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Advances in Development of Fluorescent Probes for Detecting Amyloid-Β Aggregates

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Advances in Development of Fluorescent Probes for Detecting Amyloid-Β Aggregates Acta Pharmacologica Sinica (2016) 37: 719–730 npg © 2016 CPS and SIMM All rights reserved 1671-4083/16 www.nature.com/aps Review Advances in development of fluorescent probes for detecting amyloid-β aggregates Ming-ming XU1, #, Wen-ming REN2, #, Xi-can TANG1, You-hong HU2, *, Hai-yan ZHANG1, * 1CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China; 2State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China With accumulating evidence suggesting that amyloid-β (Aβ) deposition is a good diagnostic biomarker for Alzheimer’s disease (AD), the discovery of active Aβ probes has become an active area of research. Among the existing imaging methods, optical imaging targeting Aβ aggregates (fibrils or oligomers), especially using near-infrared (NIR) fluorescent probes, is increasingly recognized as a promising approach for the early diagnosis of AD due to its real time detection, low cost, lack of radioactive exposure and high-resolution. In the past decade, a variety of fluorescent probes have been developed and tested for efficiencyin vitro, and several probes have shown efficacy in AD transgenic mice. This review classifies these representative probes based on their chemical structures and functional modes (dominant solvent-dependent mode and a novel solvent-independent mode). Moreover, the pharmaceutical characteristics of these representative probes are summarized and discussed. This review provides important perspectives for the future development of novel NIR Aβ diagnostic probes. Keywords: Alzheimer’s disease; diagnostic biomarker; amyloid-β; optical imaging; near-infrared fluorescent probes Acta Pharmacologica Sinica (2016) 37: 719–730; doi: 10.1038/aps.2015.155; published online 21 Mar 2016 Introduction relief from symptoms. Additionally, none of these treatments Alzheimer’s disease (AD) is a devastating and progressive halts the progression of this terminal disease. Therefore, early neurodegenerative disease that leads to progressive cogni- diagnosis seems to be a hopeful and promising approach to tive decline, functional impairment and loss of independence; further the understanding and clinical treatment of this disor- thus, AD represents a significant and increasing clinical chal- der. Currently, memory and behavioral tests are widely used lenge[1-3]. AD is characterized by two main hallmarks in the for late-stage AD diagnosis[4], and a definitive diagnosis is brain: the extracellular deposition of the amyloid-β (Aβ) in achieved only by postmortem examination to show the pres- senile plaques and the appearance of intracellular neurofibril- ence of Aβ plaques and NFTs. Early-stage and asymptomatic lary tangles (NFTs) consisting of hyperphosphorylated tau diagnoses remain a challenge. protein[2]. Today, more than 35 million people worldwide live As a widely studied pathological hallmark of AD, the with dementia and this number is expected to be more than aggregation of fragmented Aβ proteins into Aβ plaques is triple to 115 million by 2050[3]. The heavy social costs and care- closely connected with AD pathogenesis. Many risk fac- giving burden of AD have raised the attention for increasing tors in sporadic AD are associated with Aβ metabolism, research and potential therapeutics. However, the pathologi- and mutations of Aβ-related genes in familial AD lead cal mechanism of AD is elusive, and currently Food and Drug directly to AD pathogenesis[5-19]. Clinical research[20-25] Administration (FDA)-approved medications, including four supports the hypothesis that there is a lengthy temporal acetylcholinesterase inhibitors and one N-methyl-D-aspartate lag between the appearance of Aβ plaques and the emer - receptor (NMDA) receptor antagonist, only provide temporary gence of clinical symptoms. Sperling et al[26] proposed a bio- marker model of the preclinical stage of AD in which Aβ accu- mulation first becomes abnormal and a substantial Aβ load # These authors contributed equally to this work. accumulates before the appearance of clinical symptoms. As a * To whom correspondence should be addressed. E-mail [email protected] (Hai-yan ZHANG); consequence, the process of Aβ plaque formation, namely Aβ [email protected] (You-hong HU) accumulation, has attracted growing attention as an important Received 2015-09-15 Accepted 2015-12-25 biomarker for early AD diagnosis. Moreover, Bruggink et al[27] npg www.nature.com/aps Xu MM et al 720 recently discovered an age-dependent Aβ oligomer increase blood-brain barrier (BBB); (5) a high metabolic stability; (6) fast in the cortex and hippocampus of transgenic mice (APP/PS1) washout kinetics from normal brain regions; (7) low toxicity; along with elevated levels of soluble Aβ oligomers in human and (8) straightforward synthesis. AD brain tissue compared with controls. Therefore, increasing evidence suggests that Aβ oligomers are the proximal toxicant Aβ fluorescent probes with classical push-pull architecture forms underlying the AD pathogenesis that eventually leading In general, the emission spectra and quantum yield of fluoro- to cognitive and behavioral disorders. Central Aβ oligomers, phores are profoundly influenced by the environment and the rather than Aβ plaques, are predicted to be a better potential solvent used[39], especially the solvent polarity[40]. Most fluo- marker for early AD diagnosis. rophores are polar molecules, which contain both an electron- Based on the role of Aβ accumulation in AD diagnosis, the donating and an electron-accepting group[41, 42] and usually past decade has seen great progress in the development of display a large sensitivity to solvent polarity. Typically, fluo- imaging probes for the non-invasive detection of Aβ, mainly rophores have a larger dipole moment in the excited state than relying on techniques such as positron emission tomography in the ground state. The polar solvent can be more relaxed (PET), single-photon emission computed tomography (SPECT) around the excited state than the ground state, which lowers and magnetic resonance imaging (MRI)[28, 29]. In particular, the energy of the excited state[43-45]. The above-mentioned sol- several PET probes have shown efficacy for imaging Aβ in AD vent effects are used to determine any probe-macromolecule brains. Among them, Florbetapir (18F)[30, 31] was launched by interactions. When the fluorophore binds to the macromol- Lily in 2012 and Flutemetamol (18F)[32, 33] was launched by GE ecule, the emission spectra or quantum yields change after dis- Healthcare in 2014. However, factors such as low sensitivity of solution in solvents of different polarity[46-48]. MRI probes, high cost, narrow isotope availability, the short- The existing Aβ fluorescent probes largely share a common lived isotopes of PET probes and the radioactivity of SPECT structure, the classical push-pull architecture with terminal probes have restricted their clinical use. Currently, clinically electron donor and acceptor moieties that are interconnected available PET imaging requires expensive instruments, highly by a highly polarizable bridge. These probes are highly sensi- skilled personnel, time-consuming data analysis and unavoid- tive to solvent polarity and are essentially nonfluorescent in able radiation exposure. The cost of one PET examination is aqueous solutions, but highly fluorescent in nonpolar solvents approximately $1000, which is a relatively high burden for the or when bound to Aβ. In the following section, we introduce average family in developing countries. the different scaffold features of this mode. Therefore, alternative technologies that are relatively inex- pensive and easily applicable have recently attracted increas- Thioflavin-T and its derivatives ing attention. Optical imaging, especially near-infrared First introduced in 1959, the fluorescent dye thioflavin-T fluorescence (NIRF) imaging, when compared to PET, SPECT (ThT) (Figure 1, 1) has become a widely used “gold standard” and MRI, is highly promising because it is real-time, inexpen- for selectively staining and identifying amyloid fibrils both sive, not radioactive and of high-resolution both in vivo and in vivo and in vitro[49]. When bound to amyloid fibrils, 1 shows ex vivo[34]. Additionally, unlike PET, NIRF imaging instrument enhanced fluorescence and a characteristic red-shift of the costs are much lower, the data analysis takes less time, and excitation and emission maxima from 350 and 438 nm to 450 highly skilled personnel are not needed. Optical imaging is and 482 nm[50]. The molecule of 1 consists of a benzothiazole an imaging technique using visible, ultraviolet, and infrared (acceptor) and a benzylamine ring (donor) freely rotating light for imaging. In particular, NIRF probes are favorable for around a shared C-C bond (bridge). The hindrance in free Aβ detection in vivo because emission wavelengths in the NIR rotation of the acceptor and donor is thought to suppress range (650–900 nm) are distinct from the autofluorescence of quenching and result in a high quantum yield of fluorescence biological matter, which is especially suitable for in vivo appli- when bound to Aβ, which is rich in β-sheet structures [51]. cations. During the last decade, a variety of Aβ fluorescent However, due to its charge and an emission wavelength less probes have been developed and used to detect Aβ in vitro than 650 nm, the in vivo usage of 1 is limited. A variety of and in vivo. The current trend in technical
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