[18F]-labeled isoindol-1-one and isoindol-1,3-dione derivatives as potential PET imaging agents for detection of β-amyloid fibrils

Article abstract of DOI:10.1016/j.bmcl.2008.05.019

In this study a novel series of isoindol-1-one and isoindol-1,3-dione derivatives for β-amyloid-specific binding agents is described. Twelve compounds were synthesized and evaluated via a competitive binding assay with [¹²⁵I]TZDM against β-amyl

Full text of DOI:10.1016/j.bmcl.2008.05.019

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5701–5704
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
[18F]-labeled isoindol-1-one and isoindol-1,3-dione derivatives as potential
PET imaging agents for detection of b-amyloid fibrils
Ji Hoon Lee a,b, Seong Rim Byeon a, YoungSoo Kim a, Soo Jeong Lim c, Seung Jun Oh c, Dae Hyuk Moon c,
a,
Kyung Ho Yoo a, Bong Young Chung b, , Dong Jin Kim
*
*
a Center for Chemoinformatics Research, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea
b Department of Chemistry, Korea University, Anam-dong, Seongbuk-Gu, Seoul 136-701, South Korea
c Asan Medical Center, Department of Nuclear Medicine, 388-1, Pungnap-2-Dong, Songpa-Gu, Seoul 138-736, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study a novel series of isoindol-1-one and isoindol-1,3-dione derivatives for b-amyloid-specific
binding agents is described. Twelve compounds were synthesized and evaluated via a competitive bind-
ing assay with [125I]TZDM against b-amyloid 1–42 (Ab42) aggregates. Two new [18F]-labeled isoindole
derivatives were synthesized and evaluated as potential b-amyloid imaging probes based on the
in vivo pharmacokinetic profiles. The preliminary results suggest that these [18F]18b and [18F]18c are
promising positron emission tomography (PET) imaging probes for studying accumulation of Ab fibrils
in the brains of Alzheimer’s disease (AD) patients.
Received 3 December 2007
Revised 9 April 2008
Accepted 3 May 2008
Available online 7 May 2008
Keywords:
Alzheimer’s Disease
Ó 2008 Elsevier Ltd. All rights reserved.
[
18F]-labeled
PET
Imaging probe
Alzheimer’s disease (AD) is a neurodegenerative brain disorder
Recently, successful preliminary reports using a [11C]-labeled
benzothiazole derivative, N-methyl-[11C]2-(40-methylaminophe-
nyl)-6-hydroxybenzothiazole ([11C]PIB),8,9 for plaque visualization
in AD patients have demonstrated the potential utility of the
in vivo imaging research. However, the short half-life (t1/
2 = 20 min) of 11C may limit the use of [11C]PIB for a wide variety
of clinical applications. A [18F]-labeled derivative of naphthalene,
2-(1-{6-[(2-[18F]fluoroethyl)(methyl) amino]-2-naphthyl}ethyli-
dene)malononitrile ([18F]FDDNP), has been reported previously to
bind SPs and NFTs in the brains of AD patients.10,11 However,
accompanying progressive memory loss and decline of cognitive
functions. At present, clinical diagnosis of AD is performed via
mental status tests, physical exam, diagnostic tests, neurological
exam, and brain imaging. Brain imaging technologies utilize the
verifying presence of b-amyloid (Ab) peptide plaques and neurofi-
brillary tangles (NFTs) formed by tau proteins in the post-mortem
brain tissue.1–3 Accumulation of Ab plaques in the AD brain is be-
lieved to be one of the most significant factors associated with the
molecular etiology of the disease.4 Therefore, development of Ab
plaque-specific binding agents for direct marking of Ab aggregates
in the living brain is a highly active research area in recent years
and such technique is urgently desired for early diagnosis and
monitoring of AD progress. In addition, an increasing focus on early
identification and prevention highlights a need for non-invasive
tools and robust biological markers. However, yet the diagnosis
of this disease based on neurological observations is often difficult
and unreliable.
NC
CN
11CH3
NH
HO
S
N
18F
N
11
[
C]PIB
18
[
F]FDDNP
Several research groups have reported biomarkers to visualize
Ab plaques in AD brains. Such Ab-aggregate-specific radio-labeled
imaging probes, using positron emission tomography (PET), are
needed for pre-symptomatic detection or monitoring of the pro-
gression and effectiveness of AD treatments (Fig. 1).5–7
O
N
O
O
OH
R2
N
18F
O
[
[
18F]18b R2=NHCH3
18F]18c R2=N(CH3)2
Indoprofen
* Corresponding authors. Tel.: +82 2 958 5142; fax: +82 2 958 5189 (D.J.K.).
E-mail address: djk2991@kist.re.kr (D.J. Kim).
Figure 1. Structures of PIB, FDDNP, Indoprofen, [18F]18b, and [18F]18c.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.019

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J. H. Lee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5701–5704
pounds were evaluated by competitive binding assays against Ab
O
aggregates using [125I]TZDM.
N
R2
Syntheses of 2,3-dihydroisoindol-1-one derivatives are outlined
in Scheme 1. The first step of 2-bromomethyl-4-methoxybenzoic
acid ethyl ester 4 was achieved with N-bromosuccinimide and 2-
methyl-4-methoxybenzoic acid via esterification and bromination.
2,3-Dihydroisoindol-1-one compound 5 was readily prepared from
compound 4 and 4-nitroaniline.21 Synthesis of 5-methoxy-2-(4-
aminophenyl)isoindol-1,3-dione 10 was performed as described
in Scheme 2.
Phthalic acid 7 upon a reaction with thionyl chloride in the
presence of 1,4-diazabicyclo[2.2.0]octane gave phthalic anhydride
8, which was then treated with 4-nitroaniline to afford the corre-
sponding 9.
R1
X
18a~f, 19a~f
18a : X=CH2, R1= O(CH2)2F, R2=NH2
18b : X=CH2, R1= O(CH2)2F, R2=NHCH3
19a : X=CO, R1= O(CH2)2F, R2=NH2
19b : X=CO, R1= O(CH2)2F, R2=NHCH3
18c : X=CH2, R1= O(CH2)2F, R2=N(CH3)2 19c : X=CO, R1= O(CH2)2F, R2=N(CH3)2
18d : X=CH2, R1= O(CH2)3F, R2=NH2
18e : X=CH2, R1= O(CH2)3F, R2=NHCH3
18f : X=CH2, R1= O(CH2)3F, R2=N(CH3)2
19d : X=CO, R1= O(CH2)3F, R2=NH2
19e : X=CO, R1= O(CH2)3F, R2=NHCH3
19f : X=CO, R1= O(CH2)3F, R2=N(CH3)2
Figure 2. Structures of 18a–f and 19a–f.
The free amino derivatives, 6 and 10 were prepared from the ni-
tro compounds 5 and 9 via reduction with SnCl2. Conversion of 6 to
the monomethylamino derivative 11 was achieved via a method
previously reported reductive amination.22–24 6 and 10 were also
converted to dimethylamino derivatives, compounds 13 and 14,
via an efficient method with paraformaldehyde, sodium cyano-
borohydride and acetic acid. The monomethylamino compound
12 was achieved via alkylation with iodomethane. The O-methyl
groups were demethylated by reacting with BBr3 to give 15a–c
and 16a–c. Compounds 15b and 15c were alkylated with ethylene
glycol di-p-tosylate to give the tosylethyl precursors 17b and 17c.
The fluorinated compounds 18a–f32 and 19a–f were prepared
from 15a–c and 16a–c by a nucleophilic substitution reaction with
1-fluoro-2-tosyloxyethane or 1-fluoro-3-tosyloxypropane (Scheme
3).25 To make the desired [18F]-labeled [18F]18b and [18F]18c, the
tosylates 17b and 17c were employed as precursors (Scheme 4),
and each tosylate was mixed with [18F]TBAF in CH3CN/t-amyl alco-
hol and heated to 120 °C for 10 min.26
FDDNP has some disadvantage in practical use due to its consider-
able amount of non-specific binding in normal brain tissue.12 There
have been several previous attempts generating [18F]-labeled
radioligands, such as [18F]FPPIP,13 18F]FEM-IMPY,14 18F]FPEG-stil-
[ [
bene15 and [18F]FPEGN3-styrylpyridine,16 but, unfortunately, most
of them displayed low-binding affinities to Ab plaques. Our focus is
to develop [18F]-labeled plaque-specific imaging agents utilizing
the benefit of 18F allowing use of radioligands over a long period
of time due to its longer half-life (t1/2 = 110 min), along with a suf-
ficient blood–brain barrier (BBB) penetration property to reach Ab
plaques. The radio-labeled imaging agents should also have ade-
quate affinity toward the target and show rapid clearance of free
and non-specific bound compounds from the brain. We have
worked to develop Ab fibril-binding agents which have indoprofen
moiety as non-steroidal anti-inflammatory drugs (NSAIDs), of
which analogues were associated with delaying the formation of
Ab fibril caused by their good binding affinity to Ab.17–20 Therefore,
we have focused our efforts on the development of [18F]-labeled
imaging probes containing indoprofen moiety (Fig. 2).
Specific binding affinities of synthesized compounds to Ab42 fi-
brils were evaluated by an in vitro fibril-binding assay. The in vitro
competition binding assay using pre-formed Ab42 aggregates
In the beginning, we designed fluoroethyl- and fluoropropyl-
substituted 18a–f and 19a–f compounds. All the synthesized com-
O
O
O
i
ii
OH
OCH2CH3
OCH2CH3
Br
H3CO
H3CO
H3CO
O
2
3
4
O
iii
iv
N
NO2
N
NH2
H3CO
H3CO
5
6
Scheme 1. Reagent and reaction conditions: (i) SOCl2, EtOH, reflux, 4 h, 98%; (ii) N-bromosuccinimide, CCl4, reflux, 6 h, 49%; (iii) 4-nitroaniline, acetic acid, reflux, 12 h, 50%;
(iv) SnCl2, EtOH, reflux, 3 h, 95%.
O
O
O
O
i
ii
OH
OH
N
NO2
O
H3CO
H3CO
H3CO
O
O
7
8
9
O
ii
N
NH2
H3CO
O
10
Scheme 2. Reagents and reaction conditions: (i) 1,4-diazabicyclo[2.2.2]octane, SOCl2, CH2Cl2, 0 °C–rt, 1 h, 78%; (ii) 4-nitroaniline, acetic acid, reflux, 12 h, 92%; (iv) SnCl2,
EtOH, reflux, 3 h, 95%.

J. H. Lee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5701–5704
5703
O
O
O
i
N
NH2
N
NH
N
R2
TsO
H3CO
H3CO
O
6
11
17b : R2=NHCH3
17c : R2=N(CH3)2
iv
iv
v
ii
iv
O
O
O
vi
R2
N
X
R2
n
N
N
N
X
X
H3CO
HO
F
O
15a: X=CH2, R2=NH2
16a: X=CO, R2=NH2
13 : X=CH2
14 : X=CO
n=2, 3
18a~f, 19a~f
15b: X=CH2, R2=NHCH3 16b: X=CO, R2=NHCH3
15c: X=CH2, R2=N(CH3)2 16c: X=CO, R2=N(CH3)2
ii
O
iv
O
iii
N
NH2
N
NH
H3CO
H3CO
O
O
12
10
Scheme 3. Syntheses of 18a–f and 19a–f. Reagent and reaction conditions: (i) p-formaldehyde, NaOMe, MeOH/THF, NaBH4, reflux, 3 h; (ii) p-formaldehyde, NaBH3CN, acetic
acid, rt, 12 h; (iii) CH3I, K2CO3, DMSO, 100 °C, 5 h, 36%; (iv) BBr3, CH2Cl2, reflux, 12 h 58–68%; (v) ethylene glycol di-p-tosylate, K2CO3, DMF, 90 °C, 2 h, 75%; (vi) 1-fluoro-2-
tosyloxyethane or 1-fluoro-3-tosyloxypropane, K2CO3, DMF, 90 °C, 2 h, 68–90%.
[
18F]TBAF
CH3CN
O
O
N
R2
N
R2
TsO
18F
t-amyl alcohol
120°C, 10 min
O
O
17b : R2=NHCH3
17c : R2=N(CH3)2
[
[
18F]18b : R2=NHCH3
18F]18c : R2=N(CH3)2
Scheme 4. Radiosynthesis of [18F]18b and [18F]18c.
demonstrated that 18a–f and 19a–f competed against radioligands
such as [125I]TZDM.27–29
higher binding affinities (Ki = 0.30 nM) so that 18c with 18b (sec-
ondary amine), for its closest structural similarity to 18c (tertiary
amine), was chosen to measure brain pharmacokinetic profiles.
In vivo biodistribution and micro-PET studies showed favorable
characteristics (Table 2). The novel [18F]-labeled compounds, both
N-monomethyl, [18F]18b, and N,N-dimethyl, [18F]18c, tested in nor-
mal mice and exhibited excellent brain penetrations (9.1% and 11.1%
ID/g at maximum peaked post-injection for [18F]18b and [18F]18c,
respectively). The clearance rate test of these compounds displayed
rapid washout (3.0% and 3.7% ID/g at 30-min post-injection for
The results shown in Table 1 demonstrated that most of the
synthesized compounds displayed lower Ki values (Ki = 0.30–
0.91 nM) than PIB. In structure-activity relationship, isoindol-1-
one derivatives, 18a–f, showed slightly higher binding affinities
than isoindol-1,3-dione derivatives, 19a–f. Among the isoindol
derivatives evaluated, it is evident that compound 18c displayed
[
18F]18b and [18F]18c, respectively). Therefore, the ratio peak/
Table 1
Ki values of 18a–f and 19a–f against
aggregates
[
125I]TZDM for binding affinities to Ab42
Kia (nM)
Table 2
Compound
Biodistributions of [18F]18b and [18F]18c after iv injection in normal mouse (% ID/g)
18a
18b
18c
18d
18e
18f
19a
19b
19c
19d
19e
19f
PIB
0.61
0.91
0.30
0.40
0.51
0.71
0.59
0.60
0.69
0.74
0.78
0.85
0.77
Compound
Peakmax
30 min
60 min
120 min
[
18F]18b
Cerebrum
Cerebellum
Bone
9.1
11.0
4.9
13.3
3.1
3.0
3.3
4.1
3.0
2.9
5.0
3.3
3.4
4.8
2.6
2.0
3.1
3.2
3.0
6.6
2.5
2.3
2.5
Lung
Soft tissue
Liver
18.1
[
18F]18c
Cerebrum
Cerebellum
Bone
Lung
Soft tissue
11.1
14.4
8.2
18.1
3.1
3.7
3.7
4.3
3.2
3.3
3.9
3.9
5.1
2.9
3.0
3.7
3.8
6.0
2.8
2.6
a
Ki was calculated by the Cheng–Prusoff equation (Ki = IC50/(1+[L]/Kd))30 using
Graphpad Prism software.

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J. H. Lee et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5701–5704
17. Lee, H. J.; Lim, S. J.; Oh, S. J.; Moon, D. H.; Kim, D. J.; Tae, J. S.; Yoo, K. H. Bioorg.
Med. Chem. Lett. 2008, 18, 1628.
30 min in the normal brain is 3.0, which means that within 30 min
over 50% radioligand not bound to Ab aggregates is cleared out in
the brain and which is believed to be a promising pharmacokinetic
property for early detection of amyloid plaques in the AD brain.31
In conclusion, a series of novel fluoroethyl- and fluoropropyl-
substituted compounds were successfully synthesized and these
isoindole derivatives displayed excellent binding affinities to Ab
aggregates. Two new [18F]-labeled isoindole derivatives were syn-
thesized and evaluated as potential Ab imaging probes based on
in vivo pharmacokinetic profiles using micro-PET. In addition, they
displayed high initial brain uptake and rapid washout from brains
after injection in normal mice. The combination of high-binding
affinities to Ab fibrils, high brain uptake, and excellent clearance
of [18F]-labeled compounds provides a series of potential probe
candidates for PET imaging to diagnose accumulation of Ab aggre-
gate in AD patients.
18. Agdeppa, E. D.; Kepe, V.; Petric, A.; Satyamurthy, N.; Liu, J.; Huang, S.-C.; Small,
G. W.; Cole, G. M.; Barrio, J. R. Neuroscience 2003, 117, 723.
19. in t’ Veld, B. A.; Ruitenberg, A.; Hofman, A.; Launer, L. J.; Van Duijn, C. M.;
Stijnen, T.; Breteler, M. M. B.; Stricker, B. H. C. N. Engl. J. Med. 2001, 345, 1515.
20. Rogers, J.; Kirby, L. C.; Hempelman, S. R.; Berry, D. L.; McGeer, P. L.; Kaszniak, A.
W.; Zalinski, J.; Cofield, M.; Mansukhani, L.; Willson, P.; Kogan, F. Neurology
1993, 43, 1609.
21. Prasad, C. S. N.; Varala, R.; Adapa, S. R. Heterocycl. Commun. 2002, 8, 281.
22. Lee, J. H.; Byeon, S. R.; Lim, S. J.; Oh, S. J.; Moon, D. H.; Yoo, K. H.; Chung, B. Y.;
Kim, D. J. Bioorg. Med. Chem. Lett. 2008, 18, 1534.
23. Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709.
24. Ono, M.; Kung, M.-P.; Hou, C.; Kung, H. F. Nucl. Med Biol. 2002, 29, 633.
25. 1-Fluoro-2-tosyloxyethane and 1-fluoro-3-tosyloxypropane were purchased
from FutureChem Co., Ltd.
26.
[
18F]fluoride was produced from a cyclotron (IBA Cyclone 18/9, Belgium) and
eluted with a solution of 20
lL tetra-butylammonium bicarbonate (TBAHCO3),
300 L of H2O, and 300
l
l
L of CH3CN after collection of [18F]fluoride on a PS–
HCO3 cartridge (Macherey-Nagel, Germany). The solvent was removed under a
stream of nitrogen at 120 °C and the residue was azeotropically dried with
anhydrous CH3CN (3ꢀ 500
18F]fluoride and then added 10 mg of precursor, 50
t-amyl alcohol. Reaction time and temperature for [18F]fluorination was 10 min
at 120 °C. We checked
18F]fluorination yield with radio thin-layer
l
L) at 120 °C under nitrogen stream. We dried
[
l
L of CH3CN, and 500 L of
l
Acknowledgments
[
chromatography (radio-TLC) using EtOH/ethyl acetate, 1:1 as developing
solvent. After [18F]fluorination, we removed solvent and diluted with 1.0 mL
CH3CN and filtered to syringe filter. The residue was injected to HPLC for
purification [C8 apollo (250 mm, 10 mm), CH3CN/5 mM dimethylglutaric acid;
flow rate 4 mL/min]. After product was diluted with 20 mL water, it was passed
through the C18 Sep-Pak. (Waters, USA) The product was trapped and eluted
with 0.5 mL of EtOH.
We are grateful to the Ministry of Science and Technology
(MOST) and Ministry of Commerce, Industry and Energy (MCIE)
of Korea for financial support.
References and notes
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29. We estimated Kd value (0.13 nM) of [125I]TZDM for Ab42 aggregates. For
inhibition studies, The reaction mixture contained 50
(11.5 nM in the final concn), 50
L of inhibitors (10ꢁ6–10ꢁ12 M in DMSO), 50
of [125I]TZDM (in 40% EtOH, 0.05 nM in the final concn) and 10% EtOH in a final
volume of 1 mL. Non-specific binding was defined by adding 2 M Th-T for
125I]TZDM binding. The mixture was incubated at room temperature for 3 h
lL of Ab42 aggregates
l
lL
l
[
and the bound and the free radioactivity were separated by a vacuum filtration
through Whatman GF/B filters using a Brandel M-24R cell harvester followed
by 2ꢀ 3 mL washes of 10% EtOH at room temperature. Filters containing the
bound radioligand were counted in a gamma-counter (Cobra-II). The result of
inhibition assays were subjected to nonlinear regression analysis using
software Graphpad Prism by Ki values was calculated.
30. Cheng, Y.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099.
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32. Selected data 18b: 1H NMR (DMSO-d6, 300 MHz) d 2.68 (d, J = 4.7 Hz, 3H), 4.35
(dt, J = 3.4, 29.9 Hz, 2H), 4.77 (dt, J = 3.5, 40.1 Hz, 2H), 5.59 (m, NH), 6.58 (d,
J = 8.2 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.64
(d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6, d) 29.92, 50.73, 67.42, 67.61,
81.18, 82.84, 108.38, 111.55, 115.36, 121.54, 124.34, 125.71, 128.47, 143.24,
147.01, 161.20, 165.66; HRMS m/z Calcd for C17H17FN2O2 (M)+ 300.1274, found
300.1265. Compound 18c: 1H NMR (DMSO-d6, 300 MHz) d 2.88 (s, 6H), 4.34 (dt,
J = 3.4, 30.1 Hz, 2H), 4.78 (dt, J = 3.5, 49.1 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 7.09
(dd, J = 1.9, 8.5 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.68 (d,
J = 8.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6, d) 30.67, 50.54, 67.38, 67.63,
80.90, 83.10, 108.37, 112.63, 115.39, 120.99, 124.40, 125.62, 129.21, 143.25,
147.51, 161.26, 165.76; HRMS m/z Calcd for C18H19FN2O2 (M)+ 314.1431, found
314.1431.
15. Zhang, W.; Oya, S.; Kung, M.-P.; Hou, C.; Maier, D. L.; Kung, H. F. Nucl. Med Biol.
2005, 32, 799.
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