Synthesis and in vitro evaluation of imidazo[1,2- b ]pyridazines as ligands for β-amyloid plaques

Article abstract of DOI:10.1021/ml100005j

A series of imidazo[1,2-b]pyridazine derivatives were synthesized and evaluated for binding to amyloid plaques in vitro using synthetic aggregates of Aβ_1?40. Binding affinities of these compounds were found to range from 11.0 to >1000 nM, depending on the various substitution patterns in the 6-position and 2-position. 2-(4′-Dimethylaminophenyl)-6- (methylthio)imidazo[1,2-b]pyridazine (4) showed high binding affinity (K _i = 11.0 nM) and might be useful for the development of novel positron emission tomography radiotracers for imaging Aβ plaques.

Full text of DOI:10.1021/ml100005j

pubs.acs.org/acsmedchemlett
Synthesis and In Vitro Evaluation of Imidazo[1,2-b]-
pyridazines as Ligands for β-Amyloid Plaques
Fanxing Zeng,† David Alagille,§ Gilles D. Tamagnan,§ Brian J. Ciliax,‡ Allan I. Levey,‡ and
Mark M. Goodman*,†
†Department of Radiology and ‡Center for Neurodegenerative Disease and Department of Neurology, Emory University,
Atlanta, Georgia 30322, and §Institute for Degenerative Disorders, New Haven, Connecticut 06510
ABSTRACT A series of imidazo[1,2-b]pyridazine derivatives were synthesized and
evaluated for binding to amyloid plaques in vitro using synthetic aggregates of
Aβ1-40. Binding affinities of these compounds were found to range from 11.0
to >1000 nM, depending on the various substitution patterns in the 6-position and
2-position. 2-(40-Dimethylaminophenyl)-6-(methylthio)imidazo[1,2-b]pyridazine
(4) showed high binding affinity (Ki = 11.0 nM) and might be useful for the
development of novel positron emission tomography radiotracers for imaging Aβ
plaques.
KEYWORDS Imidazo[1,2-b]pyridazine, β-amyloid plaque, structure-activity rela-
tionship, positron emission tomography
lzheimer's disease (AD) is a common cause of de-
mentia, which is clinically characterized by progres-
sive loss of memory and decline of cognitive function.
vivo imaging agents for Aβ plaque deposition in the living
human brain (Figure 1).
A
In an attempt to develop more effective amyloid-specific
imaging agents, we have chosen to investigate a novel series
of imidazo[1,2-b]pyridazine derivatives. Imidazo[1,2-b]-
pyridazines are designed to be isosteric analogues of IMPY,
of which CH adjacent to N on the six-membered heterocyclic
ring was replaced with N. We reasoned that substitution of
aryl CH by an imino group might be effective in reducing
ligand lipophilicity, thus reducing ligand nonspecific binding.
Additionally, an appropriately substituted pyridazine ring
lends itself well to easy attachment of different groups via
heteroaromatic nucleophilic displacement reaction. We re-
port here the synthesis and in vitro evaluation of imidazo-
[1,2-b]pyridazines as potential imaging agents for detecting
Aβ plaques.
The synthesis of imidazo[1,2-b]pyridazine derivatives is
shown in Schemes 1 and 2. In all cases, the formation
of imidazo[1,2-b]pyridazine backbone was accomplished
through a condensation reaction between an R-bromoke-
tone and a 3-amino-6-halopyridazine under a mild basic
condition such as sodium bicarbonate. In fact, the successful
formation of imidazo[1,2-b]pyridazine rings in good yield
was due to the introduction of a halogen in the pyridazine
ring. In 3-aminopyridazine, the ring nitrogen that is not
adjacent to the amino group is the most nucleophilic. Thus,
alkylation by the R-bromoketone takes place preferentially
The neuropathologic signature of AD generally revealed on
postmortem brain examination is the massive deposit of β-
amyloid plaques (Aβ) and neurofibrillary tangles (NFTs).1-3
Therefore, amyloid-specific imaging agents would likely
prove useful to identify and follow individuals at risk for
AD and to assist in evaluating the efficacy of new therapeutic
approaches that act early on the neurodegenerative progress
and inhibit the accumulation of amyloid plaques and
NFTs.4-7
The development of amyloid-specific imaging agents is
generally based on conjugated dyes, such as Congo red,
Chrysamine G, and thioflavin-T, which have been used in
fluorescent staining of plaques and tangles in postmortem
AD brain sections. Several radioligands for positron emission
tomography (PET) and single photon emission computerized
tomography (SPECT), including [11 C]PIB (Pittsburgh compound
B),8-10 [11C]SB-13 (4-N-methylamino-40-hydroxystilbene),11
[11C]AZD2184 (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothia-
zol-6-ol),12 [18F]FDDNP (2-(1-{6-[(2-fluoroethyl)-(methyl)ami-
no]-2-naphthyl}ethylidene)malononitrile),13,14 [18F]GE067 (2-
(30-fluoro-40-(methylamino)phenyl)-6-hydroxybenzothiazole),15
[
18F]BAY94-9172 (4-(N-methylamino)-40-(2-(2-(2-fluoroetho-
xy)ethoxy)ethoxy)stilbene),16 [18F]AV-45 ((E)-4-(2-(6-(2-(2-
(2-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl
benzenamine),17,18 and [123I]IMPY (2-(40-dimethylamino-
phenyl)-6-iodoimidazo[1,2-a]pyridine),19 have been tested
in clinical trials and demonstrated the potential utility as in
Received Date: January 7, 2010
Accepted Date: February 28, 2010
Published on Web Date: March 11, 2010
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Figure 1. Radioligands for Aβ plaque imaging with PETand SPECT in clinical trials.
at this site, hampering an effective synthesis of the desired
bicyclic product. This was overcome by placing a halogen in
the ring, adjacent to the offending nitrogen, thus greatly
reducing the nucleophilicity of this nitrogen and returning
the preferential site of alkylation to the ring nitrogen adja-
cent to the amino function.
6-substituted-2-phenylimidazo[1,2-b]pyridazines, is outlined
in Scheme 2. R-Bromoketone 15 was prepared by R-bromi-
nation of 1-(5-(dimethylamino)pyridin-2-yl)ethanone with
pyridinium tribromide. R-Bromoketone 17 was prepared
by bromination of 2-acetyl-5-nitrothiophene with copper(I)
bromide.24
The synthesis of 6-substituted-2-phenylimidazo[1,2-b]-
pyridazines is shown in Scheme 1. 3-Amino-6-chloropyri-
dazine20 and 3-amino-6-fluoropyridazine21 were pre-
pared from 3,6-dichloro- and 3,6-difluoropyridazine by
reaction with aqueous ammonia at 130 °C, respectively.
While 3-amino-6-iodopyridazine could also be prepared
from 3,6-diiodopyridazine using the same method, the
yield was very low, and 3,6-diaminopyridazine was the
major product. Alternatively, 3-amino-6-iodopyridazine
was obtained in 81% yield by refluxing 3-amino-6-chloro-
pyridazine in 57% HI solution.22 R-Bromoketone 1 was
prepared from 40-dimethylaminoacetophenone through
dibromination and debromination procedures reported
previously.23 Nucleophilic substitution of the 6-chloro
derivative 2b by methoxide, thiomethoxide, and deproto-
nated fluoroethanol, fluoropropanol, 2-mercaptoethanol,
and 3-mercaptopropanol afforded 3-8 in good to excel-
lent yields. 2-Fluoroethylthio and 3-fluoropropylthio com-
pounds (9 and 10) were obtained by the treatment of 7 and
8 with DAST, respectively.
The free amino derivatives, 12a-c, were readily prepared
from 11a-c by reduction with SnCl2. Conversion of 12a and
12c to their N-methylamino derivatives was achieved by a
selective monomethylation reaction using sodium methox-
ide and paraformaldehyde, followed by a reduction reaction
with NaBH4. However, the 6-chloro group of 12b was also
converted to methoxyl group under the same condition
to give 13b as the only product. Alternatively, 14 was
prepared by methylation by MeI in the present of K2CO3,
while dimethylation product 2b was also observed in this
reaction.
In vitro binding affinity of imidazo[1,2-b]pyridazines for
Aβ plaques was determined via the binding competition with
[3H]BTA-1 (2-(40-(dimethylamino)phenyl)benzothiazole) using
synthetic aggregates of Aβ1-40. IMPY and PIB were also
screened under the same assay system for comparison.
Initially, we prepared 6-halogen N,N-dimethylamino, N-
methylamino, and primary amino analogues. Comparison
of the Ki values (Table 1) reveals that the tertiary amino
analogues typically have a higher affinity than their second-
ary amino analogues (2a vs 13a, 2b vs 14, and 2c vs 13c), in
accord with the previous data on the tertiary and secondary
amino analogues of IMPY,25 while the corresponding pri-
mary amino analogues show a much lower affinity. There-
fore, we decided to focus our efforts on tertiary analogues
and synthesized several 6-substituent N,N-dimethylamino
analogues. The 6-iodo N,N-dimethylamino analogue has a
higher affinity than the 6-chloro or 6-fluoro analogue, and
this trend was repeated in the corresponding secondary
amino and primary amino analogues (2c vs 2b vs 2a, 12c
vs 12b, and 13c vs 14 vs 13a). This indicates that the size and
electronegativity of the halogen atom presumably influence
the binding of these ligands. Substitution of aryl CH of IMPY
by an imino group as in 2c is effective in reducing ligand
lipophilicity (compare cLog P value with that of IMPY) but
slightly reduced binding affinity. The 6-methylthio analogue
(4) shows a higher affinity over the 6-methoxyl analogue (3).
Incorporation of ω-fluoroethyl or ω-fluoropropyl group, as
reflected in 5, 6, 9, and 10, decreases binding affinity. To
further study the structure-activity relationship (SAR) of
imidazo[1,2-b]pyridazines, we synthesized 16a, 16b, 16c,
20a, and 20b with the replacement of phenyl ring with
pyridinyl or thiophenyl ring. Unfortunately, these ligands
show significantly reduced binding affinity, indicating that
the phenyl ring might be required to retain high binding
The synthesis of 6-halogen-2-pyridinylimidazo[1,2-b]pyri-
dazines and 6-halogen-2-thiophenylimidazo[1,2-b]pyrida-
zines, based on the similar method shown above for
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Scheme 1a
a Reagents and conditions: (a) EtOH, reflux, 2 h; NaHCO3, reflux, 5 h, 52-81%. (b) NaOCH3, EtOH, reflux, 18 h, 62%. (c) NaSCH3, EtOH, reflux, 18 h,
78%. (d) FCH2CH2OH, Bu4NOH, DMF, room temperature, 18 h, 54%. (e) FCH2CH2CH2OH, Bu4NOH, DMF, room temperature, 48 h, 44%. (f)
HOCH2CH2SH, Bu4NOH, DMF, room temperature, 1 h, 83%. (g) DAST, CH2Cl2, -78 °C to room temperature, 1 h, 21%. (h) HOCH2CH2CH2SH, Bu4NOH,
DMF, room temperature, 1 h, 86%. (i) SnCl2 2H2O, EtOH, reflux, 2 h, 54-61%. (j) NaOMe, CH3OH, (CH2OH)n, NaBH4, reflux, 3 h, 42-57%. (k) MeI,
3
K2CO3, DMSO, 100 °C, 16 h, 24%.
affinity. Among all of the ligands tested, the 6-methylthio
analogue (4), which exhibits a high binding affinity (Ki =
11.0 nM) comparable to the values for PIB and IMPY, might
be of interest for evaluation as a prospective PETradioligand
if labeled with carbon-11 in N-methyl or S-methyl position.
Four is also expected to have a higher target-to-background
ratio for plaque labeling of an AD brain with regard to its
reduced lipophilicity, as compared to IMPY and its deriva-
tives. It is interesting to mention that the 6-methylthio IMPY
derivative was reported to have a low retention to Aβ in AD
patients.26
In summary, we have synthesized a series of imidazo-
[1,2-b]pyridazines with various substitution patterns in the
6-position and 2-position. The SAR studies of these com-
pounds with regard to Aβ showed that 2-N,N-dimethyl-
aminophenyl moiety might be a requirement for these
compounds to exhibit desirable binding affinities. The Ki
values of 2-dimethylaminophenyl imidazo[1,2-b]pyrida-
zines with different substituents in the 6-position range
from 10 to 50 nM, indicating moderate tolerance for
modification at this location. The 6-methylthio analogue
(4) exhibited high binding to Aβ plaques in vitro and might
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Scheme 2a
Table 1. Inhibition Constant (Ki Values) of Imidazo[1,2-b]pyri-
dazines for Binding Synthetic Amyloid Plaques Aβ 1-40
ligand
R1
R2
R3
Ar
Ki (nM)a
cLog Pb
2a
F
Cl
I
CH3 CH3 phenyl
CH3 CH3 phenyl
CH3 CH3 phenyl
CH3 CH3 phenyl
CH3 CH3 phenyl
41.4 ( 1.8
34.2 ( 1.2
18.4 ( 0.4
18.3 ( 3.3
11.0 ( 1.2
32.0 ( 1.8
47.5 ( 1.8
35.5 ( 9.9
38.8 ( 1.2
470 ( 10
3.00
3.57
3.98
3.06
3.54
3.32
3.54
3.80
4.03
1.68
2.66
2.42
3.40
2.99
2.24
2.81
3.22
2.93
3.50
3.99
4.91
2b
2c
3
OCH3
SCH3
4
5
O(CH2)2F CH3 CH3 phenyl
O(CH2)3F CH3 CH3 phenyl
S(CH2)2F CH3 CH3 phenyl
S(CH2)3F CH3 CH3 phenyl
6
9
10
12b
12c
13a
13c
14
Cl
I
H
H
H
H
H
H
phenyl
phenyl
phenyl
phenyl
phenyl
H
280 ( 46
F
CH3
CH3
CH3
91.4 ( 4.2
34.0 ( 1.1
78.8 ( 2.5
I
Cl
F
a Reagents and conditions: (a) HBr, pyridinium tribromide, HOAc,
40 °C, 18 h, 37%. (b) EtOH, reflux, 2 h; NaHCO3, reflux, 5 h,
16a
16b
16c
20a
20b
PIB
IMPY
CH3 CH3 pyridinyl
CH3 CH3 pyridinyl
CH3 CH3 pyridinyl
CH3 CH3 thiophenyl
CH3 CH3 thiophenyl
>1000
41-56%. (c) CuBr, EtOAc, reflux, 18 h, 60%. (d) SnCl2 2H2O, EtOH,
Cl
I
280 ( 6
233 ( 6
3
concentrated HCl, 0 °C to room temperature, 1 h, 57%. (e) MeI, NaH,
DMSO, room temperature, 1 h, 22%.
F
550 ( 23
336 ( 11
11.0 ( 0.2
9.0 ( 0.9
Cl
be interest for evaluation as a prospective PET radioligand
if labeled with carbon-11 in the N-methyl or S-methyl
position.
a Measured in at least three independent experiments, each per-
formed in triplicate with results given as the mean ( SD. b Calculated in
ChemDraw Ultra 11 (CambridgeSoft, Cambridge, MA).
SUPPORTING INFORMATION AVAILABLE Procedure for
the preparation of new ligands, analytical data, and in vitro binding
assay. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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ABBREVIATIONS AD, Alzheimer's disease; Aβ, β-amyloid
plaques; NFTs, neurofibrillary tangles; PET, positron emission
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