Probes for imaging and inhibiting β-amyloid aggregation

Abstract

Aggregation-induced emission molecules for imaging of beta-amyloid protein, and inhibiting aggregation of beta-amyloid protein, use and methods of preparation of probes comprising the aggregation-induced emission molecules and derivatives thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 274,945, filed on November 3, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to probes with aggregation-induced emission characteristics, which can be used to detect Aβ fibrils and inhibit the generation process of Aβ fibrils. Background Art

[0004] In 2020, Alzheimer's disease (AD), which causes cognitive impairment and memory loss, has affected more than 50 million people worldwide. Due to the complex brain tissue and its microenvironment, AD is currently considered an incurable disease. Similar to protein fibrillogenesis, the formation and accumulation of amyloid-β (Aβ) species (including soluble monomers, insoluble fibrils / aggregates and plaques) in the brain are considered to be key pathological hallmarks for the early diagnosis of AD and also play a central role in the neuropathology of AD. It is well known that Aβ peptides consist of 40 or 42 residues formed by the cleavage of amyloid precursor protein, in which monomeric Aβ peptides aggregate into insoluble plaque-associated amyloid fibrils to induce a series of biological events that subsequently lead to neuronal cell death. To date, no drugs tested in clinical trials have shown significant efficacy. Therefore, there is an urgent need to find effective therapeutic agents and imaging probes as useful tools in drug development.

[0005] A series of exogenous chemical fluorophores have been developed as imaging agents for the visualization and detection of Aβ fibrils. Examples of such chemical fluorophores include thioflavin T (ThT), Michler's hydrol blue, difluoroboron derivatives, rhodamine analogs, conjugated oligothiophenes, and semiconductor quantum dots. For about half a century, ThT has been a standard probe for amyloid determination. Despite its widespread use, it has several disadvantages, such as small Stokes shift, low specificity, poor sensitivity, false positive reactions, poor reliability, and unsuitability for kinetic studies. Due to its inherent fluorescence intensity in dilute solutions, it inevitably presents a background signal in aqueous solution, becoming an obstacle to high-fidelity imaging.

[0006] In addition to the imaging of Aβ fibrils and in vivo diagnosis of AD, a great deal of effort has been made to develop external inhibitors of fibrillogenesis. Targeting and inhibiting Aβ aggregation has been widely recognized as an effective therapeutic strategy for treating AD. For many years, numerous efforts have been made to develop potent fibril inhibitors and β-sheet disrupters that can prevent Aβ monomers from aggregating into fibrils. For example, Scyllo-cyclohexanehexol has been developed as an Aβ aggregation inhibitor, and is currently undergoing phase II clinical trials. Polyphenols and antioxidants have also been reported to inhibit Aβ fibrillogenesis, and some are currently in clinical trials.

[0007] Polymeric nanoparticles of various sizes and hydrophobicities have also been used to adsorb Aβ peptides onto the particle surface to control their fibrillogenetic kinetics. Some ligand-functionalized quantum dots have been reported to prevent the nucleation and elongation of Aβ peptides by inhibiting fibril nucleation or active sites on monomers. In addition to nanomaterials, transition metal complexes have been used as potent inhibitors of Aβ aggregation by forming coordinate bonds with the amino acid residues of the peptide. In order to be clinically useful, these inhibitors or b-sheet disrupters must also have blood-brain barrier (BBB) penetrability, low neurotoxicity, and high in vivo stability. However, these key properties have not been elucidated in these inhibitors or b-sheet disrupters.

[0008] On the other hand, small organic molecules have the potential to overcome the aforementioned difficulties encountered by the materials through rational structural design. Various small organic molecule inhibitors have been developed so far, most of which are derivatives of dyes such as ThT that can bind to Aβ fibrils Figure 1 However, recent advances in this field have not provided a rational explanation for the mechanism of the inhibitors, thus making the development of small organic molecule inhibitors still a "black box".

[0009] In addition, many of the above-reported fluorophores also contain electron donors and acceptors between which intramolecular charge transfer occurs. Such fluorophores are sensitive to the hydrophobicity of the environment, and their luminescence is enhanced upon binding to the hydrophobic regions of amyloid rich in β-sheet structure. However, when multiple fluorophore molecules accumulate in the hydrophobic sheets of the protein, π-π interactions occur between the stacked aromatic rings of them, which promotes a distorted signal from the aggregated quenched luminescence effect of fluorescence. In contrast, their intense luminescence in a dispersed state (dilute solution) inevitably generates noise to form a "constant light" mode of fluorescence.

[0010] Accordingly, there is a need in the market for improved chemical probes that can be used as Aβ fibril imaging agents. SUMMARY

[0011] Fluorophores with "aggregation-induced emission" (AIE) characteristics, which do not emit light when the molecules are dissolved, but the emission is greatly enhanced when they are aggregated, are ideal probes for studying the Aβ fibril formation process, as they are all related to aggregate formation. The water-soluble aggregation-induced emission (AIE)gens described herein function as excellent Aβ probes because (i) they do not emit light in aqueous buffer, so there is minimal interference from background emission, (ii) their aromatic core can facilitate binding to the hydrophobic surface of Aβ fibril aggregates, thus activating the intramolecular rotation restriction (RIR) process and causing them to emit light, and (iii) their emission intensity can increase to varying degrees in the nucleation, elongation, and equilibrium stages, thus enabling the assessment of amyloidogenic kinetics.

[0012] Provided herein are amphiphilic near-infrared (NIR) AIEgens. They specifically detect Aβ based on the balance of hydrophobic electron-donating groups and hydrophilic electron- withdrawing groups. By modulating the aggregation behavior, the AIEgens show Aβ plaque detection capability with high sensitivity, high signal-to-noise ratio, and exhibit effective BBB penetration. The AIEgens also affect Aβ fibrillogenesis by inhibiting the aggregation of Aβ peptides and the dissociation of Aβ fibrils, thus preventing fibril growth. Molecular docking calculations indicate that the compound has a large hydrophobic surface area that can interact strongly with specific residues of the Aβ peptide, such as hydrophobic interactions and π-π interactions. In addition, the hydrophilic part of the AIEgens can further stabilize Aβ through electrostatic interactions. These multiple interactions enable the AIEgens to significantly improve the ability to inhibit Aβ oligomerization and fibril formation and reduce Aβ-induced cytotoxicity. In vivo therapeutic studies confirm that the AIEgens can rescue memory deficits in APP / PS1 double transgenic AD mouse models without obvious toxicity.

[0013] In a first aspect, provided herein is an aggregation-induced emission molecule (AIEgen) having Formula 1:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] m is an integer selected from 1-4;

[0017] n is in each instance an integer selected from 1-6;

[0018] p is an integer selected from 1-4;

[0019] q is an integer selected from 2-6;

[0020] A is a chemical bond or a moiety having the structure:

[0021]

[0022] Y is O, S or -NR 6 -;

[0023] X is -O(C=O)- or -(R 4 )C=C(R 4 )-;

[0024] R 1 is independently hydrogen, halogen, cyano, nitro, -OR 7 、-SR 7 、-N(R 7 )2, -(C=O)R 7 、-(C=O)OR 7 、-(C=O)N(R 7 )2、-N(R 7 )(C=O)R 7 、-O(C=O)R 7 、-N(R 7 )(C=O)OR 7 、-O(C=O)N(R 7 )2, -SO2R 7 、-SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z;

[0025] R 2 is a section with the following structure:

[0026]

[0027] R 3 is hydrogen or cyano;

[0028] R 3 is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0029] R 5 is hydrogen, halogen, cyano, nitro, -OR 7 、-SR 7 、-N(R 7 )2, -(C=O)R 7 、-(C=O)OR 7 、-(C=O)N(R 7 )2、-N(R 7 )(C=O)R 7 、-O(C=O)R 7 、-N(R7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0030] R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0031] R 7 is, at each occurrence, independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z; or two R 7 , together with the atom(s) to which they are covalently bonded, form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0032] R 8 is, at each occurrence, independently hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=0)R 7 , -(C=0)OR 7 , -(C=0)N(R 7 )2, -N(R 7 )(C=0)R 7 , -0(C=0)R 7 , -N(R 7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0033] R 9 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, -(CH2) q OH, or -(CH2) q NH2; Q is an anion; and

[0034] Z is, at each occurrence, independently halogen, -CºCH, -N3, -NCS, -NCO, -OR 7 , -SR 7 , -N(R7 )2, -(C=0)R 7 , -(C=0)OR 7 , -(C=0)N(R 7 )2, -N(R 7 )(C=0)R 7 , -0(C=0)R 7 , -N(R 7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, or N-maleimide.

[0035] In certain embodiments, m and t are each independently 1 or 2.

[0036] In certain embodiments, Y is O or S; and each R 4 is hydrogen.

[0037] In certain embodiments, A is a bond or a moiety having the structure:

[0038]

[0039] In certain embodiments, m is 1; and R 1 is -OR 7 , -SR 7 , or -N(R 7 )2, wherein R 7 is, in each instance independently, hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n OH; or two R 7 together with the nitrogen to which they are covalently bonded form a 3-7 membered heterocycloalkyl.

[0040] In certain embodiments, R 2 is a moiety having the structure:

[0041]

[0042] wherein p is 1.

[0043] In certain embodiments, the AIEgen is represented by Formula 2:

[0044]

[0045] or a pharmaceutically acceptable salt thereof, wherein:

[0046] n is, in each instance, an integer selected from 1-6;

[0047] q is an integer selected from 2-6;

[0048] X is -0(C=0)- or -(H)C=C(H)-;

[0049] A is a bond or a moiety having the structure:

[0050]

[0051] R 1 independently at each occurrence is hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0052] R 2 is a moiety having the structure:

[0053]

[0054] R 3 is hydrogen or cyano;

[0055] R 5 is hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0056] R 7 is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z; or two R 7 together with the nitrogen to which they are covalently bonded form a 3-7 membered heterocycloalkyl;

[0057] R 8 is hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0058] R 9 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, -(CH2) q OH or -(CH2) q NH2; and Q is an anion.

[0059] In certain embodiments, each of R 1 , R 5 , and R 8 is hydrogen.

[0060] In certain embodiments, R 7independently at each occurrence is hydrogen, alkyl, or -(CH2) n OH; or two R 7 together with the nitrogen to which they are covalently bonded form a 3-6 membered heterocycloalkyl.

[0061] In certain embodiments, R 9 is -(CH2)qOH or -(CH2)qNH2.

[0062] In certain embodiments, the AIEgen is selected from:

[0063]

[0064]

[0065] or a pharmaceutically acceptable salt thereof, wherein Q is an anion.

[0066] In a second aspect, provided herein is a pharmaceutical composition comprising an AIEgen described herein and at least one pharmaceutically acceptable excipient or carrier.

[0067] In a third aspect, provided herein is a method comprising: contacting a compound of Formula 6:

[0068]

[0069] wherein:

[0070] m is an integer selected from 1-4;

[0071] n is an integer selected from 1-6 at each occurrence;

[0072] A is a bond or a moiety having the structure:

[0073]

[0074] Y is O, S, or -NR 6 -;

[0075] X is -O(C=O)- or -(R 4 )C=C(R 4 )-;

[0076] R 1 is, independently at each occurrence, hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7)(C=O)R 7 、-O(C=O)R 7 、-N(R 7 )(C=O)OR 7 、-O(C=O)N(R 7 )2, -SO2R 7 、-SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z;

[0077] R 4 is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0078] R 5 is hydrogen, halogen, cyano, nitro, -OR 7 、-SR 7 、-N(R 7 )2, -(C=O)R 7 、-(C=O)OR 7 、-(C=O)N(R 7 )2、-N(R 7 )(C=O)R 7 、-O(C=O)R 7 、-N(R 7 )(C=O)OR 7 、-O(C=O)N(R 7 )2, -SO2R 7 、-SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z;

[0079] R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0080] R 7 Each occurrence is independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z; or two R 7 Together with the one or more atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group; and

[0081] Z is independently at each occurrence halogen, -C≡CH, -N3, -NCS, -NCO, -OR 6 、-SR 6 、-N(R6 )2, -(C=0)R 6 , -(C=0)OR 6 , -(C=0)N(R 6 )2, -N(R 6 )(C=0)R 6 , -0(C=0)R 6 , -N(R 6 )(C=0)OR 6 , -0(C=0)N(R 6 )2, -S02R 6 , -S02N(R 6 )2, or N-maleimide;

[0082] with a secondary amine and a compound of formula 7a, 7b, or 7c, or a conjugate base thereof:

[0083]

[0084] wherein

[0085] p is an integer selected from 1-4;

[0086] R 8 independently in each occurrence is hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=0)R 7 , -(C=0)OR 7 , -(C=0)N(R 7 )2, -N(R 7 )(C=0)R 7 , -0(C=0)R 7 , -N(R 7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0087] R 9 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, -(CH2) q OH, or -(CH2) q NH2; and Q is an anion;

[0088] to form an AIEgen of formula 1.

[0089] In a fourth aspect, provided herein is a method of imaging a beta-amyloid protein, the method comprising binding the beta-amyloid protein to an AIEgen described herein; irradiating the AIEgen with electromagnetic radiation; and detecting luminescence from the AIEgen.

[0090] In certain embodiments, the beta-amyloid protein comprises Aβ 42 .

[0091] In certain embodiments, the method is performed in vivo or in vitro.

[0092] In certain embodiments, the AIEgen exhibits a luminescence wavelength maximum between 690-705 nm. em

[0093] In certain embodiments, the AIEgen exhibits a signal-to-noise ratio (S / N) of 10-15 fold.

[0094] In a fifth aspect, provided herein is a method of at least partially inhibiting Aβ fibrillogenesis, the method comprising binding an Aβ peptide to an AIEgen described herein, thereby at least partially inhibiting Aβ fibrillogenesis.

[0095] In a sixth aspect, provided herein is a method of treating Alzheimer’s disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of an AIEgen described herein. BRIEF DESCRIPTION OF DRAWINGS

[0096] The accompanying drawings, where like reference numerals refer to identical or functionally similar elements throughout the various figures, which depict certain embodiments, are used to further illustrate and explain the above and other aspects, advantages and features of the present disclosure. It will be understood that these drawings depict the described embodiment(s) only and are not therefore to be considered limiting of its scope. The application will be described and explained with additional specificity and detail through the use of the accompanying drawings.

[0097] Figure 1 Chemical structures of ThT and exemplary NIR AIEgens DCTB, DCPH and DNTPH are depicted.

[0098] Figure 2 Normalized absorption spectra of DCTB, DCPH and DNTPH in DMSO solution are depicted in (A); normalized fluorescence (PL) spectra of DCTB, DCPH and DNTPH in aggregates are depicted in (B); plots of fluorescence intensity as a function of different water content (f w , in volume percent, vol%) are depicted in (C), where I0and I are the maximum fluorescence intensities recorded before and after water was added to a THF solution of DCTB. Plots of fluorescence intensity as a function of different toluene content (f t ​, in volume percent, vol%), where I0 and I are the maximum fluorescence intensities recorded before and after the addition of toluene to DMSO solutions of DCPH and DNTPH, respectively. [AIE dye] = 10 μM.

[0099] Figure 3 Describes the AIE fluorescent dyes (A) DCTB, (B) commercial dye ThT, (C) DCPH, and (D) DNTPH in the presence of different amounts of Aβ 42 PL spectra of fibrils in PBS buffer. [AIE dye]: 1 μm

[0100] Figure 4 Describes the effect of DNTPH on Aβ 42 Determination of the binding constant of aggregates. (A) Aβ in PBS solution (pH = 7.4) 42 PL intensity and DNTPH concentration curve at the aggregate (3μM); (B) DNTPH and Aβ 42 Response time of aggregate binding. (C) To potential competitive substances and Aβ 42 High selectivity of aggregates. a: Arg, b: Gln, c: Gly, d: dextrin, e: lysozyme, f: HAS, g: insulin, h: BSA, i: α-synuclein, j: DNTPH. (D) DNTPH for Aβ compared to background signal in PBS and BSA 42 Ultra-high S / N of aggregates.

[0101] Figure 5 Describes the (A)Aβ in the absence of DNTPH 42 (B) Aβ grown after incubation in PBS at 37°C for 24 hours 42 fibrils, (C)Aβ 42 Monomers + DNTPH and (D) Aβ grown in the presence of DNTPH after incubation in PBS at 37°C for 24 h 42 TEM images of fibrils. (E) Aβ incubated in PBS with or without DNTPH at 37°C for 48 hours. 42 CD spectra of monomers and fibrils.

[0102] Figure 6 Describes two consecutive Aβ 42 Schematic diagram of the fibril structure. (A) and (B) The two optimal docking poses with the lowest binding free energy (E; kcal / mol). (C) and (D) The surface area and hydrophobic surface area of ​​DNTPH exposed to the solvent relative to its binding to Aβ. 42 A plot of the docking score during docking. By selecting a more compact hydrophobic surface area, the docking score (binding energy) decreases and becomes more compact, indicating that the hydrophobic surface area is more compact than the surface area of ​​the Aβ-embedded ...42 DNTPH in the PDMS core is better docked.

[0103] Figure 7 Depicted are (A) Cytotoxicity of Aβ monomers against human neuroblastoma PC-12 cells at 24 and 48 hours of incubation. (B) Cytotoxicity of Aβ fibrils at 24 and 48 hours of incubation. (C) Neuroprotective effect of DNTPH against Aβ fibril-induced cytotoxicity at [DNTPH]:[Aβ] ratios of 2:1, 1:2, and 1:5. (D) Effect of different concentrations of DNTPH on cell viability of PC-12 cells at 24 and 48 hours of incubation.

[0104] Figure 8 In vivo imaging of Aβ deposition in 6-month-old early AD model (APP / PS1 transgenic) mice is presented. -1 Comparison of fluorescence images 30 minutes after intravenous injection of DNTPH into wild-type mice and APP / PS1 mice, n=3.

[0105] Figure 9 Depicted are ex vivo fluorescence images of mouse brains. Fluorescence images of brains removed from APP / PS1 and normal mice 30 minutes after intravenous injection of DNTPH. Fluorescence images were acquired using an orange filter at 490 nm excitation.

[0106] Figure 10 Depicted are ex vivo fluorescence images of mouse organs. Fluorescence images of organs removed from APP / PS1 and normal mice 30 minutes after intravenous injection of DNTPH. Fluorescence images were acquired using an orange filter at 490 nm excitation. DETAILED DESCRIPTION

[0107] definition

[0108] Throughout this application, when compositions are described as having, including, or comprising particular components, or when methods are described as having, including, or comprising particular method steps, it is contemplated that compositions of the present teachings may also consist essentially of or consist of those components, and that methods of the present teachings may also consist essentially of or consist of those method steps.

[0109] In this application, when an element or component is considered to be included in a list of enumerated elements or components and / or selected from a list of enumerated elements or components, it should be understood that the element or component can be any one of the enumerated elements or components, or the element or component can be selected from a group consisting of two or more of the enumerated elements or components. In addition, it should be understood that the elements and / or features of the compositions, devices or methods described herein can be combined in various ways, whether explicitly or implicitly, without departing from the spirit and scope of the present teachings.

[0110] Unless specifically stated otherwise, use of the terms "include," "includes," "including," "have," "has," or "having" are generally to be construed as open ended and non-limiting.

[0111] Unless otherwise specifically stated, the use of the singular herein includes the plural (and vice versa). Furthermore, where the term "about" is used before a quantitative value, the present teachings also include the specific quantitative value itself, unless otherwise specifically stated. As used herein, unless otherwise stated or inferred, the term "about" refers to a variation of ±10%, ±7%, ±5%, ±3%, ±1%, or ±0% from the nominal value.

[0112] It should be understood that the order of steps or the order in which certain actions are performed is immaterial as long as the present teachings remain operable. Additionally, two or more steps or actions may be performed simultaneously.

[0113] As used herein, "halo," "halide," or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0114] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Examples of alkyl groups include methyl-, ethyl-, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (e.g., 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, and 1-ethylpropyl), hexyl, and the like. In various embodiments, an alkyl group may have from 1 to 40 carbon atoms (i.e., C1-C 40 Alkyl groups), for example, 1-30 carbon atoms (i.e., C1-C 30An "alkyl" group refers to a straight-chain or branched-chain monovalent saturated hydrocarbon group having 1 to 20 carbon atoms (i.e., C1-C20 alkyl), for example, 1 to 10 carbon atoms (i.e., C1-C10 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 4 carbon atoms (i.e., C1-C4 alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, and the like. In certain embodiments, an alkyl group can have 1 to 6 carbon atoms, and can be referred to as a "lower alkyl group." Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and i-propyl), and butyl (e.g., n-butyl, i-butyl, s-butyl, t-butyl). In certain embodiments, an alkyl group can be optionally substituted as described herein. An alkyl group is typically not substituted with another alkyl group, alkenyl group, or alkynyl group.

[0115] The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0116] As used herein, "cycloalkyl," by itself or as part of another substituent means a monocyclic hydrocarbon having 3-12 carbon atoms in the ring system, and includes hydrogen, straight chain, branched chain, and / or cyclic substituents. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0117] As used herein, "alkenyl" refers to a straight chain or branched chain alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butene) or terminal (e.g., in 1-butene). In various embodiments, an alkenyl group can have 2 to 40 carbon atoms (i.e., C2-C 40 In some embodiments, an alkenyl group can be substituted as described herein. An alkenyl group is typically not substituted with another alkenyl group, alkyl group, or alkynyl group. 20 In some embodiments, an alkenyl group can be substituted as described herein. An alkenyl group is typically not substituted with another alkenyl group, alkyl group, or alkynyl group.

[0118] As used herein, "fused ring" or "fused ring moiety" refers to a polycyclic ring system having at least two rings, at least one of which is aromatic, and such aromatic ring (carbocyclic or heterocyclic) has bonds in common with at least one other ring which can be aromatic or nonaromatic and carbocyclic or heterocyclic. These polycyclic ring systems can be highly p-conjugated and are optionally substituted as described herein.

[0119] As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen, and includes, for example, nitrogen, oxygen, silicon, sulfur, phosphorus, and selenium.

[0120] As used herein, "aryl" refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., have bonds in common) together or at least one aromatic monocyclic hydrocarbon ring is fused with one or more cycloalkyl and / or cycloheteroalkyl rings. An aryl group can have 6 to 24 carbon atoms in its ring system (e.g., C6-C 24In some embodiments, polycyclic aromatic groups include phenyl, 1-naphthyl (bicyclic), 2-naphthyl (bicyclic), anthracenyl (tricyclic), phenanthrenyl (tricyclic), pentaphenyl (pentacyclic) and other groups. The example of the polycyclic system in which at least one aromatic carbocyclic ring is fused with one or more cycloalkyl and / or cycloheteroalkyl rings especially includes the benzo derivatives (i.e., indanyl, which is 5,6-bicyclic cycloalkyl / aromatic ring system) of cyclopentane, cyclohexane (i.e., tetrahydronaphthyl, which is 6,6-bicyclic cycloalkyl / aromatic ring system), imidazoline (i.e., benzimidazolinyl, which is 5,6-bicyclic cycloheteroalkyl / aromatic ring system) and pyrans (i.e., benzopyranyl, which is 6,6-bicyclic cycloheteroalkyl / aromatic ring system). Other examples of aryl include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl etc. In some embodiments, aryl groups can be optionally substituted as described herein. Aryl ring can be substituted by substituents as described herein at one or more positions, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic radical, aromatic or heteroaromatic moiety, -CF , -CN etc. In some embodiments, aryl groups can have one or more halogen substituents, and can be referred to as " haloaryl " groups. Full haloaryl, i.e., aryl (such as -C 6 F 5 ) in which all hydrogen atoms are replaced by halogen atoms, is included in the definition of " haloaryl ". In certain embodiments, aryl groups are substituted by another aryl group, and can be referred to as biaryl groups. Each aryl group in the biaryl group can be optionally substituted as disclosed herein.

[0121] As used herein, "heteroaryl" refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from oxygen (O), nitrogen (N), sulfur (S), silicon (Si), and selenium (Se), or a polycyclic ring system in which at least one ring present in the ring system is aromatic and contains at least one ring heteroatom. Polycyclic heteroaryl groups include those having two or more heteroaryl rings fused together, as well as those having at least one monocyclic heteroaryl ring fused to one or more aromatic carbocyclic, non-aromatic carbocyclic, and / or non-aromatic ring heteroalkyl rings. A heteroaryl group as a whole can have, for example, 5 to 24 ring atoms and contain 1-5 ring heteroatoms (i.e., 5-20 membered heteroaryl). A heteroaryl group can be attached at any heteroatom or carbon atom that results in a stable structure. Generally, the heteroaryl ring does not contain O-O, S-S, or S-O bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S,S-dioxide). Examples of heteroaryl groups include 5- or 6-membered monocyclic and 5-6 bicyclic systems as shown below: wherein T is O, S, NH, N-alkyl, N-aryl, N-(arylalkyl) (e.g., N-benzyl), SiH2, SiH(alkyl), Si(alkyl)2, SiH(arylalkyl), Si(arylalkyl)2, or Si(alkyl)(arylalkyl). Examples of such heteroaryl rings include pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, isobenzofuranyl, naphthyridinyl, phtalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furanopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, and the like. Other examples of heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuranopyridinyl, and the like. In some embodiments, a heteroaryl group can be optionally substituted as described herein. A heterocycle can be substituted at one or more positions with a substituent described herein, such as halo, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocycle, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0122] The term "optionally substituted" refers to a chemical group, such as alkyl, cycloalkyl, aryl, heteroaryl, and the like, in which one or more hydrogens can be replaced by a substituent group described herein, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, or heteroaryl, -CF3, -CN, and the like.

[0123] As used herein, the expression "covalent bond" in relation to a chemical group or moiety is intended to mean a covalent linkage of the chemical group or moiety to another chemical group or moiety.

[0124] ​As used herein, the term pharmaceutically acceptable salt refers to any salt of a compound of the present application that retains its biological properties and is not toxic or otherwise unsuitable for pharmaceutical use. Such salts can be derived from various organic and inorganic counterions well known in the art, and include those herein. These salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-methylbenzoic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic, and the like acids; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or alkali or alkaline earth metal hydroxides, e.g., sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxides, ammonia, or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.In addition, examples of salts include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains a basic functional group, salts of nontoxic organic or inorganic acids can be used, such as hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethane-disulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-methylbenzenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylates, glucoheptanoates, 3-phenylpropionates, trimethylacetates, t-butylacetates, lauryl sulfates, gluconates, benzoates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylaminosulfonates, quinates, mucates, and the like.

[0125] The phrase "aggregation-induced emission" or "AIE" as used herein refers to the enhancement of emission of a fluorescent compound when the fluorescent compound is aggregated in an amorphous or crystalline (solid) state, while the fluorescent compound exhibits weak emission or substantially no emission in a dilute solution.

[0126] The term "λ ex " as used herein refers to the excitation wavelength.

[0127] The term "λ em " as used herein refers to the emission wavelength.

[0128] As used herein, "subject" refers to an individual. Thus, a "subject" can include domesticated animals (e.g., cats, dogs, and the like), livestock (e.g., cows, horses, pigs, sheep, goats, and the like), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, and the like), and birds. A "subject" can also include a mammal, such as a primate or a human.

[0129] "Prevent" or other forms of the word, means to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chance that a particular event or characteristic will occur. Prevention does not need to be compared to a control, as it is usually more absolute than, for example, reduction. As used herein, something can be reduced without being prevented, but something that is reduced can also be prevented. Similarly, something can be prevented without being reduced, but something that is prevented can also be reduced. It should be understood that where the word "reduce" or "prevent" is used, unless specifically stated otherwise, the use of the other word is also expressly disclosed.

[0130] "Treat" or other forms of the word means administering a composition or performing a method to reduce, prevent, inhibit, or eliminate a particular characteristic or event (eg, Alzheimer's disease). The term "managing" is used synonymously with the term "treating."

[0131] The term "therapeutically effective" means that the amount of the composition used is sufficient to improve one or more causes or symptoms of the disease or condition. Such improvement only requires a reduction or change, not necessarily elimination.

[0132] The terms "β-amyloid," "β-amyloid peptide," "β-amyloid," "Aβ," and "Aβ peptide" are used interchangeably herein to refer to the approximately 4-kDa internal fragment of 39-43 amino acids, such as Aβ, of a larger transmembrane glycoprotein called amyloid precursor protein. 39 , Aβ 40 , Aβ 41 , Aβ 42 and Aβ 43 .

[0133] When a trade name is used herein, Applicants intend to include independently the trade name product formulation, the generic drug, and the active pharmaceutical ingredient of the trade name product.

[0134] Provided herein is an AIEgen having formula 1:

[0135]

[0136] or a pharmaceutically acceptable salt thereof, wherein:

[0137] m is an integer selected from 1 to 4;

[0138] n is in each case an integer selected from 1 to 6;

[0139] p is an integer selected from 1 to 4;

[0140] q is an integer selected from 2-6;

[0141] A is a chemical bond or a moiety having the following structure:

[0142]

[0143] Y is O, S, or -NR 6 -;

[0144] X is -O(C=O)- or -(R 4 )C=C(R 4 )-;

[0145] R 1 independently at each occurrence is hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R 7 )(C=O)OR 7 , -O(C=O)N(R 7 )2, -SO2R 7 , -SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0146] R 2 is a moiety having the structure:

[0147]

[0148] R 3 is hydrogen or cyano;

[0149] R 4 independently at each occurrence is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0150] R 5 is hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R7 )(C=0)OR 7 7 7 7 n Z;

[0151] R 6

[0152] R 7 n Z; or two R7together with the atom or atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0153] R 8 7 7 7 7 7 7 7 7 7 7 7 7 7 7 n Z;

[0154] R 9 q OH or -(CH2) q NH2; Q is an anion; and

[0155] Z is independently at each occurrence halogen, -CºCH, -N3, -NCS, -NCO, -OR 7 7 7 ​​​​​​​​​​​​​​​​​​​​​​​​)2, -(C=0)R 7 , -(C=0)OR 7 , -(C=0)N(R 7 )2, -N(R 7 )(C=0)R 7 , -0(C=0)R 7 , -N(R 7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, or N-maleimide.

[0156] In the case where X is -0(C=0)-, the AIEgen can have Formula 3:

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , A, and m are each as defined herein.

[0159] In the case where x is -(R 4 )C=C(R 4 )-, the AIEgen can have Formula 4:

[0160]

[0161] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , A, and m are each as defined herein.

[0162] In the case where A is a bond, the AIEgen can have Formula 5:

[0163]

[0164] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , X, and m are each as defined herein.

[0165] In the case where R 2 is a benzothiazole moiety of the following formula:

[0166]

[0167] The benzothiazole moiety can be covalently bonded at the C2, C4, C5, C6, or C7 carbon, as shown below:

[0168]

[0169] In certain embodiments, m and p are each independently selected from 1-4, 1-3, 1-2, or 1.

[0170] In certain embodiments, q is 2-5, 3-5, 2-4, or 2-3.

[0171] In certain embodiments, n is 1-6, 2-6, 2-5, 2-4, or 2-3.

[0172] In certain embodiments, A is a bond or a moiety selected from:

[0173]

[0174] wherein each of Y and R5is as defined herein.

[0175] Y can be S, O, or -NR 6 , wherein R 6 is hydrogen or alkyl. In certain embodiments, Y is S or O.

[0176] R 1 may be independently selected at each occurrence from hydrogen, halogen, -OR 7 , -SR 7 , -N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R 7 )(C=O)OR 7 , -O(C=O)N(R 7 )2, -alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, and -(CH2) n Z; in certain embodiments, one occurrence of R 1 is -N(R 7 )2. In certain embodiments, one occurrence of R 1 is -N(R 7 )2, wherein each occurrence of R 7 is independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z.

[0177] In certain embodiments, R 2 is a moiety selected from:

[0178]

[0179] Among them, p, Q, R 8 and R 9 Each of which is as defined herein.

[0180] R 3 Each occurrence can independently be hydrogen or alkyl.

[0181] R 4 It can be hydrogen, -OR 7 、-SR 7 、-N(R 7 )2、-N(R 7 )(C=O)R 7 、-O(C=O)R 7 、-N(R 7 )(C=O)OR 7 、-O(C=O)N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z. In certain embodiments, R 5 It's hydrogen.

[0182] In certain embodiments, R6 is hydrogen or alkyl.

[0183] R 7 Each occurrence of is independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z; or two R 7 Together with the one or more atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl. 7 Each occurrence is independently alkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2)nZ; or two R 7 Together with the one or more atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group.

[0184] R 8 Each occurrence may be independently selected from hydrogen, halogen, -OR 7 、-SR 7 、-N(R 7 )2、-N(R 7 )(C=O)R 7 、-O(C=O)R 7 、-N(R 7 )(C=O)OR 7 、-O(C=O)N(R 7)2, -alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, and -(CH2) n Z. In certain embodiments, R 8 is hydrogen.

[0185] In certain embodiments, R 9 is alkyl, -(CH2) q OH, or -(CH2) q NH2. In certain embodiments, R 9 is -(CH2) q OH, or -(CH2) q NH2, wherein q is 2-5, 2-4, 2-3, or 2.

[0186] In certain embodiments, Z is, at each occurrence, independently halogen, -C≡CH, -N3, -NCS, -NCO, -OH, -SH, -NH2, -(C=0)H, -(C=0)OH, or N-maleimide.

[0187] Q can be any anion known in the art. In certain embodiments, Q is, at each occurrence, independently a pharmaceutically acceptable anion. Exemplary pharmaceutically acceptable anions include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, trithionomolate, and valerate. In certain embodiments, Q is, at each occurrence, bromide.

[0188] In certain embodiments, the AIEgen is selected from:

[0189]

[0190] or a pharmaceutically acceptable salt thereof, wherein

[0191] n is an integer selected from 2-4;

[0192] q is an integer selected from 2-4;

[0193] R 7 in each case is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z; or two R 7 together with the nitrogen to which they are covalently bonded form a 3-6 membered heterocycloalkyl;

[0194] R 9 is alkyl, -(CH2) q OH or (CH2) q NH2;

[0195] Z is halogen, -CºCH, -N3, -NCS, -NCO, -OH, -SH, -NH2, -(C=O)H, -(C=O)OH, or N-maleimide; and Q is a pharmaceutically acceptable anion.

[0196] In certain embodiments, the AIEgen is selected from:

[0197]

[0198] or a pharmaceutically acceptable salt thereof, wherein Q is a pharmaceutically acceptable anion.

[0199] The present disclosure also provides pharmaceutical compositions comprising an AIEgen described herein and at least one pharmaceutically acceptable excipient or carrier.

[0200] The AIEgens described herein, and pharmaceutically acceptable salts thereof, can be administered to a subject, alone or in combination with pharmaceutically acceptable excipients, carriers, and / or diluents, in a pharmaceutical composition, in accordance with standard pharmaceutical practice. The AIEgens can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous, and topical administration, with intravenous administration being the preferred method.

[0201] Accordingly, the present disclosure provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of an AIEgen described herein, formulated together with one or more pharmaceutically excipients, acceptable carriers (additives) and / or diluents. The pharmaceutical compositions of the present disclosure can be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or intradermal injection, as for example, a sterile solution or suspension or sustained-release formulation; and (2) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for oral ingestion, sublingual, and buccal ingestion, boluses, powders, granules, pastes for application to the tongue.

[0202] As described herein, certain embodiments of the AIEgens described herein may contain basic functional groups, such as amino groups, and thus be capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of the AIEgens disclosed herein. These salts can be prepared in situ during the manufacture of the administration vehicle or dosage form, or by reacting the purified AIEgens described herein in free base form with a suitable organic or inorganic acid, and isolating the salts formed in a subsequent purification process. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate, among others.

[0203] Pharmaceutically acceptable salts of the AIEgens of the present disclosure include conventional non-toxic salts or quaternary ammonium salts of the AIEgens, such as those derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochlorides, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0204] In other cases, the AIEgens described herein may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic base addition salts of the AIEgens disclosed herein. These salts can also be prepared in situ during the preparation of the administration vehicle or dosage form, or by reacting the purified free acid form of the AIEgen with a suitable base (e.g., a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate of a metal cation), ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0205] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, solubilizers, isotonic and absorption agents, and the like, can also be present in the compositions.

[0206] Methods of making these formulations include the step of bringing into association AIEgens described herein and the carrier or excipient and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the AIEgens of the present disclosure with a liquid carrier, a liquid carrier followed by a solid carrier, or a solid carrier with or without the use of excipients, and then, if necessary, shaping or packaging the product.

[0207] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include the AIEgens described herein in combination with one or more pharmaceutically acceptable, sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use, which can contain sugars, alcohols, antioxidants, buffers, bacteriostats, chelating agents, solutes which render the formulation isotonic with the blood of the intended recipient or suspending agents.

[0208] Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0209] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0210] The AIEgens described herein can be readily prepared using methods well known in the art. In certain embodiments, the AIEgens described herein are prepared according to a method comprising the step of reacting a compound of Formula 6:

[0211]

[0212] m is an integer selected from 1-4;

[0213] n is, at each occurrence, an integer selected from 1-6;

[0214] A is a bond or a moiety having the structure:

[0215]

[0216] Y is O, S, or -NR 6 -;

[0217] X is -O(C=O)- or -(R 4 )C=C(R 4 )-;

[0218] R 1 , at each occurrence, is independently hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R 7 )(C=O)OR 7 , -O(C=O)N(R 7 )2, -SO2R 7 , -SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2)nZ;

[0219] R 4 , at each occurrence, is independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl;

[0220] R 5 is hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R 7 )(C=O)OR 7 , -O(C=O)N(R 7 )2, -SO2R7 -SO2N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z; and

[0221] R 6 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl or heteroaryl;

[0222] R 7 is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or -(CH2) n Z; or two R 7 together with the atom(s) to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and

[0223] Z is independently at each occurrence halogen, -C≡CH, -N3, -NCS, -NCO, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R 7 )2, -N(R 7 )(C=O)R 7 , -O(C=O)R 7 , -N(R 7 )(C=O)OR 7 , -O(C=O)N(R 7 )2, -SO2R 7 , -SO2N(R 7 )2, or N-maleimide;

[0224] with a secondary amine and a compound of formula 7a, 7b or 7c, or a conjugate base thereof:

[0225]

[0226] wherein

[0227] p is an integer selected from 1-4;

[0228] R 8 is independently at each occurrence hydrogen, halogen, cyano, nitro, -OR 7 , -SR 7 , -N(R 7 )2, -(C=O)R 7 , -(C=O)OR 7 , -(C=O)N(R7 )2, -N(R 7 )(C=0)R 7 , -0(C=0)R 7 , -N(R 7 )(C=0)OR 7 , -0(C=0)N(R 7 )2, -S02R 7 , -S02N(R 7 )2, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or -(CH2) n Z;

[0229] R 9 is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, -(CH2) q OH, or -(CH2) q NH2; Q is an anion;

[0230] to form an AIEgen of Formula 1.

[0231] Any secondary amine can be used in the method of making an AIEgen of Formula 1. The selection of suitable secondary amines is well within the purview of one of ordinary skill in the art. In certain embodiments, the dialkylamine is of the formula HN(R 13 )2, wherein R 13 is, independently at each occurrence, alkyl, cycloalkyl, or heterocycloalkyl; or both R 13 together form a 5-6 membered heterocycloalkyl comprising a heteroatom selected from the group consisting of O, N, and S. Exemplary secondary amines include, but are not limited to, dialkylamines such as dimethylamine, diethylamine, morpholine, piperazine piperidine, pyrrolidine, and the like.

[0232] The compound of Formula 6, the secondary amine, and the compound of Formula 7a or 7b can be contacted in any order. In certain embodiments, all or some of the reagents are added substantially simultaneously, sequentially, or a combination thereof. In certain embodiments, the secondary amine is contacted with the compound of Formula 6, followed by contacting the compound of Formula 7a or 7b. In other embodiments, the compound of Formula 6 is contacted with the compound of Formula 7a or 7b, followed by contacting the secondary amine.

[0233] The preparation of the AIEgen of Formula 1 can be performed in any solvent, neat, or using the secondary amine as the solvent. Exemplary solvents include polar solvents such as water, polar protic organic solvents, polar aprotic organic solvents, and mixtures thereof. Exemplary solvents include, but are not limited to, alcohols, ketones, formamides, halogenated alkanes, aromatic solvents, ethers, dialkylsulfoxides, and mixtures thereof. In certain embodiments, the solvent is methanol, ethanol, 1-propanol, 2-propanol, or mixtures thereof.

[0234] Preparation of the AIEgen of Formula 1 can be performed at a temperature of 23-120 °C. In certain embodiments, preparation of the AIEgen of Formula 1 can be performed at a temperature of 23-100 °C, 23-90 °C, 30-90 °C, 40-90 °C, 50-120 °C, 60-90 °C, 70-90 °C, or 70-80 °C.

[0235] The present disclosure also provides a method of imaging a beta-amyloid protein, the method comprising contacting the beta-amyloid protein with an AIEgen described herein; illuminating the AIEgen with electromagnetic radiation; and detecting luminescence from the AIEgen. The method can be performed in vivo, in vitro, or ex vivo.

[0236] The beta-amyloid protein can be Aβ 39 , Aβ 40 , Aβ 41 , Aβ 42 , and Aβ 43 , or a mixture thereof. In certain embodiments, the beta-amyloid protein is Aβ 42 .

[0237] The electromagnetic radiation can have an absorption wavelength λabsbetween 400-600 nm, 450-550 nm, 450-525 nm, 450-500 nm, 470-500 nm, or 480-500 nm.

[0238] The luminescence can have a luminescence wavelength λembetween 600-750 nm, 600-725 nm, 600-710 nm, 600-705 nm, 600-700 nm, 600-690 nm, 650-700 nm, 690-705 nm, or 660-690 nm. em .

[0239] In certain embodiments, the AIEgen exhibits a signal-to-noise ratio (S / N) of 5-15 fold, 6-15 fold, 7-15 fold, 8-15 fold, 9-15 fold, 10-15 fold, 11-15 fold, 12-15 fold, 13-15 fold, or 14-15 fold.

[0240] The present disclosure also provides a method of at least partially inhibiting Aβ fibrillogenesis, the method comprising contacting an Aβ peptide with an AIEgen described herein, thereby at least partially inhibiting Aβ fibrillogenesis. In certain embodiments, the step of at least partially inhibiting Aβ fibrillogenesis comprises inhibiting the formation of a beta-sheet structure Aβ peptide.

[0241] Also provided herein is a method of treating Alzheimer's disease in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of an AIEgen described herein. In certain embodiments, the subject is a human.

[0242] DCTB and DCPH were synthesized and their structure-activity relationship was investigated. Figure 1 ) They exhibited emission maxima at 601 and 690 nm, respectively, due to strong ICT nature. Figure 2 For hydrophobic DCTB, it was soluble in THF but aggregated in poor solvent water. It showed very weak AIE effect with less than 2-fold increase when the water fraction (f Figure 2

[0243] For DCPH, it was more water and polar solvent soluble due to the introduction of pyridinium salt with hydroxyl group. The AIE properties were investigated in DMSO / toluene mixtures with different toluene fractions (f t ) and found that the PL intensity in aggregates (f t ) was enhanced about 2-fold compared to that in DMSO solution. Figure 2 D) However, to achieve more obvious emission enhancement with low background signal, the TICT and AIE properties can be further modified. In contrast, upon the variation of the stronger electron-donating moiety with a wide aromatic thiophene bridge, an amphiphilic AIEgen exemplified by DNTPH was developed with prominent AIE phenomenon and good water solubility. DNTPH did not emit in aqueous solution and its NIR fluorescence at 683 nm kept increasing until the volume fraction of toluene (f t ) and the fluorescence enhancement increased to about 40-fold Figure 2 D) Moreover, the initial weak fluorescence intensity of DNTPH in aqueous solution and the prominent emission enhancement behavior in aggregated state make it an ideal candidate for detecting protein fibril formation such as Ab aggregates.

[0244] Examples

[0245] Example 1 - Synthesis of DCTB

[0246] A mixture of 7-(diethylamino)-2-oxo-2H-chromene-3-carbaldehyde (245 mg, 1.0 mmol), benzothiazole-2-acetonitrile (195 mg, 1.1 mmol) and a few drops of piperidine in ethanol (EtOH, 5 mL) was heated under reflux for 5 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by silica gel chromatography using n-hexane / DCM = 3:1, v / v as eluent to give the red product (320 mg, 78% yield). 1 ​H NMR (chloroform-d, 400MHz): δ=8.91 (s, 1H), 8.40 (s, 1H), 8.09 (d, J=8.2Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.50 (t, J= 7.7Hz, 1H), 7.46-7.39 (m, 2H), 6.66 (d, J=9.0Hz, 1H), 6.50 (s, 1H), 3.48 (q, 4H), 1.27 (t, J=7.1Hz, 6H) ppm.

[0247] Example 2 - Synthesis of DCPH

[0248] A mixture of 7-(diethylamino)-2-oxo-2H-chromene-3-carbaldehyde (245 mg, 1.0 mmol), 1-(2-hydroxyethyl)-4-methylpyridinium bromide (310 mg, 1.1 mmol) and a few drops of piperidine in EtOH (5 mL) was heated at reflux for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by silica gel chromatography using DCM / MeOH=10:1, v / v as eluent to give a red product (250 mg, 56% yield). 1 H NMR (DMSO-d6, 400MHz): δ=8.77 (d, J=6.6Hz, 2H), 8.24 (s, 1H), 8.17 (d, J=6. 4Hz, 2H), 7.83 (d, J=16.08Hz, 1H), 7.68 (d, J=16.04, 1H), 7.54 (d, J=9.0Hz, 1 H), 6.80 (d, J=8.04Hz, 1H), 6.60 (s, 1H), 5.27 (t, J=5.24Hz, 1H), 4.52 (t, J= 4.84, 2H), 3.86-3.82 (m, 2H), 3.52-3.40 (m, 4H), 1.15 (t, J = 6.24Hz, 6H) ppm.

[0249] Example 3 - Synthesis of DNTPH

[0250] A mixture of 5-(6-(dimethylamino)naphthalene-2-yl)thiophene-2-carboxaldehyde (140 mg, 0.5 mmol), benzothiazole-2-acetonitrile (160 mg, 0.6 mmol) and a few drops of piperidine in EtOH (5 mL) was heated to reflux overnight. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by silica gel chromatography using DCM / MeOH=10:1, v / v as eluent to give a dark red product (150 mg, 64% yield). 1H NMR (DMSO-d6, 400MHz): δ=8.82 (d, J=6.4Hz, 2H), 8.25 (d, J=15.9, 1H), 8.20 ( d, J=6.4Hz, 2H), 8.08 (s, 1H), 7.82 (d, J=9.1Hz, 1H), 7.73 (s, 2H), 7.66 (d, J= 3.72Hz, 1H), 7.56 (d, J = 3.92Hz, 1H), 7.28-7.25 (m, 1H), 7.16 (d, J = 15.91Hz, 1H), 6.96 (s, 1H), 4.54 (t, J=4.9Hz, 2H), 3.88-3.84 (q, 2H), 3.05 (s, 6H)ppm.

[0251] Example 4 - Aβ fibril detection ability

[0252] We investigated whether DNTPH has a fluorescent response when it binds to Aβ aggregates. 42 When the fibrils were titrated with DNTPH, a strong and gradual increase in red fluorescence intensity (up to about 18-fold) was observed, which took about 30 minutes to reach a plateau. Without wishing to be bound by theory, it is believed that DNTPH is able to bind to the hydrophobic surface of aggregated amyloid fibrils with the help of the binding unit, resulting in a reduction in conformational freedom and rotational restriction. In contrast, DCTB and DCPH showed no significant effect on Aβ. 42 The much lower fluorescence response of fibrils (less than 2-fold) ( Figure 3 ). Although ThT showed stronger fluorescence intensity when bound to Aβ aggregates, it showed a similar fluorescence response of only 5 times. This is because these three probes showed high background signals, which resulted in a low S / N ratio even with good fluorescence response to the test object. In contrast, DNTPH has a minimized background in aqueous solution (only 1 / 10 times that of ThT) due to its water solubility and AIE effect, which provides a prerequisite for ultra-high S / N ratio for Aβ detection ( Figure 4 ).

[0253] Example 5 - Aβ fibril inhibition and mechanism of action studies

[0254] Surprisingly, inhibition of Aβ fibrillation occurred when the morphology of Aβ with or without the dye was microscopically investigated by transmission electron microscopy (TEM). After incubation with 20 μM Aβ peptide at 37°C for 1 and 2 days, many short and branched Aβ fibrils and more tangled fibrils were observed. However, when 10 μM DNTPH was added to the peptide solution before the 2-day incubation, the nucleation phase and extension were greatly slowed down. After further incubation, the Aβ fibrils disintegrated into spherical and amorphous aggregates ( Figure 5 ).

[0255] Far-UV CD spectroscopy was used to monitor the changes in the secondary structure of Aβ fibrils in the presence and absence of DNTPH ( Figure 5 E). As shown in the figure, Aβ fibrils show a clear negative CD band at 218 nm, which is characteristic of β-sheet structure, while the intensity of Aβ peptide is much weaker. In contrast, Aβ incubated in the presence of DNTPH 42 2 days resulted in a much lower CD intensity at 218 nm, indicating that DNTPH can effectively inhibit the formation of β-sheet structure. TEM images and CD spectra are consistent with the ThT assay results, which clearly confirms that DNTPH can effectively inhibit Aβ fibril formation and promote the disassembly of Aβ fibrils.

[0256] Previous studies have shown that the initial stage of the amyloidosis process is characterized by excessive accumulation of Aβ monomers caused by unbalanced Aβ clearance. Therefore, most peptide-based inhibitors, antibodies and small molecules are well designed to target Aβ monomers and disrupt the structure and assembly dynamics. Without wishing to be bound by theory, it is speculated that DNTPH can bind to amino acid residues at specific sites of pre-aggregated Aβ peptides, delaying the slowed fibril formation. In order to gain a mechanistic understanding of the binding process of DNTPH to Aβ peptides, docking calculations were performed. In order to search for possible binding modes, large-scale flexible docking was performed between DNTPH and a collection of protein structures, generating 1,000 flexible docking conformations, and the 100 most reliable conformations were selected. The lowest docking score was in Figure 6 The solvent accessible surface area of ​​​​DNTPH is plotted relative to that of DNTPH. When we further selected the hydrophobic surface area of ​​DNTPH and docked it with Aβ peptide, a more concise docking score distribution was obtained. The two poses with the lowest energy were both achieved under fibril formation conditions. The top binding poses with the lowest energies of -8.04 and -7.77 kcal / mol showed a common structural feature: the phenyl ring of DNTPH contacts the hydrophobic residues of Aβ peptide, such as leucine, valine, phenylalanine and tyrosine. During fibril formation, the chains of Aβ peptide are randomly folded with large structural flexibility. This enhances the possibility of its hydrophobic residues being exposed to the solvent, which in turn promotes the binding of DNTPH through hydrophobic interactions ( Figure 6 C and 6D). In addition, the hydroxyl group of DNTPH can interact with hydrophilic residues such as arginine and asparagine through hydrogen bonds, providing a strong driving force. Therefore, the binding of DNTPH to this fragment may interfere with the structural rearrangement of the monomer and hinder the assembly of Aβ fibrils, providing a unique mechanistic approach to inhibiting protein amyloid formation.

[0257] Example 6 - In vitro imaging of Aβ fibrils and cells recovered from Aβ fibril-induced cellular toxicity by DNTPH Figure 7

[0258] The remarkable inhibitory effect of DNTPH on amyloid fibril formation prompted the use of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay to check the ability of DNTPH to prevent Aβ 42 fibrils to induce cytotoxicity. As shown in Figure 7 , DNTPH had little effect on the viability of neuroendocrine PC12 cells even at high concentrations of 100 μM. In contrast, Aβ 42 fibrils significantly reduced cell survival to 75% and 60% ( Example 7 - Ex vivo and in vivo imaging and mapping with Aβ plaques ) after 24 and 48 hours of incubation, indicating high toxicity of Aβ 42 fibrils to PC12 cells. No significant cytotoxicity was observed for Aβ monomers at concentrations of 5-20 μM for less than 24 hours of exposure. However, when the incubation time was increased to 48 hours, significant cytotoxicity was shown at a concentration of 20 μM with 50% cell death. This indicates that the neurotoxicity of Aβ 42 also comes from the growing soluble oligomeric Aβ species, which is consistent with the recent increasing evidence. It is noteworthy to see the neuroprotective effect of DNTPH in the cytotoxic activity. The original toxicity of Aβ to neuronal cells was greatly inhibited when DNTPH was incubated with Aβ monomers and fibrils at a ratio of 0.2. Further confocal imaging showed that DNTPH displayed its high selectivity to Aβ even in the presence of complex cellular environment. This selectivity was confirmed with ThT labeling, which was previously reported to specifically target Aβ fibrils in vitro. The results of MTT assay and confocal imaging indicate that DNTPH effectively reduces Aβ 42 aggregate-induced cytotoxicity by targeting and inhibiting Aβ fibrils.

[0259] Figure 8

[0260] To further explore the potential clinical application of DNTPH, its feasibility to cross the BBB in live animals and to image Aβ plaques in vivo in transgenic mice was demonstrated ( Figure 9 and 9 ). Tail vein injection and brain immersion with DNTPH were performed in 6-month-old non-transgenic and transgenic mice, which started to show human Aβ plaques development in the brain. As shown in Figure 10As shown, the strong fluorescence signal was concentrated in the ventricle and could be captured very effectively. In particular, the fluorescence intensity of DNTPH in the brain region of APP / PS1 mice was much higher than that of wild-type mouse controls only 30 minutes after injection, indicating that the probe DNTPH specifically captured Aβ plaques in vivo. In addition, histological studies were conducted to assess the impact of AIEgens on live mice. Fluorescence imaging of organs removed from APP / PS1 mice and wild-type mice revealed that no obvious damage or inflammatory lesions were observed in the major organs (brain, heart, lung, liver, spleen, and kidney) of the mice after treatment with AIEgens, indicating good biocompatibility ​ ).

Claims

1. An aggregation-induced emission molecule, wherein the aggregation-induced emission molecule is selected from: or a pharmaceutically acceptable salt thereof, wherein Q is an anion.

2. A pharmaceutical composition comprising the aggregation-induced emission molecule of claim 1 and at least one pharmaceutically acceptable excipient or carrier.

3. Use of the aggregation-induced emission molecule according to claim 1 in the preparation of a preparation for imaging β-amyloid protein.

4. The use according to claim 3, wherein the β-amyloid protein comprises Aβ 42 .

5. The method according to claim 3, wherein the aggregation-induced emission molecule exhibits a λ between 690 and 705 nm. em Maximum luminescence wavelength. The use according to claim 3 , wherein the aggregation-induced emission molecule exhibits a signal-to-noise ratio (S / N) of 10-15 times.

7. Use of the aggregation-induced emission molecule according to claim 1 in the preparation of a preparation for partially inhibiting Aβ fibril formation.

8. Use of a therapeutically effective amount of the aggregation-induced emission molecule according to claim 1 in the preparation of a medicament for treating Alzheimer's disease in a subject in need thereof.

Images