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RSC
Medicinal Chemistry
REVIEW
Cite this: RSC Med. Chem.,2023,14,
2231
Received 13th July 2023,
Accepted 11th September 2023
DOI: 10.1039/d3md00330b
rsc.li/medchem
Recent progress of small-molecule-based
theranostic agents in Alzheimer's disease
Furong Gao, Jiefang Chen, Yuancun Zhou, Letong Cheng,
Ming Hu and Xiaohui Wang *
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. As a multifactorial
disease, AD involves several etiopathogenic mechanisms, in which multiple pathological factors are
interconnected with each other. This complicated and unclear pathogenesis makes AD lack effective
diagnosis and treatment. Theranostics, exerting the synergistic effect of diagnostic and therapeutic
functions, would provide a promising strategy for exploring AD pathogenesis and developing drugs for
combating AD. With the efforts in small drug-like molecules for both diagnosis and treatment of AD, small-
molecule-based theranostic agents have attracted significant attention owing to their facile synthesis, high
biocompatibility and reproducibility, and easy clearance from the body through the excretion systems. In
this review, the small-molecule-based theranostic agents reported in the literature for anti-AD are classified
into four groups according to their diagnostic modalities. Their design rationales, chemical structures, and
working mechanisms for theranostics are summarized. Finally, the opportunities for small-molecule-based
theranostic agents in AD are also proposed.
Introduction
Alzheimer's disease (AD), one of the most common types of
neurodegenerative diseases, gradually destroys memory,
thinking, behavior and social skills.
1
It is the leading cause of
dementia and the fifth-leading cause of death in older
individuals (aged ≥65 years). The global number of AD
patients is growing as the elderly population rises,
and it will exceed 150 million by 2050,
2
resulting in massive
demand for medication to postpone the illness's start and
ameliorate its symptoms. However, the drug development for
AD treatment is very difficult due to the complicated and
unclear pathogenesis of the disease. Up to the year 2018, only
a few drugs (e.g., tacrine, donepezil, rivastigmine,
galantamine, and memantine) have been approved by the US
Food and Drug Administration (FDA) to ameliorate the
symptoms of AD.
3
With unceasing efforts, advances in
therapy have been achieved in very recent years. Notably, GV-
971 (sodium oligomannate) has become the first drug
approved for treatment of AD since 2003. It was approved by
China's National Medical Products Administration (NMPA) for
improvement of cognition in patients with mild-to-moderate
AD dementia in 2019.
4,5
The USA FDA approved two anti-
amyloid monoclonal antibodies, aducanumab and
lecanemab, for disease-modifying therapy of AD in 2021 and
2023, respectively.
6–8
However, these recent approvals are
fraught with controversy due to the safety concerns associated
with these antibodies. For example, they may weaken the
blood vessels to worsen the brain bleeding.
9
On the other
hand, the optimal time window for early treatment is elusive,
due to the lack of timely and accurate diagnosis. Moreover,
the diagnostic agents and drugs are usually pursued
separately in the traditional approaches, which is time-
consuming and unfavorable to prove the clinical efficacy of
new drugs. Therefore, the development of effective strategies
is still needed to fight this devastating disease.
Theranostics, combining diagnostic and therapeutic
capabilities into a single agent, is a promising strategy that
has exhibited the ability to assess therapy efficacy in real-
time with improved biodistribution and minimum side
effects, leading to personalized medicine.
10,11
Since its first
definition in 1998, theranostics has gained remarkable
development in the management of various diseases.
12–14
As
for AD, theranostics would also have the potential to
positively address the challenges mentioned above. Over the
past few years, a large number of theranostic systems have
been reported for anti-AD.
3,15–17
Among them, nanosystem-
based theranostics (nanotheranostics) are the main types in
the literature, probably due to the general characteristics of
nanosystems, including easy multifunctionalization for
achieving diagnostics and therapeutics against various
RSC Med. Chem., 2023, 14, 2231–2245 | 2231This journal is © The Royal Society of Chemistry 2023
Institute of Chemical Biology and Functional Molecules, State Key Laboratory of
Materials-Oriented Chemical Engineering, School of Chemistry and Molecular
Engineering, Nanjing Tech University, Nanjing 211816, P. R. China.
E-mail: wangxhui@njtech.edu.cn
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pathological factors of AD simultaneously, and the potential
to cross the blood–brain barrier (BBB).
15
Nevertheless, most
of the AD nanotheranostics remain at the laboratory level
and confront many challenges for clinical translation. By
comparison, small-molecule-based theranostic agents have
attracted more attention owing to their facile synthesis, high
biocompatibility and reproducibility, and easy clearance from
the body through the excretion systems, with significant
advances in small drug-like molecules for both diagnosis and
treatment of AD.
18–21
To date, a variety of small-molecule-
based theranostic agents have been developed to
concomitantly detect the biomarkers and hit the pathological
targets. Different diagnostic modalities have been employed
to guide the treatment, including fluorometry, luminometry,
positron emission tomography (PET), and magnetic
resonance imaging (MRI).
In this review, we will focus on the developments of small-
molecule-based theranostics in AD. We attempt to cover the
representative works in this field. The small-molecule-based
theranostic agents are classified into fluorescence-guided
theranostic agents, luminescence-guided theranostic agents,
PET-guided theranostic agents, and MRI-guided theranostic
agents, according to the diagnostic modalities. Their design
rationales, chemical structures, and working mechanisms for
theranostics are described. The challenges and perspectives
for future development are also proposed.
Design principles of small-molecule-
based theranostic agents in AD
Given the combination of diagnostics and therapeutics in
theranostics, the ideal targets of the small-molecule-based
theranostic agents in AD would act as both biomarkers and
neuropathological factors of the disease. Currently, the most
accepted biomarkers of AD are amyloid-βpeptides (Aβ) and
hyperphosphorylated tau proteins (ptau), which can
aggregate into amyloid plaques and neurofibrillary tangles,
respectively, which are the major hallmarks of AD.
22
Quantitation of Aβor ptau in the brain, cerebrospinal fluid
(CSF) or plasma through in vivo imaging or in vitro detection
can provide valuable information for AD diagnosis.
23–28
On
the other hand, as a multifactorial disease, AD is believed to
be caused by a combination of genetic, environmental,
ageing, and lifestyle factors. Although the exact pathogenesis
of AD is not fully understood, multiple pathological factors
are tightly involved in the onset and development of the
disease, such as amyloid aggregation, metal dyshomeostasis,
oxidative stress, inflammation, and mitochondrial
dysfunction.
29
Several hypotheses have been proposed to
explain the pathological roles of these factors.
15,30
Among
them, amyloid cascade hypothesis, the most widely accepted
one, postulates that Aβaggregation is the causative factor,
which triggers a series of neurodegenerative cascade to
induce AD by neurotoxic Aβaggregates.
31
Accordingly, Aβ
aggregates, especially oligomers (the most toxic Aβspecies)
and fibrils, have been considered as drug targets for AD
treatment.
7
Similar to Aβ, ptau would be another potential
target according to the tau hypothesis, which states that the
aggregation of ptau can lead to AD through destroying
neuronal functions.
19,32,33
Therefore, Aβand ptau aggregates
as both biomarkers and pathological factors can be potential
targets for the design of small-molecule-based theranostic
agents. In fact, most of the reported small-molecule-based
theranostic agents for anti-AD have directed to Aβ. Besides
the targets, BBB permeability, biocompatibility, and toxicity
are also important parameters for the design of theranostic
agents in AD.
From the examples already reported, there are typically
two main rational strategies to construct small-molecule-
based theranostic agents: linking and fusing (Fig. 1). In the
first strategy, a linker group connects the sensing and
therapeutic moieties. Typically, scaffolds of probes and
medications with promise for AD diagnosis and therapy
are incorporated, which would encourage a synergistic
action of the two moieties. The therapeutic target and
biomarker can be the same species (I) or different ones (II).
However, this strategy is also more likely to produce agents
with high molecular weight, which would have poor BBB
permeability. In the second strategy, a probe and a drug
share a single structural framework that commonly interacts
with the species as both the therapeutic target and the
biomarker. This strategy is more likely to construct low
molecular weight agents with better drug-likeness.
Fluorescence-guided theranostic
agents
Fluorescence probes could be excellent candidates as
theranostic agents for anti-AD, due to the important merits
of fluorescence in biomarker sensing, such as simple
operation, high sensitivity, and availability in real-time
tracking.
34
Notably, near-infrared (NIR) fluorescence,
including the first NIR window (NIR-I, 650–900 nm) and the
second NIR window (NIR-II, 1000–1700 nm), is suitable for
in vivo bioimaging in imaging-guided theranostics, owing to
its inherent advantages in minimizing tissue absorption,
photon scattering, and autofluorescence.
35
To date, most of
the AD theranostic agents have been derived from
fluorescence probes of pathological factors.
20,36,37
In this
section, the reported fluorescence-guided theranostic agents
were classified into five categories according to their
structural characteristic: cyanine derivatives, phenothiazine
Fig. 1 Design strategies of small-molecule-based theranostic agents.
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derivatives, fluorescent chelators, aggregation-induced
emission luminogens (AIEgens), and others.
Cyanine derivatives
SLOH is one of the first examples of cyanine fluorophore-
based theranostic agents that can image Aβfibrils and
inhibit Aβfibrillogenesis (Fig. 2).
38
SLOH was designed by
modification of the cyanine moiety with a quinolinium
group. The fluorophore exhibited high binding affinity to Aβ
fibrils with significant fluorescence enhancement (∼82 fold)
centered at 638 nm, attributed to the large reduction in the
non-radiative decay of the photo-excited cyanine group due to
a restricted rotation upon binding to the β-sheet conformer
of fibrils. SLOH can pass through the BBB and visualize Aβ
plaques in the brain slices of 6-month-old transgenic mice
after tail vein injection. On the other hand, the agent also
showed a neuroprotective effect against Aβ40-induced
cytotoxicity towards SH-SY5Y cells owing to its inhibitory
effect on Aβfibril growth. Recent studies showed that SLOH
can attenuate AD-related neuropathology, e.g.,Aβdeposition,
tau levels and its hyperphosphorylation, by modulating
protein kinase B (AKT) and promoting protein 2A activity in 3
×Tg AD mice of 4-month-old.
39
The treatment of SLOH can
also improve cognitive ability and reverse synaptic deficit by
regulation of the Ca
2+
-dependent CaMKII/CREB signaling
pathway in younger AD mice. Although the analog SLM
showed weaker fluorescence enhancement for Aβfibrils than
SLOH,
38
the longer emission centered at 650 nm and higher
binding affinity to Aβfibrils make the SLM more suitable for
testing in vivo. The treatment of triple transgenic AD mice
with SLM showed a substantial decrease in both Aβ
oligomers and tau proteins in the cerebral hippocampal
region of the brain.
40
As a result, significant recovery of
cognitive decline was observed in those SLM-treated AD mice.
Moreover, SLM successfully performed NIR imaging of Aβ
species in AD mice in vivo, demonstrating its good
theranostic potential for AD.
To further shift the emission to the NIR region and
enhance the inhibitory effect on Aβaggregation, the same
group developed a series of SLOH derivatives adopting the
donor–π–acceptor (D–π–A) structural motifs with emission
maxima in the range of 650–700 nm.
41
Thereinto, DBA-SLOH
showed the highest binding affinity to Aβ40 species with
remarkable fluorescence enhancement (Fig. 2), due to the
incorporation of lipophilic alkyl chains with moderate length
into the charged skeleton. Such a structural feature also
endows DBA-SLOH with excellent BBB permeability and
biocompatibility. Based on these properties, DBA-SLOH
exhibited strong ability to simultaneously image Aβspecies/
plaques in APP/PS1 transgenic mice in vivo and prevent Aβ
from aggregation and forming toxic oligomers. Another
derivative DBAN-SLM was obtained as a theranostic agent by
employing the dibutyl-2-naphthylamine group as the
donating moiety to replace the aniline group (Fig. 2),
42
which
exhibited higher binding selectivity for Aβoligomers and
monomers than fibrils with fluorescence enhancement and
bathochromic shift of emission in the NIR window.
Fig. 2 Chemical structures of SLOH and its derivatives.
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Consequently, it was applied for NIR imaging of Aβin AD
mice in vivo. The probe can also inhibit Aβaggregation and
suppress Aβ-induced generation of reactive oxygen species
(ROS), thereby detoxifying Aβ-induced toxicity in SH-SY5Y
cells.
An oligomer-targeting theranostic agent F-SLOH was
designed through decorating a fluorine group to the cyanine
lead structure of SLOH (Fig. 2).
43
The fluorine group would
facilitate the higher binding affinity of F-SLOH to oligomers
than monomers and fibrils through intermolecular CH⋯F
interactions, combining with hydrophobic and
intermolecular CH⋯O interactions between F-SLOH and Aβ
oligomers. Accordingly, F-SLOH gave off a stronger
fluorescence increase upon incubation with oligomers
compared to incubation with monomers and fibrils. The
selectivity of F-SLOH toward Aβoligomers in the brain were
further verified by fluorescence imaging ex vivo and in vivo.
F-SLOH can detect Aβoligomers in the transgenic mice at the
young age of 7 months with good BBB penetrability,
indicating its potential for early diagnosis of AD. Similar to
SLOH, the non-toxic F-SLOH can also prevent Aβ-induced
toxicities through inhibiting Aβoligomerization and
fibrillation. Recently, the in vivo therapeutic efficacy of F-
SLOH was investigated in 5XFAD and 3XTg-AD mice.
44
F-
SLOH can bind to Aβaggregates and inhibit the formation of
oligomers and plaques. Importantly, the F-SLOH-treated mice
demonstrated a decreased level of toxic Aβoligomers and
plaques, probably resulting from the activation of
transcription factor EB that subsequently promotes an
autophagy lysosomal degradation pathway and lysosomal
biogenesis. In addition, the levels of amyloid precursor
protein and tau aggregates were also reduced by the same
pathway as that for Aβclearance. Consequently, F-SLOH can
alleviate neuro-inflammation and mitigate synaptic deficits
in the preclinical AD mouse models with significantly
improved learning and spatial memory, highlighting its
potential for therapeutics of AD.
Very recently, a multifunctional theranostic carbazole-
based cyanine SLCOOH was designed by modification of
SLOH with a carboxyl group on the quinolinium ring (Fig. 2).
45
Similar to SLOH,SLCOOH exhibited Aβ-selective
fluorescence enhancement, which can be used to monitor Aβ
contents in different age groups of Tg AD mice through real-
time imaging. Interestingly, SLCOOH can also treat multiple
AD-related pathologies simultaneously to exert multiple
therapeutic benefits in young 3XTg-AD mice (Fig. 3),
including mitigation of cognitive impairment with alleviation
of Aβand tau neuropathologies and amelioration of synaptic
loss and dysfunction with a reduced load of intercellular Ca
2+
by activating the Ca
2+
-dependent CaMKII/CREB signaling
pathway and modulating the balance of NMDARs,
highlighting its theranostic potential for early AD.
A series of cyanine-based D–π–A photosensitizers (QM20–
QM22) were reported as NIR photooxygenation theranostic
Fig. 3 (A) In vivo fluorescence brain imaging of SLCOOH for Aβplaques in 5XFAD Tg mice. The multiple therapeutic benefits of SLCOOH on
synapses (B), tau levels (C), and dendritic spines (D).
45
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agents for simultaneously mapping and modulating Aβ
aggregation (Fig. 4).
46
They were composed of a quinolinium
scaffold as the electron acceptor, a dimethylaniline group as
the electron donor, and vinyl groups with different length as
π-bridges. The authors believed that the binding of the
photosensitizers with Aβaggregates would turn on their NIR
fluorescence and promote the production of singlet oxygen
through the inhibition of intramolecular rotation of the
structure and twisted-intramolecular charge transfer (TICT)
process. Experiments validated that all the photosensitizers
exhibited excellent selectivity for Aβfibrils with fluorescence
enhancement against the other Aβspecies and proteins.
Among them, QM21 showed the best detection performance
with a maximum increase in both fluorescence emission and
quantum yield. Inspired by these findings, QM21 was
employed to investigate its theranostic potential toward Aβ
aggregates. QM21 can not only stain Aβfibrils in the brain
slices of APP/PSI mice, but also inhibit Aβaggregation and
disaggregate the preformed Aβaggregates via
photooxygenation under laser irradiation. Furthermore, the
photooxygenated Aβaggregates were more degradable by the
phagocytosis of BV2 microglial cells. The QM21-induced
photooxygenation of Aβaggregates can efficiently decrease
the Aβ-induced cytotoxicity toward PC12 cells.
Phenothiazine derivatives
4a1 (Fig. 5), the first phenothiazine-based theranostic agent,
was reported to act both as an inhibitor of Aβaggregation
and as an NIR fluorescence imaging probe for Aβplaques in
AD.
47
It showed a significant fluorescence increase upon
binding to Aβ42 aggregates with high affinity (K
d
= 7.5 nM),
which can be used to stain the Aβplaques in the brain and
eye slices in vitro. Additionally, it also exhibited an inhibitory
effect on Aβaggregation and disaggregated preformed Aβ
fibrils. To improve the theranostic activity, the same group
Fig. 4 (A) Chemical structures of QM20–QM22. (B) Fluorescence imaging of QM20–QM22 for Aβfibrils in the brain slices of APP/PSI mice.
Adapted with permission from ref. 46. Copyright 2022 American Chemical Society.
Fig. 5 (A) Chemical structures of 4a1,5a1, and 4. (B) Inhibition of Aβ42 aggregation followed by fluorescence imaging using 4a1. Adapted with
permission from ref. 47. Copyright 2017 American Chemical Society.
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designed a series of phenothiazine-based NIR fluorophores
through adjusting the length of the vinyl moiety and the
substituents of the thioxothiazolidinone group.
48
As a
representative, 5a1 exhibited better fluorescence performance
than 4a1 toward Aβaggregates (Fig. 5), which can even be
used to monitor its inhibitory effect on Aβaggregation.
However, the poor solubility of the above-mentioned
phenothiazine-based fluorophores limits their applicability
in vivo. Thus, the authors further optimize the structure
through introducing water solubilizing groups into the
thioxothiazolidinone framework.
49
As a result, the compound
4can penetrate the BBB and label Aβplaques in the brain of
12-month-old double transgenic mice (C57BL/6, APP/PS1)
in vivo. It can also prevent the formation of toxic oligomers
and attenuate the toxicity of Aβaggregation in SHSY5Y cells.
Fluorescent chelators
The pathogenic roles of metal ions (e.g., copper, zinc, and
iron) in AD have been widely recognized.
50,51
They can
coordinate with Aβand accelerate Aβaggregation. In
addition, copper and iron as redox active metals can also
induce Aβ-mediated ROS production, thereby leading to
oxidative stress. In this regard, metal chelators would be
valuable to reduce metal-induced Aβaggregation, ROS
generation, and neurotoxicity through capturing metal ions
from metal-bound Aβspecies.
52
Therefore, fluorescent
chelators that integrate fluorescence sensing and metal
chelating functions into one scaffold would be potential
theranostic agents for anti-AD.
Thioflavin T (ThT), a commonly used fluorescent probe
for monitoring amyloid fibril assembly, provides an excellent
starting framework for developing Aβ-targeting
fluorophores.
53
Accordingly, several fluorescent chelators
have been constructed for AD theranostics by linking the
metal-chelating groups with ThT derivatives. Two
bifunctional chelators L1 and L2 that contain metal-binding
N-(2-pyridylmethy)amine groups, Aβ-interacting
2-phenylbenzothiazole, and o-vanillin molecular fragments
were designed for probing Aβand controlling metal-
mediated Aβ42 aggregation (Fig. 6).
54
Both of them exhibited
high binding affinity to Cu and Zn ions and Aβfibrils. L1 can
give off increased fluorescence upon binding to fibrils.
Moreover, L1 and L2 were able to inhibit and disaggregate
Aβ42 aggregation both in the absence and presence of Cu
2+
or Zn
2+
. Owing to their strong chelating ability, they can also
efficiently reduce the production of H
2
O
2
for Cu–Aβ42
species. However, L2 led to an increased cytotoxicity in
Neuro2A cells in the presence of Cu
2+
and Aβ42, probably
due to the formation of toxic Aβ42 oligomers resulting from
the ability of L2 to inhibit fibril formation and promote fibril
disaggregation.
Our group reported a ThT-derivated fluorescent chelator
TBT as the first dual-functional probe and disaggregator for
self-monitoring the disassembly of Zn
2+
-orCu
2+
-associated
Aβaggregates by fluorescence (Fig. 6).
55
TBT consists of a
metal-chelating 1,4,7,10-tetraazacyclododecane (cyclen) group
and 2-phenylbenzothiazole group. TBT can give sensitive
fluorescence responses for both Zn
2+
and Cu
2+
with high
selectivity against other relevant biological metal ions. In
addition, TBT exhibited higher binding affinity to Zn
2+
–or
Cu
2+
–Aβaggregates than to Aβself-aggregates. Disaggregation
experiments validated that TBT can specifically disassemble
Zn
2+
-orCu
2+
-induced Aβ40 aggregates over metal-free
aggregates through capturing the Aβ-bound metal ions. Based
on this property, TBT can detoxify the neurotoxicity of metal–
Aβaggregates in PC12 cells. Importantly, the fluorescence of
TBT changed simultaneously, correlating with the reduced
degree of metal-induced Aβaggregation, which can be used
for self-monitoring the disaggregation in the brain
homogenates of AD mice, indicating its theranostic potential
for anti-AD. To improve the selectivity toward Cu
2+
-associated
Aβaggregation, we further synthesized another fluorescent
chelator BTTA by extending the distance between cyclen and
2-phenylbenzothiazole (Fig. 6),
56
thereby offering a high
selectivity of fluorescence response for Cu
2+
. As expected,
BTTA can selectively recognize Cu
2+
via decreased
fluorescence without interference from other metal ions
including Zn
2+
, the most abundant metal ion in Aβ
aggregates. Similar to TBT,BTTA can attenuate Cu
2+
-induced
Aβaggregation and detoxify Cu
2+
–Aβ-induced neurotoxicity in
PC12 cells owing to its ability to capture Cu
2+
from Cu
2+
–Aβ
aggregates. It also showed theranostic potential through self-
monitoring disaggregation of Cu
2+
–Aβaggregates by its
Fig. 6 Chemical structures of ThT and ThT-derived fluorescent chelators.
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synchronous fluorescence response. In contrast, no
fluorescence response and attenuation effect of BTTA were
observed for metal-free Aβaggregation. Moreover, BTTA can
fluorescently stain Aβaggregates from the brain of AD mice
with good BBB permeability.
A ThT-derivated fluorescent chelator BPB was also
reported as a β-sheet-targeted theranostic agent for
diagnosing and preventing Aβaggregation (Fig. 6).
57
It was
obtained by merging two ThT analogs 2-phenylbenzothiazole
and 2-(phenoxymethyl)-1H-benzoimidazole with the
capabilities of targeting the β-sheet and chelating metal ions.
BPB showed significant fluorescence enhancement with
different modes for Aβ40 and Aβ42. It can also stain Aβ
plaques in the brain with efficient BBB penetration. On the
other hand, BPB exhibited an inhibitory effect on metal-
induced and -free Aβaggregation and ROS generation in
buffer. It can also disassemble Aβaggregates from the brain
homogenates of 7-month-old APPswe transgenic mice.
Furthermore, BPB was less toxic to the PC12 cells, but can
reduce the neurotoxicity induced by metal–Aβ40 or Aβ40
alone.
Curcumin has exhibited high Aβ-binding affinity due to
its conjugated structure and exerted therapeutic potential for
AD in many studies.
58
On the basis of the scaffold of
curcumin, a series of difluoroboronate-modified curcumin
derivatives CRANAD have been designed and developed as
NIR fluorescence probes for Aβspecies over the past
decade.
37
A CRANAD compound CRANAD-17 was reported as
a fluorescent chelator that can attenuate the cross-linking of
Aβ42 induced by the coordination of Cu
2+
with imidazoles on
H13 and H14 of Aβ(Fig. 7).
59
To achieve the Cu
2+
-chelating
function, two imidazole rings were decorated onto the
benzene groups to form two monodentate moieties for metal
ions. Thus, CRANAD-17 was expected to chelate Cu
2+
with
minimal disruption of brain metal homeostasis. Fluorescence
spectroscopic studies showed that the fluorescence of
CRANAD-17 increased with a blue-shift in response to Aβ
binding. Depending on the competition with copper
coordination at the H13 position, CRANAD-17 showed
significantly higher capacity for attenuating Cu
2+
-induced
Aβ42 cross-linking than curcumin and its CRANAD analogs.
To overcome the low quantum yield (QY) limitation of
curcumin derivatives, CRANAD-28 was designed by
employing metal-chelating pyrazole groups with phenyl
substitution at their N-1 position (Fig. 7),
60
which could
improve the QY due to the reduction of tautomerization of
pyrazole. Although CRANAD-28 demonstrated the decreased
fluorescence upon binding to Aβspecies, it can still be used
for two-photon imaging of Aβplaques in 9-month-old APP/
PS1mice in vivo thanks to its high QY. Additionally, similar to
CRANAD-17,CRANAD-28 could also inhibit the cross-linking
of Aβinduced by copper, indicating its potential in AD
theranostics.
Some fluorescent chelators were designed by fusing the
fluorophores with metal-chelating acylhydrazone groups.
61–63
For example, a turn-on copper probe FI contains two
fluorophores, i.e., indole-3-carboxaldehyde and ring-closed
fluorescein, and an acylhydrazone group as a linker (Fig. 7).
61
The coordination of FI with Cu
2+
can induce fluorescein ring-
opening, subsequently resulting in a Förster resonance
energy transfer (FRET) between indole and xanthene
moieties, which turns on the fluorescence of ring-opened
fluorescein. Moreover, FI showed high selectivity and
sensitivity for Cu
2+
. Based on these features, FI was next used
to interact with Cu
2+
-induced Aβaggregates. The results
indicated that FI was able to chelate Cu
2+
from Cu
2+
–Aβ40
aggregates, leading to the fluorescence enhancement of FI
and disruption of the copper-induced Aβaggregates. An
anthracene-derived probe 1can selectively chelate Cu
2+
through coordination between the acylhydrazone group and
Cu
2+
(Fig. 7).
63
As a result, the fluorescence of 1was
quenched due to the decrease of intramolecular charge
transfer and paramagnetic nature of Cu
2+
. It can also inhibit
self-and Cu
2+
-induced Aβ42 aggregation with good capacities
of anti-oxidation.
AIEgens
AIEgens are usually not emissive or weakly emissive in the
dissolved state in solution, but emit strongly in the
aggregated state or solid state.
64
This feature makes AIEgens
suitable for amyloid recognition, avoiding the aggregation-
caused quenching (ACQ) effect of traditional fluorescence
probes when gathered on the amyloid aggregates.
65,66
In
addition, the higher degree of the aggregation of amyloid
proteins would yield stronger fluorescence of the AIEgens
with high signal-to-noise ratios and quantum yields.
67
Fig. 7 Chemical structures of CRAND-17,CRAND-28,FI, and 1.
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Reasonably, AIEgens have exhibited large potential for AD
theranosis, especially through targeting Aβ.
A multifunctional AIE-active probe Cur-N-BF
2
was
constructed for both detection and modulation of Aβfibrils
(Fig. 8).
68
The probe showed decreased emission with
increasing water fraction in the THF/water mixture due to its
strong donor–acceptor structural features and the TICT
effect, but enhanced emission with increasing viscosity of
media, implying its AIE properties. When Cur-N-BF
2
was co-
incubated with Aβfibrils, the fluorescence of the probe
increased with longer incubation time. In addition, Cur-N-
BF
2
can only give off strong fluorescence for fibrils even at
high concentrations. This selective response ability of Cur-N-
BF
2
for fibrils made the probe capable of staining Aβplaques
in the brain slices from plaque-rich APPswe/PSEN1dE9
transgenic mice. On the other hand, the probe also exhibited
therapeutic potential through inhibiting Aβfibrillation and
disaggregating preformed fibrils.
A cyanine-derived NIR AIEgen DNTPH was designed
through balancing hydrophobic and hydrophilic moieties to
yield appropriate lipophilicity for high BBB permeability
(Fig. 8).
69
In the structure of DNTPH, a lipophilic thiophene-
bridge was employed to enhance the intramolecular charge
transfer (ICT) for NIR emission and aromatic rotors were
introduced to ensure a strong AIE effect upon binding to Aβ
species. As expected, DNTPH showed a significant AIE feature
with the increasing fraction of poor solvent. The NIR
fluorescence of DNTPH increased (up to approximately 18-
fold) upon binding to Aβ42 fibrils through the hydrophobic
interactions between the aromatic part of DNTPH and the
exposed hydrophobic residues of the fibrils, attributed to the
restricted intramolecular rotation of the probe. TEM and CD
spectra validated that DNTPH can efficiently inhibit the
formation of the β-sheet structure by limiting nucleation and
elongation processes and promoting the disassembly of Aβ42
fibrils. In PC12 cells, DNTPH can stain Aβ42 fibrils and
reduce the Aβ-induced cytotoxicity at a low dosage. Based on
the good performance in vitro, the theranostic potential of
DNTPH was further investigated in APP/PS1 transgenic AD
mice in vivo. The probe can cross the BBB efficiently and
track Aβfibrils in real-time via fluorescence imaging of the
brain of 7 months old APP/PS1 transgenic mice. Furthermore,
DNTPH-treated AD mice exhibited a decreased level of Aβ42
plaques in the brain and improved spatial learning and
memory.
Others
Styrylquinolines have provided promising scaffolds for
constructing Aβ-targeting fluorophores.
70
A styrylquinoline-
based fluorescent probe 3for Aβ42 was reported as a
potential theranostic agent for AD (Fig. 9).
71
It can bind to
Aβ42 and inhibit the aggregation of Aβ42, determined by
ThT-based fluorometric assay. In the meantime, the
fluorescence of 3increased with the hypsochromic shift,
when the probe reacted with Aβ42. A ThT-derived two-photon
imaging agent PiB-C for Aβplaques also exhibited a
remarkable inhibitory effect on Aβaggregation (Fig. 9).
72
It
consists of a framework of PiB (Pittsburg Compound B, PET
imaging agent for Aβplaques) and a 12-crown-4 ether. The
crown ether can form stable adducts with protonated amino
groups of Aβthrough hydrogen bonds, which would alter the
folding property Aβvia changing the surface charges of the
peptide. The fluorescence of PiB-C exhibited a red shift when
the probe was mixed with fibrillary Aβ40 owing to the
interaction of the crown ether with Aβ.In vitro experiments
verified the ability of PiB-C to reduce Aβaggregation and
Aβ42-induced toxicity in SH-SY5Y neuronal cells. Importantly,
it can efficiently cross the BBB and label the plaques in the
brain of APP-PS1 mice via two-photon fluorescence imaging
in vivo.
Luminescence-guided theranostic
agents
Compared with fluorescence, the metal-centered
luminescence of metal complexes possess longer emission
lifetimes, larger Stokes shifts, and higher photostability,
which allow the removal of interference from background
fluorescence in biological systems using time-resolved
luminescence measurements for biosensing or bioimaging
Fig. 8 Chemical structures of Cur-N-BF
2
and DNTPH.
Fig. 9 Chemical structures of 3and PiB-C.
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with high signal-to-noise ratios.
73
For example, the
luminescent complexes of d
6
transition metals (e.g.,
iridium(III), ruthenium(II), and rhenium(I)) can emit
luminescence through the intersystem crossing from the
singlet to the triplet state due to their strong spin–orbit
coupling.
74
A large number of lanthanide complexes can also
give off luminescence through energy transfer from the
antenna groups to the metal ions.
75
On the other hand, metal
complex-based drugs have already been important candidates
in the drug development for the treatment of various diseases
due to their fascinating properties as compared with
common organic drugs, including the synergistic effect
between metal ions and their ligands for interacting with
biomolecular targets and tunable geometries of the
complexes.
76
These features have led to the development of
luminescent complex-based theranostic agents for AD. The
linking strategies have been usually employed to design
luminescent complex-based theranostic agents through
modifying the luminescent metal centers with functional
ligands. Nevertheless, their theranostic properties are still
limited within in vitro studies, owing to some common issues
of the luminescent complexes, such as short excitation/
emission wavelengths, weak BBB permeability, and
undetermined neurotoxicity in vivo. Therefore, more works to
address these issues are needed for the design of such
luminescent complexes.
The pioneering work of iridium(III) complex-based
theranostic agents, named as 1a (Fig. 10), was reported in
2011, bearing two planar aromatic 2-phenylpyridine as C^N
co-ligands and two H
2
O as labile ligands.
77
1a showed an
obvious inhibitory effect on Aβ40 aggregation probably
attributed to the synergetic effect between the coordination
of the metal center with the histidine residues of Aβand the
planar aromatic ligands. The complex also exhibited
remarkable luminescence enhancement (∼134-fold at a
maximum wavelength) in response to Aβ40 fibrils. The
coordination between 1a and Aβmay shelter the metal center
in a hydrophobic environment and reduce the solvent-
mediated non-radiative decay of the excited state, leading to
the enhancement of luminescence. Later, the same group
also investigated the theranostic potential of kinetically inert
Ir(III) complexes.
78
The complex 14 is one of the best for
detecting and inhibiting Aβfibrillation (Fig. 10). 14 contains
benzoquinoline as C^N co-ligands and a phenol-imidazo-
Fig. 10 Chemical structures of 1a,14,[Ru(dmbpy)(dcbpy)dppz],cis-[Ru(phen)
2
(3,4Apy)
2
]
2+
, and EC.
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phen N^N ligand and can bind to the Aβ40 peptide via non-
covalent interactions. It showed ca. 18-fold luminescence
enhancement at the maximum wavelength (540 nm) upon
reaction with Aβ40 fibrils. TEM and total internal reflection
fluorescence microscopy (TIRFM) imaging verified the ability
of 14 to inhibit Aβ40 aggregation. Nearly complete inhibition
was observed in the presence of 50 μMof14. The complex
also displayed a neuroprotective effect against Aβ40-induced
cytotoxicity in SH-SY5Y cells and mouse primary cortical cells
at a low dosage.
An amyloid binding aptamer-mediated strategy for sensing
and inhibiting Aβaggregation was developed by using a Ru(II)
complex [Ru(dmbpy)(dcbpy)dppz] (dmbpy; 4,4′-dimethyl-2,2′-
bipyridine, dcbpy; 4,4′-dicorboxy-2,2′-bipyridine, dppz;
dipyridophenazine) (Fig. 10).
79
[Ru(dmbpy)(dcbpy)dppz] per
se can hardly influence the aggregation of Aβand the
negligible change in the luminescence intensity of the
complex was observed in the presence of the Aβmonomer.
However, the complex can bind to the amyloid binding
aptamer with significantly increased luminescence, which
can be subsequently quenched by the addition of soluble Aβ
peptides that capture the aptamer due to the high binding
affinity of each other. Adopting this aptamer-mediated
manner, the complex was able to detect soluble Aβspecies
with a low detection limit (50 nM) and high selectivity against
the other proteins. Additionally, the binding between the
aptamer and Aβresulted in efficient inhibition of Aβfibril
formation. Thus, the aptamer–Ru(II) complex system can
function as both the sensor and inhibitor for Aβaggregates.
Another Ru(II) complex-based theranostic agent cis-
[Ru(phen)
2
(3,4Apy)
2
]
2+
was fabricated by using two 1,10-
phenanthroline (phen) and a 3,4-diaminopyridine (Apy) as
ligands (Fig. 10).
80
The complex showed stable luminescence
with long lifetime, which was used to monitor the
conformational changes of Aβby time-correlated single
photon counting fluorescence lifetime imaging microscopy
(TCSPC-FLIM). The non-covalent interactions of the complex
with Aβplay an important role in the site-specific
conformation alterations in the peptide. In addition, cis-
[Ru(phen)
2
(3,4Apy)
2
]
2+
also exhibited therapeutic potential
through antioxidant activity attributed to the hydroxyl radical
scavenging effect of Apy and inhibitory activity on human
acetylcholinesterase and butyrylcholinesterase enzymes
probably due to the binding of the planar phen and the
protonated ammonium substituent of Apy to the active sites
of the enzymes.
Our group constructed a pincer-like europium(III) complex
(EC) for Aβoligomer-targeted theranostics of AD (Fig. 10).
81
EC is composed of a diethylenetriaminepentaacetate (DTPA)-
based Eu(III) chelating center and two 4-(imidazole[1,2-a]
pyridine-2-yl)aniline (IPA) groups. The complex showed a
preferred binding to low molecular weight (LMW) Aβ
oligomers along with decreased luminescence, due to the
limited energy transfer from IPA to Eu
3+
, resulting from the
non-covalent interactions between IPA and hydrophobic
regions of LMW oligomers. Based on this binding mode, EC
can dramatically accelerate and promote Aβaggregation into
non-fibrillar aggregates via bicomponent co-assembly. More
importantly, the EC–Aβco-aggregates were almost non-toxic
in SH-SY5Y cells and degradable in BV-2 microglial cells
through upregulating autophagy upon phagocytosis. The
in vivo effects of EC-mediated co-assembly of Aβoligomers
were finally investigated in the transgenic Caenorhabditis
elegans (C. elegans) model of AD. EC was able to delay the
paralysis and improve the chemotaxis behavior of C. elegans
through attenuating Aβ42-induced toxicity.
PET-guided theranostic agents
PET imaging has provided a great opportunity to visualize
and quantify specific neurochemical and molecular
pathophysiological changes in the brain of AD by using
radiotracers labeled with positron-emitting isotopes such as
11
C,
18
F, and
64
Cu.
82
To date, amounts of PET radiotracers
have been developed for imaging of various pathological
factors in AD, including brain glucose metabolism,
83
Aβ
deposition,
84
tau aggregation,
85
neuroinflammation,
86
acetylcholine system,
87
and synaptic density.
88
Some of them
have been approved for clinical use.
89
Unfortunately, only a
few PET radiotrace-based theranostic agents have been
reported for anti-AD.
An amphiphilic compound (LS-4) and its
64
Cu complex
(
64
Cu-LS-4) were reported for inhibition and PET imaging of
Aβplaques (Fig. 11).
90
LS-4 was prepared by linking a
hydrophobic amyloid-binding distyrylbenzene fragment with
a hydrophilic metal-chelating triazamacrocycle. LS-4
exhibited nanomolar affinity for both Aβ42 oligomers and
fibrils with fluorescence enhancement, which can be used to
monitor the on-pathway aggregation of Aβ42 in solution and
probe both oligomers and fibrils in the AD brain. It was
proved that the hydrophilic azamacrocycle moiety made a
great contribution to the high binding affinity of LS-4 to Aβ
species. Moreover, the triazamacrocycle endows the
compound with strong Cu
2+
-chelating ability. Accordingly,
the copper complex of LS-4 (Cu-LS-4) can be easily obtained.
Interestingly, Cu-LS-4 showed similar binding behaviors with
LS-4 toward Aβspecies, supporting the possibility of
64
Cu-LS-
4as the PET imaging agent for Aβplaques in AD. As
predicted,
64
Cu-LS-4 can penetrate the BBB and label the
amyloid plaques specifically with higher autoradiography
intensity in 5xFAD than in age-matched wild-type mice.
Owing to its strong interactions with both oligomers and
fibrils, LS-4 can significantly mitigate the aggregation of Aβ
and their neurotoxicity, as well as reduce microglia activation
in 5xFAD mice, indicating the therapeutic potential of this
framework in vivo. However, the therapeutic effect of Cu-LS-4
on AD mice was not investigated in vivo, probably due to its
low brain uptake.
Similarly, an Aβoligomer-targeted cyclic(aza)peptide (7)
and its
64
Cu-radiolabeled conjugates (
64
Cu-9) showed
promising potential in early diagnosis via PET imaging and
treatment of AD (Fig. 11).
91
First, the peptide 7was obtained
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by replacing the residues in an Aβoligomer-targeted cyclic
peptide (c-[Lys
1
-D-Leu
2
-Nle
3
-D-Trp
4
-His
5
-D-Ser
6
]) with aza-
glycine (azaGly) to add extra hydrogen-bond donors for
enhancing triple helix stability. 7can bind to the residues
F19 and F20 of Aβ42 oligomers and inhibit Aβaggregation
and toxicity in vitro. Based on these features, 7showed
abilities to reduce the levels of Aβoligomers and delay the
lifespan of AD transgenic C. elegans. It can also cross the BBB
and improve the memory and cognition of transgenic 5xFAD
mice with significant reduction of Aβspecies in the neurons
of cornu ammonis (CA1) and dentate gyrus (DG). To
investigate the PET imaging of Aβ, the peptide 9was
prepared by attaching a Cu-chelating 2,2′,2″-(1,4,7-
triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) to 7for
theranostic studies. 9retained the ability to reverse
completely the pathological effect of Aβin PC12 cells to some
extent. As a result,
64
Cu-9 gave off a PET imaging signal for
amyloid species in 44-day-old presymptomatic transgenic
5xFAD mouse brains.
MRI-guided theranostic agents
MRI, another clinically useful neuroimaging technology, has
been recommended by the National Institute on Aging and
the Alzheimer's Association to identify MCI and AD,
depending on its ability to reveal the changes of brain
morphology and activities.
92
Owing to the relatively low
sensitivity of MRI, contrast agents are commonly used to
increase the image contrast through enhancing the relaxation
rate. Notably, gadolinium(III) complexes have been frequently
used as MRI contrast agents in the clinical practice due to
their high paramagnetism and stability, as well as efficient
biodistribution and post-scan elimination.
93
In this context,
Aβ-targeted MRI contrast agents would offer the parent
frameworks for the design of MRI-guided theranostics in AD.
A negatively charged gadolinium(III) complex Gd(L
4
)was
designed as a MRI-guided theranostic agent for AD by
combining the GdDOTA (DOTA = 1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelate with a
PiB group (Fig. 12).
94
Although the negative charge could
weaken the binding strength to Aβ, the complex can still
inhibit Aβaggregation and reduce the formation of fibrils,
according to the TEM images and CD data. On the hand, the
binding of the monomeric form of Gd(L
4
)to Aβplaques can
obviously elevate the relaxivity of the complex at the magnetic
fields due to the slower and more restricted local motion of
Fig. 11 Chemical structures of LS-4,
64
Cu-LS-4,7, and
64
Cu-9.
Fig. 12 Chemical structures of Gd(L
4
)and Dyad-3.
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the Gd
3+
center, thereby obtaining higher MRI efficacy of
Gd(L
4
). Another theranostic Gd(III) complex (Dyad-3) consists
of a Gd(DOTA) chelating moiety and a carbazole-based
cyanine group (Fig. 12),
95
which are connected by the Cu(I)-
catalyzed azide-alkyne cycloaddition click reaction. Owing to
the turn-on fluorescence upon interacting with Aβ, the Aβ-
targeting capability of Dyad-3 ex vivo and in vivo was verified
by fluorescence imaging of Aβspecies in the brain of the
5xFAD AD mouse model. The large longitudinal relaxivity (r
1
= 4.42 mM
−1
S
−1
), good BBB permeability and high stability
made the complex available for T
1
-weighted MRI of cerebral
Aβin the double Tg, APP/PS1 mouse in vivo. In addition,
Dyad-3 also displayed great potential for AD intervention
through attenuating Aβaggregation and its neurotoxicity as
well as ROS generation.
Conclusions and outlook
AD is an incurable neurodegenerative disease so far. The
constantly rising number of AD patients and the growing
cost of caring for AD expedite huge demands for effective
strategies to combat the disease. Theranostics, combining
therapy and diagnosis, has been successfully applied in
oncology and would also provide a promising strategy for
anti-AD. In this review, we summarized the representative
small-molecule-based theranostic agents for anti-AD in
terms of design rationales, chemical structures,
pharmacological properties, and working mechanisms. The
properties of these representative agents for AD theranosis
are listed in Table 1. Although they have tremendous
potential, almost all the works remain at the laboratory
level. For the purpose of clinical translation, some key
aspects need to be strengthened in the design and
improvement of small-molecule-based theranostics: (i)
Discovery of the reliable targets and their targeting
groups. Aβoligomers as both biomarkers and therapeutic
targets have attracted more and more attention for the
diagnosis and treatment of early AD.
7
The development of
small-molecule-based probes that can precisely recognize
Aβoligomers in the specific aggregation state would
dramatically benefit the personalized treatment of AD. (ii)
Synergistic effect between the diagnosis and therapeutic
Table 1 The properties of the representative small-molecule-based theranostic agents against AD
Agents Diagnostic target Diagnostic modality Therapeutic target
Therapeutic
availability Ref.
SLOH Aβfibrils Ex vivo fluorescence imaging Aβ, tau, protein kinase B,
intercellular Ca
2+
In vivo 38, 39
SLM Aβfibrils In vivo fluorescence imaging Aβ, tau In vivo 38, 40
DBA-SLOH Aβfibrils In vivo fluorescence imaging AβIn vitro 41
DBAN-SLM Aβoligomers and
monomers
In vivo fluorescence imaging AβIn vitro 42
F-SLOH Aβoligomers In vivo fluorescence imaging Aβ, amyloid precursor protein, tau In vivo 43, 44
SLCOOH Aβfibrils In vivo fluorescence imaging Aβ, tau, intercellular Ca
2+
In vivo 45
QM21 Aβfibrils In vitro fluorescence imaging AβIn vitro 46
4a1 Aβfibrils In vitro fluorescence imaging AβIn vitro 47
5a1 Aβfibrils In vitro fluorescence imaging AβIn vitro 48
4Aβfibrils In vitro fluorescence imaging AβIn vitro 49
L1 Aβfibrils In vitro fluorescence imaging Aβ,Cu
2+
,Zn
2+
In vitro 54
TBT Cu
2+
,Zn
2+
In vitro fluorescence Aβ,Cu
2+
,Zn
2+
In vitro 55
BTTA Cu
2+
Ex vivo fluorescence imaging Aβ,Cu
2+
In vitro 56
BPB Aβfibrils Ex vivo fluorescence imaging Aβ,Cu
2+
,Zn
2+
In vitro 57
CRANAD-17 Aβfibrils In vitro fluorescence Aβ,Cu
2+
In vitro 59
CRANAD-28 Aβfibrils In vivo fluorescence imaging Aβ,Cu
2+
In vitro 60
FI Cu
2+
In vitro fluorescence Aβ,Cu
2+
In vitro 61
1Cu
2+
In vitro fluorescence Aβ,Cu
2+
In vitro 63
Cur-N-BF
2
Aβfibrils Ex vivo fluorescence imaging AβIn vitro 68
DNTPH Aβfibrils In vivo fluorescence imaging AβIn vivo 69
3Aβfibrils In vitro fluorescence AβIn vitro 71
PiB-C Aβfibrils In vivo fluorescence imaging AβIn vitro 72
1a Aβfibrils In vitro luminescence AβIn vitro 77
14 Aβfibrils In vitro luminescence AβIn vitro 78
[Ru(dmbpy)(dcbpy)dppz] Soluble AβIn vitro luminescence AβIn vitro 79
cis-[Ru(phen)
2
(3,4Apy)
2
]
2+
AβIn vitro luminescence imaging Acetylcholinesterase,
butyrylcholinesterase
In vitro 80
EC Aβoligomers In vitro luminescence Aβoligomers In vivo 81
64
Cu-LS-4 Aβfibrils, oligomers Ex vivo PET imaging Aβ,Cu
2+
In vivo 90
64
Cu-9 Aβoligomers Ex vivo PET imaging Aβoligomers In vivo 91
Gd(L
4
)Aβfibrils In vitro MRI AβIn vitro 94
Dyad-3 Aβfibrils In vivo MRI and fluorescence
imaging
Aβ, reactive oxygen species In vitro 95
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moieties. Constructing the prodrugs that can be activated
with both diagnosis signals and therapy efficacy by a
single stimulus would be a useful strategy for optimizing
the synergistic effect with minimum side effects. (iii) BBB
permeability. It should be noted that combining multiple
functions into a single framework may elevate the
complexity of the structures and weaken the BBB
permeability of the theranostic agents. Accordingly, a
balance between theranostic properties and BBB
permeability should be warranted in the design of the
small-molecule-based theranostic agents. From the current
trends, it is desirable that small-molecule-based
theranostics will become an effective strategy to exploit
AD pathogenesis and to precisely prevent the disease.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We appreciate the financial support from the National
Natural Science Foundation of China (Grant: 21771105), the
Natural Science Foundation of Jiangsu Province (Grant:
BK20170103), and the Natural Science Foundation of the
Jiangsu Higher Education Institutions of China (Grant:
23KJB150012).
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