Imaging Beta-Amyloid Peptides Aggregation

Patent metadata

Field	Value
Publication number	US-2016243264-A1
Application number	US-201615049126-A
Country	US
Kind code	A1
Filing date	Feb 21, 2016
Priority date	Apr 21, 2011
Publication date	Aug 25, 2016
Grant date	—

Abstract

The present invention is in the field of pharmaceuticals and chemical industries. In particular, one aspect of the present invention relates to methods for labeling, imaging and detecting the beta-amyloid (Aβ) peptides, oligomers, and fibrils in vitro and in vivo via magnetic resonance and florescence imaging by using modified carbazole-based fluorophores. A further aspect of the present invention relates to a method of reducing and preventing aggregation of beta-amyloid peptides for Alzheimer's disease (AD) as well as of treating and/or preventing Alzheimer's disease by using the modified carbazole-based fluorophore. The modified carbazole-based fluorophore according to an embodiment of the present invention is prepared by conjugating a carbazole-based fluorophore with magnetic nanoparticles to form a conjugate which is permeable to blood brain barrier of a subject being introduced therewith.

First claim

What is claimed is:

1 . A method for imaging and detection of beta-amyloid (Aβ) peptides aggregation via magnetic resonance imaging (MRI) based on modified carbazole-based fluorophores comprising a formula S series:

said method comprising:
conjugating said carbazole-based fluorophores to magnetic nanoparticles to form a conjugate of said carbazole-based fluorophores and said magnetic nanoparticles;
introducing said conjugate to a subject with beta-amyloid (Aβ) peptides aggregation; and
applying magnetic resonance imaging (MRI) to image and detect said conjugate bound to the beta-amyloid (Aβ) peptides aggregation in said subject;
wherein Ar is a heteraromatic ring selected from the group consisting of pyridinyl, substituted pyridinyl, quinolinyl, substituted quinolinyl, acridinyl, substituted acridinyl, benzothiazolyl, substituted benzothiazolyl, benzoxazolyl, and substituted benzoxazolyl;
R 1 is a radical selected from the group consisting of polyethylene glycol chain, alkyl, substituted alkyl, peptide chain, glycosidyl, and C(O)NHCH((CH 2 CH 2 O) 2 CH 3 ) 2 ;
R 2 is selected from the group consisting of ethenyl, ethynyl, azo and azomethinyl.
R 3 is a radical selected from the group consisting of alkyl, HO-alkyl, HS-alkyl, H 2 N-alkyl, HNalkyl-alkyl, alkyl-COOalkyl, alkyl-CONH 2 , alkyl-CONHalkyl, alkyl-COOH, alkyl-COO − , (alkyl) 3 N + -alkyl, and (Ph) 3 P + -alkyl and polyethylene glycol chain;
X is an anion selected from the group consisting of F, Cl, Br, I, HSO 4 , H 2 PO 4 , HCO 3 , tosylate, and mesylate;
Y is selected from the group consisting of H, F, Cl, OH, OCH 3 , and R 2 —Ar—R 3 .

2 . The method according to claim 1 , wherein when Y is substituted by R 2 —Ar—R 3 , said carbazole-based fluorophores are represented by a formula V series:

wherein Ar is a heteraromatic ring selected from the group consisting of pyridinyl, substituted pyridinyl, quinolinyl, substituted quinolinyl, acridinyl, substituted acridinyl, benzothiazolyl, substituted benzothiazolyl, benzoxazolyl, and substituted benzoxazolyl; R 2 is selected from the group consisting of ethenyl, ethynyl, azo and azomethinyl; R 3 is a radical selected from the group consisting of alkyl, HO-alkyl, HS-alkyl, H 2 N-alkyl, HNalkyl-alkyl, alkyl-COOalkyl, alkyl-CONH 2 , alkyl-CONHalkyl, alkyl-COOH, alkyl-COO − , (alkyl) 3 N + -alkyl, and (Ph) 3 P + -alkyl, and polyethylene glycol chain.

3 . The method according to claim 1 , wherein when Ar is substituted by quinolinyl, R 1 is substituted by polyethylene glycol chain, R 2 is substituted by ethenyl, R 3 is substituted by alkyl-COOH, X is substituted by Br, Cl or I, and Y is substituted by H, said carbazole-based fluorophores are represented by the formula SLCOOH and the derivatives therefore are represented by the formula SLCOOH-n:

wherein n=2-20.

4 . The method according to claim 1 , wherein said conjugate is permeable to blood-brain barrier.

5 . The method according to claim 1 , wherein the magnetic nanoparticles are superparamagnetic and anti-ferromagnetic.

6 . The method according to claim 3 , wherein the magnetic nanoparticles comprising SiO 2 @Fe 3 O 4 , and said conjugate is represented by one of the following formulae:

wherein

represents said SiO 2 @Fe 3 O 4 ; X represents Br, I, or Cl.

7 . The method according to claim 1 , further comprising administering said conjugate to said subject in vivo.

8 . The method according to claim 1 wherein said beta-amyloid (Aβ) peptides aggregation is associated with Alzheimer's disease.

9 . The method according to claim 1 wherein said conjugate is introduced to said subject with beta-amyloid (Aβ) peptides aggregation via intravenous injection.

10 . The method according to claim 1 , wherein said conjugate is introduced at about 10 mg/kg to the body weight of said subject.

11 . A method for imaging and detection of beta-amyloid (Aβ) peptides aggregation via fluorescence imaging based on modified carbazole-based fluorophores comprising a formula S series:

said method comprising:
conjugating said carbazole-based fluorophores to magnetic nanoparticles to form a conjugate of said carbazole-based fluorophores and said magnetic nanoparticles;
introducing said conjugate to a subject with beta-amyloid (Aβ) peptides aggregation; and
applying fluorescence imaging to image and detect said conjugate bound to the beta-amyloid (Aβ) peptides aggregation in said subject;
wherein Ar is a heteraromatic ring selected from the group consisting of pyridinyl, substituted pyridinyl, quinolinyl, substituted quinolinyl, acridinyl, substituted acridinyl, benzothiazolyl, substituted benzothiazolyl, benzoxazolyl, and substituted benzoxazolyl;
R 1 is a radical selected from the group consisting of polyethylene glycol chain, alkyl, substituted alkyl, peptide chain, glycosidyl, and C(O)NHCH((CH 2 CH 2 O) 2 CH 3 ) 2 ;
R 2 is selected from the group consisting of ethenyl, ethynyl, azo and azomethinyl.
R 3 is a radical selected from the group consisting of alkyl, HO-alkyl, HS-alkyl, H 2 N-alkyl, HNalkyl-alkyl, alkyl-COOalkyl, alkyl-CONH 2 , alkyl-CONHalkyl, alkyl-COOH, alkyl-COO − , (alkyl) 3 N + -alkyl, and (Ph) 3 P + -alkyl and polyethylene glycol chain;
X is an anion selected from the group consisting of F, Cl, Br, I, HSO 4 , H 2 PO 4 , HCO 3 , tosylate, and mesylate;
Y is selected from the group consisting of H, F, Cl, OH, OCH 3 , and R 2 —Ar—R 3 .

12 . The method according to claim 11 , wherein when Y is R 2 —Ar—R 3 , said carbazole-based fluorophores are represented by a formula V series:

wherein Ar is a heteraromatic ring selected from the group consisting of pyridinyl, substituted pyridinyl, quinolinyl, substituted quinolinyl, acridinyl, substituted acridinyl, benzothiazolyl, substituted benzothiazolyl, benzoxazolyl, and substituted benzoxazolyl; R 2 is selected from the group consisting of ethenyl, ethynyl, azo and azomethinyl; R 3 is a radical selected from the group consisting of alkyl, HO-alkyl, HS-alkyl, H 2 N-alkyl, HNalkyl-alkyl, alkyl-COOalkyl, alkyl-CONH 2 , alkyl-CONHalkyl, alkyl-COOH, alkyl-COO − , (alkyl) 3 N + -alkyl, and (Ph) 3 P + -alkyl, and polyethylene glycol chain.

13 . The method according to claim 11 , wherein when Ar is substituted by quinolinyl, R 1 is substituted by polyethylene glycol chain, R 2 is substituted by ethenyl, R 3 is substituted by alkyl-COOH, X is substituted by Br, Cl or I, and Y is substituted by H, said carbazole-based fluorophores are represented by the formula SLCOOH and the derivatives thereof are represented by the formula SLCOOH-n:

wherein n=2-20.

14 . The method according to claim 11 ,

Assignees

• Univ Hong Kong Baptist Univ

Inventors

• Li Yinhui
• Xu Di
• Ho See-Lok
• Poon Chung-Yan
• Chan Hei-Nga
• Li Hung Wing
• Wong Ricky M S

Classifications

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61M5/007

  for contrast media · CPC title

• A61K49/0052

  Small organic molecules (oligomers, polymers, dendrimers A61K49/0054) · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K49/085

  conjugated systems · CPC title