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Red/near-infrared AIE probe and preparation method thereof, and application of red/near-infrared AIE probe in detection of Abeta aggregate and fibrotic plaques of Abeta aggregate

A near-infrared, aggregate technology, applied in the field of fluorescent probes, can solve the problems of the probe's limited ability to penetrate the blood-brain barrier, poor photostability, short probe excitation and emission wavelengths, etc., to achieve photostability and photostability. The effect of excellent bleaching, high signal-to-noise ratio and resolution, and best in vivo imaging performance

Active Publication Date: 2020-08-25
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently commercially available probes for detecting Aβ aggregates and their fibrotic plaques, such as gold standard probes Thioflavin T (ThT) and Congo red, have obvious defects in in vivo imaging: first, these probes often have good The water solubility of these probes leads to the limited ability of probes to penetrate the blood-brain barrier, and it is impossible to accumulate a sufficient amount of probe doses in the brain lesion area; secondly, the excitation and emission wavelengths of these probes are relatively short, so their excitation light source and emission It is difficult for light to pass through the skull, which further weakens the imaging effect of the probes; again, these probes are aggregation-induced fluorescence quenching (ACQ) probes, and most ACQ probes have poor photostability, are not resistant to photobleaching, and have a low signal-to-noise ratio. As a result, the fluorescence imaging life of the probe is short and the detection effect is limited.
However, the emission wavelength of most AIE probes developed so far is in the relatively short-wave region, which will affect the tissue penetration of the probe during the imaging process, and on the other hand, the background fluorescence of the organism is easy to overlap with the emission of the probe, thereby affecting Imaging effect
More importantly, most of the existing work can only achieve good detection in vitro, and the results of in vivo and in vivo experiments are still not ideal
Although there are some red / near-infrared luminescent AIE probes, the synthetic raw materials of the developed AIE probes are expensive and the synthesis steps are cumbersome, so it is difficult to develop and put them into commercial use.
In addition, with Aβ 42 Aggregates and fibrotic plaques are examples. Although there are a few in vivo imaging results based on AIE probes, it is impossible to detect Aβ 42 Early detection and imaging of aggregates and fibrotic plaques, which are central to the diagnosis and treatment of Alzheimer's disease
In short, the existing fluorescent detection system is still unable to achieve early detection of Aβ aggregates and fibrotic plaques, so it is urgent to develop new fluorescent probes to achieve early detection of Aβ aggregates and fibrotic plaques. Detection and imaging for effective diagnosis and treatment of Alzheimer's disease

Method used

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  • Red/near-infrared AIE probe and preparation method thereof, and application of red/near-infrared AIE probe in detection of Abeta aggregate and fibrotic plaques of Abeta aggregate
  • Red/near-infrared AIE probe and preparation method thereof, and application of red/near-infrared AIE probe in detection of Abeta aggregate and fibrotic plaques of Abeta aggregate
  • Red/near-infrared AIE probe and preparation method thereof, and application of red/near-infrared AIE probe in detection of Abeta aggregate and fibrotic plaques of Abeta aggregate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (Z)-3-(4-(4-(1-cyano-2-(4-(dimethylamino)phenyl)vinyl)phenyl)pyridin-1-yl-1-yl)propane- 1-sulfonic acid sodium salt

[0045] Under nitrogen protection, add 1.1–1.5 equivalents of 4-pyridineboronic acid, 1 equivalent of 4-bromophenylacetonitrile and 0.01–0.1 equivalents of tetrakistriphenylphosphine palladium(0) to tetrahydrofuran / water mixture of potassium carbonate, 85–100 Stir and reflux at ℃ for 10-12 hours. After the reaction, add water, extract with dichloromethane three times, evaporate the solvent, perform silica gel column chromatography (petroleum ether: ethyl acetate), and obtain the product of the first step. Under the protection of nitrogen, the product of the first step and 2-5 equivalents of sodium 3-bromopropanesulfonate were refluxed in acetonitrile for 48-96 hours, filtered to obtain a solid, and then washed with acetonitrile and water respectively to obtain the product of the second step. Under the protection of nitrogen, the second step product and 0...

Embodiment 2

[0050] (Z)-3-(4-(4-(1-cyano-2-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)vinyl)phenyl )pyridin-1-ium-1-yl)propane-1-sulfonic acid sodium salt

[0051] The raw materials are: bromine-substituted aryl acetonitrile is (1 equivalent of 4-bromophenylacetonitrile), arylboronic acid is (1.1-1.5 equivalents of 4-pyridineboronic acid), and linear halogenated compound is (2-5 equivalents of 3-bromopropane Sodium sulfonate) aldehyde-substituted aromatic compound is (0.9-1.2 equivalents of 4'-(dimethylamino)-[1,1'-biphenyl]-4-formaldehyde)

[0052] Preparation method is with embodiment 1, 1 H NMR (400MHz, DMSO-d 6 )δ (ppm): δ9.14 (d, J = 6.9Hz, 2H), 8.60 (d, J = 6.9Hz, 2H), 8.31–8.21 (m, 3H), 8.05 (dd, J = 13.3, 8.6 Hz, 4H), 7.85(d, J=8.5Hz, 2H), 7.69(d, J=8.9Hz, 2H), 6.84(d, J=8.9Hz, 2H), 4.74(t, J=6.7Hz, 2H), 2.98(s, 6H), 2.46(d, J=7.0Hz, 2H), 2.29–2.23(m, 2H).

[0053] The specific structure of the product obtained is as follows:

[0054]

Embodiment 3

[0056] (Z)-3-(4-(4-(1-cyano-2-(5-(4-(dimethylamino)phenyl)thiophen-2-yl)vinyl)phenyl)pyridine-1 -yl-1-yl)propane-1-sulfonic acid sodium salt

[0057] Bromine-substituted aryl acetonitrile is (1 equivalent of 4-bromophenylacetonitrile) aryl boronic acid is (1.1-1.5 equivalents of 4-pyridine boronic acid), and the linear halogenated compound is (2-5 equivalents of 3-bromopropanesulfonate sodium) Aldehyde-substituted aromatic compounds are (0.9-1.2 equivalents of 5-(4-(dimethylamino)phenyl)thiophene-2-carbaldehyde)

[0058] Preparation method is with embodiment 1, 1 H NMR (400MHz, DMSO-d 6 )δ (ppm): δ9.12 (d, J = 6.9Hz, 2H), 8.58 (d, J = 6.9Hz, 2H), 8.49 (s, 1H), 8.23 ​​(d, J = 8.7Hz, 2H) ,7.95(d,J=8.6Hz,2H),7.77(d,J=4.2Hz,1H),7.61(d,J=8.9Hz,2H),7.51(t,J=5.6Hz,1H),6.80 (d, J=9.0Hz, 2H), 4.72(t, J=6.9Hz, 2H), 2.99(s, 6H), 2.45(d, J=7.0Hz, 3H), 2.29–2.23(m, 2H) .

[0059] The specific structure of the product obtained is as follows:

[0060]

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Abstract

The invention belongs to the technical field of biological imaging, and relates to a red / near-infrared AIE probe, a preparation method thereof and an application of the red / near-infrared AIE probe indetection of Abeta aggregates and fibrotic plaques of the Abeta aggregates. The probe has a general formula, and the preparation method comprises the following steps: carrying out Suzuki reaction on bromine-substituted aryl acetonitrile and arylboronic acid, carrying out substitution or salification reaction on the reaction product and a straight-chain halogenated compound, and finally carrying out Knoevenagel condensation reaction on the reaction product and an aldehyde-substituted aromatic compound to obtain a target compound. Compared with the prior art, the aggregation-induced emission (AIE) probe disclosed by the invention overcomes the fluorescence quenching effect caused by aggregation, so that the AIE probe has higher luminous efficiency and signal-to-noise ratio. And the probe canrealize high-selectivity and high-sensitivity detection of the A beta aggregate. More importantly, the probe can realize early imaging of A beta fibrotic plaques in vivo.

Description

technical field [0001] The invention relates to the field of fluorescent probes, in particular to a novel red / near-infrared aggregation-induced luminescent fluorescent probe, a preparation method thereof, and an application in detecting Aβ aggregates and fibrotic plaques thereof. Background technique [0002] Alzheimer's disease (AD) is a degenerative disease of the nervous system, and the aggregation of β-amyloid (Aβ) and the formation of fibrotic plaques are one of the main symptoms of AD. Therefore, clinically, early detection of Aβ aggregates and fibrotic plaques plays a vital role in the diagnosis and treatment of AD patients. Fluorescence detection technology has the advantages of high sensitivity, high selectivity and low cost, and has a very broad application prospect in the diagnosis and treatment of Alzheimer's disease. Currently commercially available probes for detecting Aβ aggregates and their fibrotic plaques, such as gold standard probes Thioflavin T (ThT) an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/57C07D409/10C07D213/84C07D241/44C07D275/02C09K11/06G01N21/64G01N21/35G01N21/359
CPCC07D213/57C07D409/10C07D213/84C07D241/44C07D275/02C09K11/06G01N21/6428G01N21/6486G01N21/35G01N21/359C09K2211/1029C09K2211/1044C09K2211/1037C09K2211/1092C09K2211/1007C09K2211/1014
Inventor 田禾王毅朴梅菊
Owner EAST CHINA UNIV OF SCI & TECH
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