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Compound for antemortem diagnosis of alzheimer's disease and i(IN VIVO) imaging and prevention of amyloid deposition

A compound and amyloid protein technology, applied in the preparation of tin organic compounds, organic compounds, preparations for in vivo tests, etc., can solve problems such as low bioavailability and difficulty in passing through macromolecules

Inactive Publication Date: 2001-02-28
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of antibody probes is the difficulty of getting these large molecules across the blood-brain barrier
Another problem with the mechanism of azo dye metabolism is that a large amount of administered drug is already metabolized by intestinal bacteria before absorption
Although the released metabolites are harmless, their low bioavailability is also a disadvantage

Method used

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  • Compound for antemortem diagnosis of alzheimer's disease and i(IN VIVO) imaging and prevention of amyloid deposition
  • Compound for antemortem diagnosis of alzheimer's disease and i(IN VIVO) imaging and prevention of amyloid deposition
  • Compound for antemortem diagnosis of alzheimer's disease and i(IN VIVO) imaging and prevention of amyloid deposition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Embodiment 1. Synthesis of Chrysamine G and derivatives thereof

[0139] Synthesis of Chrysamine G

[0140]The synthesis of Chrysamine G (ie 4,4'-bis(3-carboxy-4-hydroxyphenylazo)-biphenyl) requires the following reaction steps. These reaction steps should be referred to as "chrysamine G synthesis" conventional methods. Benzidine·2HCl (28.9 mg, 0.11 mmole, Sigma Chemical Company, St. Louis, MO) was added to a 50 mL round bottom flask containing 1.5 mL of 1:1 dimethylsulfoxide:distilled / deionized water. The individual reaction steps were performed at 0°C unless otherwise stated. 29 μl of concentrated hydrochloric acid was added and a clear solution was obtained after stirring. Add 15.5 mg (0.22 mmole) NaNO dropwise to the biphenyl gum solution 2 In 300 μl 1:1 DMSO / H 2 solution in O. The pH of the resulting solution was about 2-3. The reaction mixture was stirred for 45 minutes. Then in this benzidine tetrazide mixture, dissolve in 2.0ml containing 250m...

Embodiment 2

[0230] Example 2 Binding specificity of Chrysamine G and Chrysamine G derivatives to Aβ

[0231] Binds to synthetic Aβ(10-43)

[0232] Chrysamine G binds well to synthetic Aβ(10-43) peptides in vitro. Figure 4A shows Scatchard analysis of Chrysamine G binding to A[beta](10-43). Its higher affinity component has a K D is 0.257 μM, and Bmax is 3.18 nmol Chrysamine G / mg Aβ(10-43). These data alone are not sufficient to define the lower affinity components well, but show that their K D 4.01 μM, B max It is 18.7 namol Chrysamine G / mg Aβ(10-43). This low-affinity fraction represents the high concentration of Chrysamine G binding to a different low-affinity site rather than binding to an impurity in the preparation. Since the in vivo injected amount of Chrysamine G was so low that there was no binding of the low affinity components. At very low concentrations, the ratio of high-affinity binding to low-affinity binding is very large.

[0233] Such as Figure 5 As shown, the a...

Embodiment 3

[0251] Example 3 Using Chrysamine G to Distinguish Normal Brain and Alzheimer's Brain

[0252] Chrysamine G binding to AD brain features

[0253] To understand the enhanced binding of Chrysamine G to AD brain, Scatchard analysis was performed on AD brain samples bound to Chrysamine G and its derivatives (Fig. 4B, Table 1). Under the conditions applied, control and AD brains showed a single binding component. K in the AD brain D 16% lower than in the control group, but the difference was not significant (p=0.29). B in the AD brain max It was 36% higher than that in the brain of the control group, but the difference also did not reach significance (p=0.09). Thus, the increased binding in AD brains was primarily due to the presence of more bound components in control brains, rather than the presence of a single component.

[0254] KD(μM) Bmax(pmol / μg port) Control group (n=6) 0.47±0.049 0.576±0.092 AD (n=5) 0.39±0.048 0.784±0.061

[0255] The...

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Abstract

Disclosed are amyloid-binding compounds which are Chrysamine G derivatives, pharmaceutical compositions containing these compounds, and the use of these compounds in vivo to identify Alzheimer's disease and to diagnose other diseases characterized by amyloidosis such as The method of Down's congenital dementia. Also disclosed are pharmaceutical compositions containing Chrysamine G and its derivatives and the use of these compositions for the prevention of cell degeneration and amyloid-induced toxicity in amyloidosis-related diseases. At the same time, it also discloses a quantitative method for amyloid deposition in tissue homogenates of biological living tissues and post-mortem tissues by using the chrysamine derivatives.

Description

[0001] This invention was made with assistance from the National Institute of Aging under Grant Nos. AG-05443, AG-05133 and AG-08974. This application is a continuation-in-part of U.S. Patent Application No. 08 / 432,019 (filed May 1, 1995), which is U.S. Patent Application No. 08 / 282,289 Application (filing date: July 29, 1994) is a partial continuation application. Background of the invention [0002] The present invention relates to the identification of compounds suitable for imaging amyloid deposition in living patients. More specifically, the invention relates to methods of imaging brain amyloid deposits in vivo to enable ante-mortem diagnosis of Alzheimer's disease. The invention also relates to the therapeutic use of these compounds. [0003] Alzheimer's Disease (abbreviated "AD") is a neurodegenerative disease characterized by memory loss and other cognitive deficits. McKhann et al., Neurology 34:939 (1984). The disease is the most common cause of de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/53A61K31/603A61K31/665A61K49/00A61K49/04A61K49/06A61P25/00C07C65/19C07C229/64C07C233/87C07C235/56C07C243/22C07C245/08C07C245/10C07C251/24C07C251/86C07C309/46C07D213/80C07D257/04C07D261/20C07D271/10C07F7/22C09B35/10G01N33/566G01N33/68
CPCA61K49/0433C07C245/08C07D217/24C07D261/20C07C243/22C07D271/10C07D221/14G01N2800/2821C07D265/26C07D257/04C07C229/64G01N33/6896C07C245/10C07C2103/24C07D209/48C07C233/87C07C251/24A61K49/06G01N2333/4709C07D237/26C07D265/02C07C2103/18C07C251/86C07C2603/18C07C2603/24A61K49/10A61K51/0402A61P25/00
Inventor W·E·克伦克J·W·佩特格鲁小C·A·马蒂斯
Owner UNIVERSITY OF PITTSBURGH
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