99mTc- and Re-labeled 6-dialkylamino-2-naphthylethylidene derivatives as imaging probes for β-amyloid plaques

Article abstract of DOI:10.1016/j.bmcl.2010.11.096

Based on the conjugate strategy, two neutral ^99mTc labeled 2-(1-(6-(dialkylamino)naphthalen-2-yl)ethylidene)malononitrile (DDNP) and 1-(6-(dialkylamino)naphthalen-2-yl)ethanone (ENE) derivatives, and their corresponding rhenium complexes were synthesized. In vitro fluorescent staining indicated that the corresponding rhenium derivatives selectively stained the β-amyloid (Aβ) plaques in the brain sections of AD model mice with low background. Compared with FDDNP and FENE, the affinities of the corresponding rhenium derivatives to Aβ aggregates decreased about 10-14-fold. In vivo biodistribution experiments in normal mice showed that ^99mTc-MAMA-ENE displayed medium initial brain uptake (0.65 %ID/g at 2 min) with a reasonable washout from the brain (0.19 %ID/g at 2 h) while ^99mTc-MAMA-DDNP showed a low brain uptake (0.28 %ID/g at 2 min). Further optimize these ^99mTc-labeled tracers in order to improve their binding affinities to Aβ plaques and diffusion through the blood brain barrier may generate useful imaging agents for SPECT.

Full text of DOI:10.1016/j.bmcl.2010.11.096

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1064–1068
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
99mTc- and Re-labeled 6-dialkylamino-2-naphthylethylidene derivatives
as imaging probes for b-amyloid plaques
⇑
Mengchao Cui, Ruikun Tang, Zijing Li, Huiying Ren, Boli Liu
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China
a r t i c l e i n f o
a b s t r a c t
Based on the conjugate strategy, two neutral 99mTc labeled 2-(1-(6-(dialkylamino)naphthalen-2-yl)ethyl-
idene)malononitrile (DDNP) and 1-(6-(dialkylamino)naphthalen-2-yl)ethanone (ENE) derivatives, and
their corresponding rhenium complexes were synthesized. In vitro fluorescent staining indicated that
the corresponding rhenium derivatives selectively stained the b-amyloid (Ab) plaques in the brain sec-
tions of AD model mice with low background. Compared with FDDNP and FENE, the affinities of the cor-
responding rhenium derivatives to Ab aggregates decreased about 10–14-fold. In vivo biodistribution
experiments in normal mice showed that 99mTc-MAMA-ENE displayed medium initial brain uptake
(0.65 %ID/g at 2 min) with a reasonable washout from the brain (0.19 %ID/g at 2 h) while 99mTc-
MAMA-DDNP showed a low brain uptake (0.28 %ID/g at 2 min). Further optimize these 99mTc-labeled
tracers in order to improve their binding affinities to Ab plaques and diffusion through the blood brain
barrier may generate useful imaging agents for SPECT.
Article history:
Received 3 July 2010
Revised 30 October 2010
Accepted 20 November 2010
Available online 4 December 2010
Keywords:
Alzheimer’s disease
b-Amyloid
Technium-99m
Imaging agent
Ó 2010 Elsevier Ltd. All rights reserved.
Senile plaques (SPs) composed of misfolded b-amyloid (Ab)
peptides and neurofibrillary tangles (NFTs) made of hyperphos-
phorylated tau aggregates are two of the pathological hallmarks
of AD.1,2 Development of imaging probes targeting amyloid pla-
ques or neurofibrillary tangles for positron emission tomography
(PET) and single photon emission computed tomography (SPECT)
will be crucial for early diagnosis of AD.3 Based on the structure
of Thioflavin-T and Congo red, several types of Ab imaging agents
have been synthesized and evaluated in the past decade. Some of
them have so far reached clinical stage, such as [18F]FDDNP,4–6
Two broad strategies (conjugate approach or integrated approach)
have been used in the design of 99mTc-labeled Ab imaging agents in
order not to reduce the affinity and selectivity or decrease the
brain uptake.18 Previous studies of 99mTc-labeled Congo Red and
Chrysamine G derivatives based on the conjugate strategy have
been reported.19,20 But these 99mTc complexes are both too large
and charged molecules and therefore, cannot penetrate the
blood-brain barrier (BBB). Attempts to prepare small, neutral and
more lipophilic ligands such as derivatives of benzothiazole aniline
(BTA),21–23 stilbene,24 flavone25, chaclone,26 and biphenyl27 labeled
with 99mTc have been reported (Fig. 1). A biphenyl derivative based
on the integrated strategy, showed high initial brain uptakes, with
a brain uptake up to 1.18% dose/organ at 2 min, but it failed to bind
to the Ab plaques in the postmortem human brain tissue of pa-
tients with confirmed AD.27 Through the conjugate strategy, our
group reported that 99mTc-labeled BTA derivatives using monoa-
mide–monoamine (MAMA) as the chelator, displayed high brain
uptake in normal mice (1.34 %ID/g at 2 min).28
[
[
11C]PIB,7,8
[ [ [
11C]SB-13,9,10 11C]BF-227,11 18F]AV-45,12,13 and
123I]IMPY.14–16 Although the clinical evaluations of these agents
are encouraging, 11C and 18F have their distinct features, such as
short half-life and high cost of nuclear production from cyclotron,
which decreased the potential use of these agents in clinical.
Among the medical radio-nuclides, 99mTc (T1/2 = 6 h, 140 keV) is
the most widely used radioisotope for in vivo diagnostic imaging
in SPECT with some favorable factors: it can be easily produced
from a 99Mo/99mTc generator, the medium gamma-ray energy
emitted by 99mTc (140 keV) is suitable for gamma camera detection
and the half-life is compatible with the biological localization and
residence time required for imaging.17 Thus, the successful devel-
oping of 99mTc labeled imaging agents for Ab plaques would pro-
vide a simple and widespread method for clinical diagnosis of AD
using SPECT. However, in order to introduce the transition metal
99mTc to an organic molecule, a chelating structure is obligatory.
[
18F]FDDNP and its analog [18F]FENE are two small molecules
with compact naphthalene core and high affinity for both Ab pla-
ques and neurofibrillary tangles.4 Previous reports indicated that
they bind to Ab aggregates on a distinct binding site.29 The aim
of this study was to synthesize neutral 99mTc/rhenium labeled
derivatives of FDDNP and FENE, and to evaluate their biological
characteristics.
The synthesis of the 99mTc- and Re-labeled 6-dialkylamino-
2-naphthylethylidene derivatives is outlined in Scheme 1.
Compounds 3 and 5 were obtained according to the literature
previously reported.30 Then bromination of the hydroxyl group
⇑
Corresponding author. Tel./fax: +86 010 5880 8891.
E-mail address: liuboli@bnu.edu.cn (B. Liu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.11.096

M. Cui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1064–1068
1065
tBu
N
tBu
tBu
N
N
N
N
N
HO
N
OH
Tc
NH
NaO3S
N
N
SO3Na
HOOC
O
COOH
S
Tc
N
N
O
N
N
N
S
N
N
tBu
NH2
H2N
O
O
N
S
n = 3 or 5
X = CH3 or C=O
O
N
NH2
X
N
O
O
n
N
N
O
N
S
5
Tc
O
Tc
O
S
S
S
S
H
N
O
Tc
S
S
O
Tc
N
Tc
N
S
S
N
S
O
NH
N
N
N
N
N
S
O
O
O
Figure 1. Structures of 99mTc-labeled amyloid imaging probes.
O
O
O
O
b
a
c
HO
F
O
N
e
HO
N
1
2
4
e
3
d
NC
CN
NC
CN
NC
CN
O
f
c
Br
Br
HO
F
N
N
N
N
6
7
8
5
f
NC
CN
O
O
O
HN
HN
S
S
MBz
MBz
MBz
MBz
N
N
S
S
N
N
9
10
NC
g
g
CN
O
O
HN
O
HS
HS
HN
HS
N
N
N
HS
N
11
12
i
h
i
h
NC
CN
O
O
N
O
S
O
S
N
S
M
O M
N
N
N
S
N
13a: M = Re 13b: M = 99m Tc
14a: M = Re 14b: M = 99m Tc
Scheme 1. Reagents and conditions: (a) 37% HCl, reflux; (b) CH3NHCH2CH2OH, Na2S2O5, H2O, 140 °C; (c) DAST, CH2Cl2, À78 to 0 °C; (d) CH2(CN)2, pyridine, 110 °C; (e) CH2Cl2,
NBS, PPh3, 0–25 °C; (f) acetonitrile, MAMA-MBz (p-methoxy benzyl), DIEA, reflux; (g) anisole, CH3SO3H, TFA, 0–25 °C; (h) ReOCl3(PPh3)2, CH3OH, CH2Cl2, 90 °C; (i) 99mTc-GH,
100 °C.
was performed in CH2Cl2 with NBS, giving 6 and 7 with the yields
of 79.3% and 76.7%, respectively. Then the compound 6 and 7 were
conjugated to MAMA (thiol groups were protected with p-methoxy
benzyl to prevent oxidation) in CH3CN with N,N-diisopropylethyl-
amine (DIEA) as base to generate compound 9 (yield 32.3%) and 10
(yield 25.3%). After deprotection of the thiol groups using trifluoro
acetic acid (TFA) and CH3SO3H at 0 °C, precursor 11 and 12 were
obtained with the yields of 42.0% and 57.0%, respectively.

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M. Cui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1064–1068
Table 1
Inhibition constants (Ki,
and HPLC profiles
Fluorinated compounds 4 (FENE) and 8 (FDDNP) were also ob-
tained from 3 and 5 reacted with diethylamino sulfur trifluoride
(DAST).
Rhenium complexes generally display similar physical and bio-
distributional properties to those of technetium complexes and
have been normally adopted as non-radioactive surrogates for
99mTc complexes for structure identification. In this study, the cor-
responding rhenium complexes 13a (yield 23.2%) and 14a (yield
20.4%) were obtained from 11 and 12 by reacting with
ReOCl3(PPh3)2 in CH2Cl2.
l
M) for the binding to Ab1–42 aggregates versus [125I]IMPY
Compound
Kia
(l
M)
Retention time (min)
4 (FENE)
13a
13b
8 (FDDNP)
14a
14b
0.39 0.05
3.65 0.49
n.d.
0.33 0.09
4.64 0.77
n.d.
n.d.
25.83
26.15
n.d.
24.92
25.35
a
Measured in triplicate with results given as the mean SD.
99mTc-labeled complexes 13b and 14b were prepared by ligand
exchange reaction employing the precursor 99mTc-glucoheptonate
(GH), after heating in boiling water bath for 15 min. The labeling
yields detected by radio-HPLC were higher than 95%. After purifica-
tion by HPLC, the radio-chemical purities of 13b and 14b were both
greater than 98%. They were stable in saline more than 6 h at room
temperature. The radio-chemical identities of the 99mTc labeled
tracers were verified by co-elution with the corresponding rhe-
nium complexes on HPLC profiles (See in Supplementary data).
The affinity of rhenium complexes 13a and 14a for Ab1–42
aggregates was determined by competition binding assay using
background (Fig. 3A and D). The similar pattern of Ab plaques
was also stained with Thioflavin-S using the adjacent brain sec-
tions (Fig. 3B and E). No plaques were found in control sections
(Fig. 3C and F). The results indicated that these derivatives show
specific binding to Ab plaques. Because of the similar characteris-
tics of technetium and rhenium, 99mTc-labeled complexes could
also bind to Ab plaques.
It is believed that small molecular size (<600 Da) and moderate
lipophilicity (Log P values in the range of 1–3) are two of the major
factors for BBB penetration.29,31 The partition coefficients of the
[
125I]IMPY as radio-ligand, FDDNP and FENE were also screened
using the same system for comparison. The inhibition curves
shown in Figure 2 suggest that the rhenium complexes inhibit
the binding of [125I]IMPY in a dose-dependent manner. However,
their binding affinities for Ab1–42 aggregates were relative lower
with the Ki values in the micromolar range. Under the same exper-
imental conditions FDDNP and FENE also showed low binding
affinities to Ab aggregates (Table 1). The reason may be due to
the different binding sites between IMPY and FDDNP. Compared
with FDDNP and FENE, the affinities of the corresponding rhenium
complexes to Ab aggregates decreased about 10–14-fold, which
indicate that introducing the oxorhenium core chelated by a
MAMA moiety through conjugate approach reduce the binding
affinity.
The specific nature of rhenium complexes 13a and 14a to Ab
plaques was investigated by neuropathological staining with the
brain sections of a 12-month-old AD transgenic model (Tg-C57),
which encoded a double mutant form of APP and PS1. Many Ab
plaques were clearly stained by these compounds with low
Figure 3. Inhibition curves of 4, 8, 13a and 14a for the binding to aggregates of
Ab1–42 versus [125I]IMPY.
Figure 2. Fluorescent staining of 13a (A) and 14a (D) on the brain slices (5 lm) of a AD transgenic model (APP/PS1) and wild control (C and F). Plaques were also confirmed by
the staining of the adjacent sections with Thioflavin-S (B and E).

M. Cui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1064–1068
1067
Table 2
Biodistribution experiments of 13b and 14b in normal micea
Tissue
Time after injection (min)
30
2
10
60
120
13b Log D = 1.89 0.04
Blood
Heart
Liver
Spleen
Lung
5.81 0.95
6.88 1.03
9.31 0.96
2.78 0.41
8.27 2.03
6.56 0.63
0.65 0.09
2.55 0.81
2.07 0.19
2.85 0.25
13.85 1.25
2.51 0.3
3.17 0.13
4.12 0.62
0.44 0.02
1.64 0.27
1.22 0.38
1.35 0.4
3.84 0.56
12.49 1.85
2.98 0.36
4.31 0.48
4.67 0.71
0.60 0.04
2.26 0.52
12.79 2.97
2.13 0.21
2.66 0.4
3.66 0.52
0.36 0.06
8.63 2.09
1.21 0.23
1.50 0.34
2.24 0.53
0.19 0.03
Kidney
Brain
14b Log D = 1.70 0.02
Blood
Heart
Liver
Spleen
Lung
6.35 0.59
10.77 1.1
18.31 3.23
3.57 0.44
10.59 1.74
11.01 1.88
0.28 0.03
2.43 0.39
5.47 0.43
21.12 3.83
3.21 0.35
4.67 0.85
8.56 0.84
0.21 0.02
1.71 0.31
2.94 0.46
16.95 1.89
2.34 0.29
3.24 0.43
5.93 0.87
0.17 0.03
1.14 0.13
1.86 0.29
15.48 3.63
1.50 0.23
2.29 0.31
4.18 0.47
0.12 0.02
0.73 0.08
1.25 0.3
13.9 3.61
1.08 0.23
1.47 0.21
3.14 0.74
0.10 0.04
Kidney
Brain
a
All data are expressed as the mean percentage (n = 4) of the injected dose per gram of wet tissue (%ID/g) the standard deviation of the mean.
radiotracers were determined using a described procedure,32 Log D
values of 13b and 14b were 1.70 0.02 and 1.89 0.04, respec-
tively, which are in a good range for BBB penetration. As their
molecular weight does not exceed 600 Da, 13b and 14b are ex-
pected to pass through the BBB and show better brain uptake.
In vivo biodistribution experiment was carried out on ICR nor-
viding the Paraffin-embedded brain sections of Tg-C57 mouse
and Dr. Xiaoyan Zhang (College of Life Science, Beijing Normal Uni-
versity) for assistance in the in vitro neuropathological staining.
This work was funded by NSFC (20871021).
Supplementary data
mal mice (weight 18–22 g). A saline solution (100
lL) containing
Supplementary data (procedure for the preparation of 99mTc-
and Re-labeled DDNP derivatives, in vitro binding assay, fluores-
cent staining and biodistribution experiments) associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2010.11.096.
7
l
Ci purified radiotracer was injected directly into the tail vein.
The mice were sacrificed at various time points after intravenous
administration. The biodistribution data are shown in Table 2.
Complex 13b displayed a medium initial brain uptake (0.65 %ID/g
at 2 min pi) and a reasonable washout of the radioactivity from
the brain (0.19 %ID/g at 2 h pi) while 14b showed a low brain up-
take (0.28 %ID/g at 2 min). Although the lipophilicity of 13b and
14b was in a moderate range and their molecular weight did not
exceed the threshold of 600 Da, they cannot cross the BBB to a suf-
ficient degree, since the brain uptake was also dependent on other
factors, such as hydrogen bonding, percentage of intact tracer
in vivo, etc. Compared with that of the 99mTc-labeled BTA reported
by our group,28 the initial brain uptake of these 99mTc-labeled
DDNP derivatives appears insufficient for in vivo imaging. There-
fore, further optimizations are needed to improve the pharmacoki-
netics of these 99mTc-labeled DDNP derivatives in vivo.
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