Design and synthesis of new theranostic agents for near-infrared imaging of β-amyloid plaques and inhibition of β-amyloid aggregation in Alzheimer's disease

Article abstract of DOI:10.1016/j.dyepig.2017.07.071

The presence of amyloid plaques predisposes clinical symptoms of cognitive impairment, which occurs much earlier than other clinical symptoms and plays a crucial role in the neuropathology of AD. Thus, developing probes for Aβ species imaging could be used for early diagnosis of AD, and blocking the initial steps of Aβ aggregation with small molecules has emerged as a valid disease-modifying therapy for Aβ. Herein, we report the design, synthesis and evaluation of a series of new theranostic agents, which can simultaneously perform near infra-red imaging of Aβ plaques, prevent self-aggregation of Aβ monomer, disaggregate preformed Aβ fibrils and play a protective effect on the toxicity of human neuroblastoma cells (SHSY5Y) induced by Aβ_1–42. Most of these probes displayed maximum emission in PBS (>650 nm), which falls in the good range for NIRF probes. Importantly, these probes are found to have a high binding affinity toward Aβ aggregates, to exhibit a large fluorescence enhancement upon interaction with Aβ aggregates accompanied by a blueshift in the emission spectra of 20–40 nm and to show an excellent targeting ability for Aβ plaques in slices of brain and eye containing retina tissue from double transgenic mice. These molecules show a promising potential as theranostic agents for the diagnosis and therapy of AD.

Full text of DOI:10.1016/j.dyepig.2017.07.071

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Accepted Manuscript
Design and synthesis of new theranostic agents for near-infrared imaging of β-
amyloid plaques and inhibition of β-amyloid aggregation in Alzheimer's disease
Pascal Dao, Feifei Ye, Zhi Yun Du, Qian Chen, Kun Zhang, Chang Zhi Dong, Bernard
Meunier, Huixiong Chen
PII:
S0143-7208(17)31013-6
10.1016/j.dyepig.2017.07.071
DYPI 6160
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 3 May 2017
Revised Date: 2 July 2017
Accepted Date: 31 July 2017
Please cite this article as: Dao P, Ye F, Du ZY, Chen Q, Zhang K, Dong CZ, Meunier B, Chen H,
Design and synthesis of new theranostic agents for near-infrared imaging of β-amyloid plaques and
inhibition of β-amyloid aggregation in Alzheimer's disease, Dyes and Pigments (2017), doi: 10.1016/
j.dyepig.2017.07.071.
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
Design and synthesis of new theranostic agents for near-infrared imaging of
β-amyloid plaques and inhibition of β-amyloid aggregation in Alzheimer's
disease
Pascal Dao1, Feifei Ye1, Zhi Yun Du1, Qian Chen1, Kun Zhang1, Chang Zhi Dong1,3, Bernard
Meunier1,4, Huixiong Chen1,2,
*
1. Faculty of Light Industry and Chemical Engineering, Guang Dong University of Technology, Guang Dong,
510006, China;
2. CNRS, UMR8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CBNIT,
Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 75006 Paris, France;
3. Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 75013 Paris, France
;
4. Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex, France.
* Corresponding author: Huixiong Chen, UFR Biomédicale, Université Paris Descartes, Tel: (+33)142864085,
Email: huixiong.chen@parisdescartes.fr
Abstract: The presence of amyloid plaques predisposes clinical symptoms of cognitive
impairment, which occurs much earlier than other clinical symptoms and plays a crucial role in the
neuropathology of AD. Thus, developing probes for Aβ species imaging could be used for early
diagnosis of AD, and blocking the initial steps of Aβ aggregation with small molecules has emerged as
a valid disease-modifying therapy for Aβ. Herein, we report the design, synthesis and evaluation of a
series of new theranostic agents, which can simultaneously perform near infra-red imaging of A
β
plaques, prevent self-aggregation of A monomer, disaggregate preformed A fibrils and play a
β
β
protective effect on the toxicity of human neuroblastoma cells (SHSY5Y) induced by Aβ1–42. Most of
these probes displayed maximum emission in PBS (> 650 nm), which falls in the good range for NIRF
probes. Importantly, these probes are found to have a high binding affinity toward A
β aggregates, to
exhibit a large fluorescence enhancement upon interaction with A aggregates accompanied by a
β
blueshift in the emission spectra of 20-40 nm and to show an excellent targeting ability for Aβ plaques
in slices of brain and eye containing retina tissue from double transgenic mice. These molecules show
a promising potential as theranostic agents for the diagnosis and therapy of AD.
Keywords: Alzheimer’s disease, Beta-amyloid, Cytotoxicity, NIRF imaging, Inhibitors,
Theranostic agents
1. Introduction
Alzheimer’s disease (AD), a complex neurodegenerative process is the most common
form of dementia characterized by neuronal loss, progressive cognitive decline, loss of self-
care abilities, and eventual death. One of the main pathological hallmarks is the formation and
1

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accumulation of β-amyloid (Aβ) plaques in the brain, which is thought to play a vital role in
AD onset and appears to be good diagnostic and predictive biomarker for this disease [1–3].
The most common Aβ peptide found in senile plaques is Aβ1-42, which also shows the
strongest propensity for spontaneous aggregation in solution [4-5]. Aβ can aggregate into
insoluble amyloid fibrils through a number of intermediate structural forms such as soluble
oligomers or protofibrils [6,7]. All these Aβ species may differentially affect neuronal
function and viability in vitro and in vivo [8,9]. In particular, Aβ oligomers can directly
induce synaptic dysfunction and neuronal death in the cerebral cortex, involved in memory
and cognition [10–12] and trigger events such as oxidative damage, inflammation and calcium
deregulation [13–15], which are responsible for AD initiation and progression. The soluble
Aβ oligomers can also result in tau hyperphosphorylation, leading to disruption of the
microtubule skeleton and neuritic degeneration [16]. The presence of amyloid plaques
predisposes clinical symptoms of cognitive impairment, which occurs much earlier than other
clinical symptoms and plays a crucial role in initiating AD neuropathology and in directly
damaging the brain [17,18], suggesting that these abnormal brain deposits participate in
events leading to the clinical presentation of dementia [19]. Despite much work devoted to the
elucidation this process, the Aβ fibrillization pathway is still not completely clear.
Thus, tremendous effort has been expended in recently years on developing small
molecules as inhibitors of Aβ aggregation [20,21]. Unfortunately, no compounds to halt or
reverse the progression of such devastating disease have entered into clinical use to date. The
failure of many drug candidates might be attributed to their administration at a late stage,
when the pathology is too advanced and too much irreversible damage has been done. In this
context, the development of appropriate biomarkers for early diagnosis and disease
monitoring appears to be important for an efficacious therapy, although it is very challenging.
Molecular theranostics is referred to as a treatment strategy that combines therapeutics
with diagnostics, aiming to monitor the response to treatment and increase drug efficacy and
safety, which would be a key part of personalized medicine. By combining molecular imaging
with molecular therapy, the field of theranostics could be applied in many aspects of
personalized treatment, such as early detection of disease, disease staging, recognizing
adverse effects at early stages of the treatment and a tailored treatment based on the diagnostic
and imaging results, thereby providing more specific and efficient systems for the curing of
disease. Moreover, several distinct advantages are attractive for the intrinsic ability to confer
2