Pi-extended acedan derivatives, their application for two-photon microscopy imaging, and their application for two-photon microscopy imaging of amyloid-beta plaque in an alzheimer's disease animal model

Patent metadata

Field	Value
Publication number	US-9658235-B2
Application number	US-201514745973-A
Country	US
Kind code	B2
Filing date	Jun 22, 2015
Priority date	Jan 14, 2015
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Provided are acedan derivatives having an extended π bond, a method for preparing the acedan derivatives, and a method for two-photon microscopy imaging of amyloid-beta plaque using the acedan derivatives; more particularly, to two-photon absorbing fluorescent compounds having a longer absorption wavelength and emission wavelength than acedan and acedan derivatives which are conventional two-photon absorbing fluorophores. The compounds provided may be usefully used for in vivo imaging studies by imaging cells or tissue using the compounds, and may also be usefully used for diagnosing Alzheimer's disease by imaging amyloid-beta plaque using the compounds.

First claim

What is claimed is:

1. An acedan derivative represented by the following Formula 1:

wherein, in Formula 1, R 1 and R 2 each are a hydrogen (H), a methyl (Me) group, an allyl group, an unsubstituted alkyl group having 2 to 12 carbon atoms, or a cyclic secondary amine;
R 3 is —(C═O)—R 5 , —(C═O)H, —CH═C(CN) 2 , or a cycloalkyl group formed with R 4 ;
R 4 is a hydrogen, or a cycloalkyl group formed with R 3 , where the cycloalkyl group formed with R 3 and R 4 is

and
R 5 is a methyl (Me), an ethyl, or an unsubstituted alkyl group having 2 to 12 carbon atoms.

2. The acedan derivative according to claim 1 , wherein the acedan derivative is a compound selected from the group consisting of the compounds with the following Formulas 4 to 8:

3. The acedan derivative according to claim 1 , wherein the acedan derivative is a two-photon absorbing fluorophore.

4. A method for imaging a cell or tissue comprising:
treating a cell or tissue with the acedan derivative according to claim 1 , and
observing the cell or tissue using a fluorescent microscope.

5. The method according to claim 4 , wherein the imaging method is a method for imaging amyloid-beta plaque in a tissue.

6. The method according to claim 4 , wherein the fluorescent microscope is a one-photon fluorescence microscope or a two-photon fluorescence microscope.

7. A method for diagnosing Alzheimer's disease, comprising administering the acedan derivative according to claim 1 to a subject in need thereof.

8. A method of preparing an acedan derivative represented by the Formula 4, according to claim 2 , from 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde, comprising synthesizing 8-(dimethylamino)-2,3,4a-tetrahydro-1H-benzo[b]xanthene-1-one by adding 2-cyclohexene-1-one and 1,4-diazabicyclo[2.2.2]octane to 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde.

9. A method of preparing an acedan derivative represented by the Formula 5, according to claim 2 , from 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde, comprising synthesizing 7-(dimethylamino)-3,3a-dihydrobenzo[g]cyclopenta[b]chromene-1(2H)-one by adding 2-cyclopentene-1-one and 1,4-diazabicyclo[2.2.2]octane to 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde.

10. A method of preparing an acedan derivative represented by the Formula 6, according to claim 2 , from 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde, comprising synthesizing 1-(8-(dimethylamino)-2H-benzo[g]chromene-3-yl)ethanone by adding 3-butene-2-one, magnesium iodide, tetramethylethylenediamine, and 4-dimethylaminopyridine to 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde.

11. A method of preparing an acedan derivative represented by the Formula 7, according to claim 2 , from 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde, comprising synthesizing 6-(dimethylamino)-3-(propynyl-2-oxy)-2-naphthaldehyde by adding propargyl bromide and potassium carbonate to 6-(dimethylamino)-3-hydroxy-2-naphthaldehyde, and adding malononitrile and copper iodide thereto.

12. A method of preparing an acedan derivative represented by the Formula 8, according to claim 2 , from 6-(dimethylamino)-3-(propynyl-2-oxy)-2-naphthaldehyde, comprising synthesizing 2-(((8-dimethylamino)-2H-benzo[g]chromene-3-yl)methylene)malononitrile by adding malononitrile, copper iodide, and triethylamine to 6-(dimethylamino)-3-(propynyl-2-oxy)-2-naphthaldehyde.

Assignees

• Postech Academy-Industry Found

Inventors

• Ahn Kyo Han
• Moon Hyunsoo
• Kim Dokyoung
• Kim Ki Hean
• Ryu Hye Gun

Classifications

• C07D311/92

  Naphthopyrans; Hydrogenated naphthopyrans · CPC title

• G01N33/6896

  Neurological disorders, e.g. Alzheimer's disease · CPC title

• G01N21/6428

  Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53) · CPC title

• G01N2333/4709

  Amyloid plaque core protein · CPC title

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title