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Curcumin Derivatives for Amyloid-Beta Plaque Imaging

Inactive Publication Date: 2011-08-25
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The inventors show herein that by modifying curcumin's structure it is possible to shift derivative compounds' emission wavelength to an ideal range for NIR imaging. Accordingly, the invention provides “smart” probes with significant fluorescence property changes upon binding. In addition, derivative compounds are provided having improved lipophilicity relative to curcumin.

Problems solved by technology

Both memory and behavior tests, however, are not reliable and not suitable for the early detection because of the lack of noticeable syndrome at the early stage {20}.
Therefore, the early detection of AD still presents a challenge.
Although these studies indicate that molecular MRI is a promising diagnostic modality, its low sensitivity could be an obstacle for its application in clinic.
In recent years, researches have demonstrated that PET can be used as an imaging modality to detect AD pathology; however, its high cost and narrow availability of contrast agents prevent its broad usage {23}.
Although multiphoton microscopy could be very useful in animal research, it is invasive and only provides very small field-of-view information {23; 7; 5; 6; 8}.
However, curcumin is not practical for in vivo NIR imaging because of its short emission wavelength and low lipophilicity (log P<2){35}.

Method used

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example 1

Methods and Materials

[0096]Reagents used for synthesis were purchased from Aldrich without further purification. Column chromatography was performed on silica gel (SiliCycle Inc., 60 Å, 40-63 mm) slurry packed into glass columns. Thioflavin S was purchased from Aldrich. Synthetic amyloid-b protein (1-40) was purchased from rPeptide (Bogart, Ga., 30622) and aggregates for in vitro studies were generated followed the reported procedure. BSA was purchased from Sigma, and human serum was obtained from Invitrogen (type AB). 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz respectively, and are reported in ppm downfield from tetramethylsilane. Fluorescence studies were carried out with F-4500 Fluorescense Spectrophotometer. Fluorescence quantum yields were determined using aqueous solution of Cy5.5-maleimide as a standard (y=0.23). High resolution mass spectra were obtained at the Harvard University, Department of Chemistry Instrumentation Facility. Transgenic Tg2576 mice {45} ...

example 2

AD Tissue Staining

[0136]The inventors conducted tissue staining with 25 micron brain sections from 12-month old APP-PS1 mice by all the compounds listed in FIG. 12. As reported, curcumin, PiB, thioflavin T and CRANAD2 stained the plaques brightly; while as expected, CRANAD-2, CRANAD-3 and CRANAD-5 yielded good staining as well (FIG. 12B). These data indicate that these compounds are specific to Aβ plaques.

Preparation of CRANAD-3 and CRANAD-5 Compounds

[0137]Boric oxide (700.0 mg, 10.0 mmol) was dissolved in DMF (10.0 mL) at 120° C. Ensuring most of boric oxide dissolved was very crucial for high yield. To this solution, acetylacetone (1.1 mL, 10.0 mmol) was added, followed by tributyl borate (5.4 mL, 20.0 mmol) at 110° C. and stirred for 5 min. To the above borate complex, 4-N,N′-dimethylamino-benzaldehyde (3.1 g, 20.0 mmol) was added and stirred for 5 min. A mixture of 1,2,3,4-tetrahydroquinoline (0.2 mL) and acetic acid (0.4 mL) in DMF (4.0 mL) was added to the reaction mixture and...

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Abstract

The present invention provides curcumin-derived near infrared (NIR) imaging probes. Upon interacting with amyloid β aggregates, these probes undergo a range of changes, qualifying them as “smart” probes. The inventors have demonstrated that probes of the invention have the capacity to monitor the progression of Alzheimer's disease in an in vivo animal model. In addition, the present invention encompasses probes useful as PET imaging agents, MRI imaging agents and multimodal imaging agents, as well as related methods of detecting and imaging amyloid β aggregates and plaques.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional application 61 / 085,076, filed Jul. 31, 2008, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]Not Applicable.FIELD OF THE INVENTION[0003]The invention relates generally to molecular probes for amyloid-(3 plaque imaging. In particular, the invention is related to various curcumin derivatives useful for imaging amyloid-β plaques in human subjects.BACKGROUND OF THE INVENTION[0004]Amyloid-β (Aβ) deposits are a well known pathological hallmark for Alzheimer's disease (AD). Their formations arise from aggregated peptides Aβ40 and Aβ42, which are generated from amyloid peptide precursor (APP) by cleaving with β- and γ-secretases {11; 15}. Normally, the concentrations of the generated Aβ40 and Aβ42 monomers are maintained at a reasonable level through the balance between generation and clearance. Upon the initiatio...

Claims

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Application Information

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IPC IPC(8): A61B6/00A61K51/04A61K49/00C07F5/02C07D401/06C07C225/22
CPCA61K49/0021A61K51/0455G01N33/6896G01N2333/4709G01N2800/2821A61M5/007G01R33/5601A61B6/037A61B5/4088A61B5/1455A61B5/14546G01N2800/28A61K49/0002A61P25/28
Inventor CHONGZHAO, RANMOORE, ANNA
Owner THE GENERAL HOSPITAL CORP
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