other derivatives (2.36−3.12). Consider-
ing the results of the binding to Aβ plaques in vitro together
with the biodistribution studies in vivo, we selected [18F]PQ-6
for further characterization in living brain tissue.
showed the clearest labeling of Aβ plaques in the brain sections
from AD patients. In biodistribution studies, PQ derivatives
displayed good uptake into and washout with time from the
brain. Their radioactivity profiles in the brain were comparable
to that of [18F]AV-45. In addition, ex vivo autoradiograms of
brain sections from Tg2576 mice after the injection of [18F]PQ-
6 showed the feasibility of imaging Aβ plaques, although
nonspecific binding was also observed. Further structural
optimization based on [18F]PQ-6 to reduce nonspecific binding
in the white matter may lead to more useful PET probes for
imaging Aβ plaques in the brain.
We carried out autoradiography ex vivo with [18F]PQ-6 in
Tg2576 and wild-type mice. Tg2576 mice show marked Aβ
deposition in the brain by 11−13 months of age and have been
frequently used to evaluate the specific binding of Aβ plaques in
experiments in vitro and in vivo.21−24 Ex vivo autoradiograms
after the injection of [18F]PQ-6 into a Tg2576 mouse showed
extensive labeling of Aβ plaques in the brain (Figure 4A). No
ASSOCIATED CONTENT
■
S
* Supporting Information
Results of the partition coefficient values, the biodistribution
experiments for all organs, and the autoradiography ex vivo
using a Tg2576 mouse with [18F]PQ-3, procedures for the
preparation of PQ-1−6 and [18F]PQ-1−6, partition coefficient,
binding assays using Aβ1−42 aggregates, autoradiography in vitro
using brain tissue from AD patients, biodistribution in vivo in
normal mice, and autoradiography ex vivo using Tg2576 mice.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*(M.O.) Phone: +81-75-753-4608. Fax: +81-75-753-4568. E-
mail: ono@pharm.kyoto-u.ac.jp.
Funding
This research was granted by the Japan Society for the
Promotion of Science (JSPS) through the “Funding Program
for Next Generation World-Leading Researchers (NEXT
Program),” initiated by the Council for Science and
Technology Policy (CSTP).
Figure 4. Ex vivo autoradiogram from a Tg2576 mouse (A) and a
wild-type mouse (B) with [18F]PQ-6. The same sections (A,B) were
also stained with thioflavin-S (C and D, respectively).
Notes
such labeling was observed in the wild-type mouse brain
(Figure 4B). However, both brains showed high nonspecific
radioactivity accumulation despite that [18F]PQ-6 displayed not
only washout with time from the normal mouse brain in
biodistribution studies but also low nonspecific radioactivity
accumulation in white matter in the AD brain in vitro. This
high nonspecific radioactivity accumulation was observed in the
corpus callosum, external capsule, anterior commissure, and
olfactory tract in the mouse brain. These areas are known to
have a high density of myelin sheaths, suggesting that [18F]PQ-
6 may bind to myelin fibers in the white matter. We also carried
out autoradiography ex vivo in Tg2576 and wild-type mice with
[18F]PQ-3. Different from [18F]PQ-6, [18F]PQ-3 exhibited no
marked specific binding to Aβ plaques in the autoradiograms
(see Supporting Information, Figure S1). These results
reflected the finding that the affinity of PQ-3 in the binding
assay was over 100-fold lower than that of PQ-6, in addition to
the marked difference in the autoradiographic experiments
using AD brain sections.
In conclusion, we designed and synthesized new 6 PQ
derivatives and evaluated their structure−activity relationship to
Aβ aggregates and their biodistribution in normal mice. In
binding assays, PQ-6 showed the highest affinity for Aβ
aggregates with a Ki of 0.895 nM. The affinity of PQ derivatives
to Aβ aggregates significantly differed with the substituted
position of the fluoroethoxy group in the PQ scaffold. As
reflected by the extremely high binding affinity, [18F]PQ-6 also
The authors declare no competing financial interest.
ABBREVIATIONS
■
Aβ, β-amyloid; AD, Alzheimer’s disease; SP, senile plaque;
NFT, neurofibrillary tangle; PET, positron emission tomog-
raphy; SPECT, single photon emission computed tomography;
ThT, thioflavin T; TBSCl, tert-butyldimethylsilyl chloride;
TBAF, tetrabutylammonium fluoride; NaOMe, sodium meth-
oxide; THF, tetrahydrofuran; Boc, tert-butoxycarbonyl; TsCl, p-
toluenesulfonyl chloride; DMAP, N,N-dimethyl-4-aminopyr-
idine; IMPY, 6-iodo-2-(4′-N,N-dimethylamino)phenylimidazo-
[1,2-a]pyridine
REFERENCES
■
(1) Holtzman, D. M.; Morris, J. C.; Goate, A. M. Alzheimer’s disease:
the challenge of the second century. Sci. Transl. Med. 2011, 3, 77sr1.
(2) Selkoe, D. J. Alzheimer’s disease: genes, proteins, and therapy.
Physiol. Rev. 2001, 81, 741−766.
(3) Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer’s
disease: progress and problems on the road to therapeutics. Science
2002, 297, 353−356.
(4) Finder, V. H. Alzheimer’s disease: a general introduction and
pathomechanism. J. Alzheimer’s Dis. 2010, 22 (Suppl. 3), S5−S19.
(5) 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.
D
dx.doi.org/10.1021/ml4000707 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Imaging brain amyloid in Alzheimer’s disease with Pittsburgh
Compound-B. Ann. Neurol. 2004, 55, 306−319.
phenylquinoxaline derivatives as potential positron emission tomog-
raphy probes for in vivo imaging of β-amyloid plaques. Eur. J. Med.
Chem. 2012, 57, 51−58.
(6) Villain, N.; Chetelat, G.; Grassiot, B.; Bourgeat, P.; Jones, G.;
Ellis, K. A.; Ames, D.; Martins, R. N.; Eustache, F.; Salvado, O.;
Masters, C. L.; Rowe, C. C.; Villemagne, V. L. Regional dynamics of
amyloid-β deposition in healthy elderly, mild cognitive impairment
and Alzheimer’s disease: a voxelwise PiB-PET longitudinal study. Brain
2012, 135, 2126−2139.
(18) Zhang, W.; Kung, M. P.; Oya, S.; Hou, C.; Kung, H. F. 18F-
labeled styrylpyridines as PET agents for amyloid plaque imaging.
Nucl. Med. Biol. 2007, 34, 89−97.
(19) Ono, M.; Watanabe, R.; Kawashima, H.; Kawai, T.; Watanabe,
H.; Haratake, M.; Saji, H.; Nakayama, M. 18F-labeled flavones for in
vivo imaging of β-amyloid plaques in Alzheimer’s brains. Bioorg. Med.
Chem. 2009, 17, 2069−2076.
(20) Ono, M.; Watanabe, R.; Kawashima, H.; Cheng, Y.; Kimura, H.;
Watanabe, H.; Haratake, M.; Saji, H.; Nakayama, M. Fluoro-pegylated
chalcones as positron emission tomography probes for in vivo imaging
of β-amyloid plaques in Alzheimer’s disease. J. Med. Chem. 2009, 52,
6394−6401.
(21) Hsiao, K.; Chapman, P.; Nilsen, S.; Eckman, C.; Harigaya, Y.;
Younkin, S.; Yang, F.; Cole, G. Correlative memory deficits, Aβ
elevation, and amyloid plaques in transgenic mice. Science 1996, 274,
99−102.
(22) Kung, M. P.; Hou, C.; Zhuang, Z. P.; Zhang, B.; Skovronsky, D.;
Trojanowski, J. Q.; Lee, V. M.; Kung, H. F. IMPY: an improved
thioflavin-T derivative for in vivo labeling of β-amyloid plaques. Brain
Res. 2002, 956, 202−210.
(23) Ono, M.; Watanabe, H.; Kimura, H.; Saji, H. BODIPY-based
molecular probe for imaging of cerebral β-amyloid plaques. ACS Chem.
Neurosci. 2012, 3, 319−324.
(24) Snellman, A.; Rokka, J.; Lopez-Picon, F. R.; Eskola, O.; Wilson,
I.; Farrar, G.; Scheinin, M.; Solin, O.; Rinne, J. O.; Haaparanta-Solin,
M. Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its
binding to beta amyloid deposits in a mouse model of Alzheimer’s
disease. Eur. J. Nucl. Med. Mol. Imaging 2012, 39, 1784−1795.
(7) Driscoll, I.; Troncoso, J. C.; Rudow, G.; Sojkova, J.; Pletnikova,
O.; Zhou, Y.; Kraut, M. A.; Ferrucci, L.; Mathis, C. A.; Klunk, W. E.;
O’Brien, R. J.; Davatzikos, C.; Wong, D. F.; Resnick, S. M.
Correspondence between in vivo 11C-PiB-PET amyloid imaging and
postmortem, region-matched assessment of plaques. Acta Neuropathol.
2012, 124, 823−831.
(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) Joshi, A. D.; Pontecorvo, M. J.; Clark, C. M.; Carpenter, A. P.;
Jennings, D. L.; Sadowsky, C. H.; Adler, L. P.; Kovnat, K. D.; Seibyl, J.
P.; Arora, A.; Saha, K.; Burns, J. D.; Lowrey, M. J.; Mintun, M. A.;
Skovronsky, D. M. Performance characteristics of amyloid PET with
florbetapir F 18 in patients with alzheimer’s disease and cognitively
normal subjects. J. Nucl. Med. 2012, 53, 378−384.
(10) Doraiswamy, P. M.; Sperling, R. A.; Coleman, R. E.; Johnson, K.
A.; Reiman, E. M.; Davis, M. D.; Grundman, M.; Sabbagh, M. N.;
Sadowsky, C. H.; Fleisher, A. S.; Carpenter, A.; Clark, C. M.; Joshi, A.
D.; Mintun, M. A.; Skovronsky, D. M.; Pontecorvo, M. J. Amyloid-β
assessed by florbetapir F 18 PET and 18-month cognitive decline: a
multicenter study. Neurology 2012, 79, 1636−1644.
(11) 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. Imaging of amyloid β in Alzheimer’s disease with
18F-BAY94−9172, a novel PET tracer: proof of mechanism. Lancet
Neurol. 2008, 7, 129−135.
(12) Barthel, H.; Luthardt, J.; Becker, G.; Patt, M.; Hammerstein, E.;
Hartwig, K.; Eggers, B.; Sattler, B.; Schildan, A.; Hesse, S.; Meyer, P.
M.; Wolf, H.; Zimmermann, T.; Reischl, J.; Rohde, B.; Gertz, H. J.;
Reininger, C.; Sabri, O. Individualized quantification of brain β-
amyloid burden: results of a proof of mechanism phase 0 florbetaben
PET trial in patients with Alzheimer’s disease and healthy controls.
Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 1702−1714.
(13) Barthel, H.; Gertz, H. J.; Dresel, S.; Peters, O.; Bartenstein, P.;
Buerger, K.; Hiemeyer, F.; Wittemer-Rump, S. M.; Seibyl, J.;
Reininger, C.; Sabri, O. Cerebral amyloid-β PET with florbetaben
(18F) in patients with Alzheimer’s disease and healthy controls: a
multicentre phase 2 diagnostic study. Lancet Neurol. 2011, 10, 424−
435.
(14) Nelissen, N.; Van Laere, K.; Thurfjell, L.; Owenius, R.;
Vandenbulcke, M.; Koole, M.; Bormans, G.; Brooks, D. J.;
Vandenberghe, R. Phase 1 study of the Pittsburgh compound B
derivative 18F-flutemetamol in healthy volunteers and patients with
probable Alzheimer disease. J. Nucl. Med. 2009, 50, 1251−1259.
(15) Vandenberghe, R.; Van Laere, K.; Ivanoiu, A.; Salmon, E.;
Bastin, C.; Triau, E.; Hasselbalch, S.; Law, I.; Andersen, A.; Korner, A.;
Minthon, L.; Garraux, G.; Nelissen, N.; Bormans, G.; Buckley, C.;
Owenius, R.; Thurfjell, L.; Farrar, G.; Brooks, D. J. 18F-flutemetamol
amyloid imaging in Alzheimer disease and mild cognitive impairment:
a phase 2 trial. Ann. Neurol. 2010, 68, 319−329.
(16) Cui, M.; Ono, M.; Kimura, H.; Liu, B.; Saji, H. Novel
quinoxaline derivatives for in vivo imaging of β-amyloid plaques in the
brain. Bioorg. Med. Chem. Lett. 2011, 21, 4193−4196.
(17) Yu, P.; Cui, M.; Wang, X.; Zhang, X.; Li, Z.; Yang, Y.; Jia, J.;
Zhang, J.; Ono, M.; Saji, H.; Jia, H.; Liu, B. 18F-labeled 2-
E
dx.doi.org/10.1021/ml4000707 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX