Curcumin derivatives for amyloid-β plaque imaging

• US 10,149,644 B2
• Filed: 10/16/2014
• Issued: 12/11/2018
• Est. Priority Date: 07/31/2008
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Ran, Chongzhao, Moore, Anna
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): Donohue, Sean R
• Application Number:
  US14/515,665
• Publication Number:
  US 20150087937A1
• Time in Patent Office: 1,517 Days
• Field of Search: 424 189
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/4088 Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia
• CPC Class Codes: A61B 6/037 Emission tomography
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61M 5/007 for contrast media
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein
• CPC Class Codes: G01N 2800/28 Neurological disorders
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

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.

Claims

1. A method for detecting an amyloid beta plaque in a sample, comprising:

(a) contacting a sample comprising an amyloid beta plaque with a compound, such that said compound binds the amyloid beta plaque, wherein the compound has the formula Ar¹-L-Ar² and wherein;

L is a divalent linking group comprising an alkenylene having 5 to 15 backbone carbon atoms, wherein at least two of the backbone carbon atoms form part of a difluoroboronate ring; and

Ar¹ and Ar² are each independently alkyl amine-substituted aryl or heteroaryl groups;

(b) illuminating said compound bound to the amyloid beta plaque with near infrared light of a wavelength absorbable by said compound; and

(c) detecting fluorescence emitted by the compound wherein said fluorescence corresponds to the amyloid beta plaque contained in said sample;

wherein the compound exhibits increased fluorescence intensity upon binding to an amyloid beta plaque as compared to the fluorescence intensity exhibited by the compound when not bound to an amyloid beta plaque.

2. The method according to claim 1, wherein L is

3. The method according to claim 2, wherein Ar¹ and Ar² are independently selected from

4. The method according to claim 3, wherein said compound has the structure:

5. The method according to claim 1, wherein Ar¹ and Ar² are independently selected from

6. An in vivo optical imaging method for amyloid beta plaque detection, comprising:

(a) administering to a subject a compound, wherein said compound binds an amyloid beta plaque, wherein the compound has the formula Ar¹-L-Ar² and wherein;

L is a divalent linking group comprising an alkenylene having 5 to 15 backbone carbon atoms, wherein at least two of the backbone carbon atoms form part of a difluoroboronate ring; and

Ar¹ and Ar² are each independently alkyl amine-substituted aryl or heteroaryl groups;

(b) illuminating the subject with near infrared light of a wavelength absorbable by said compound; and

(c) detecting fluorescence emitted by the compound wherein said fluorescence corresponds to the amyloid beta plaque present in the subject;

wherein the compound exhibits increased fluorescence intensity upon binding to an amyloid beta plaque as compared to the fluorescence intensity exhibited by the compound when not bound to an amyloid beta plaque.

7. The method according to claim 6, wherein L is

8. The method according to claim 7, wherein Ar¹ and Ar² are independently selected from

9. The method according to claim 8, wherein said compound has the structure:

10. The method according to claim 6, wherein Ar¹ and Ar² are independently selected from

11. The method according to claim 6, wherein the fluorescence detected in step (c) is used in an additional step to construct an image of said amyloid beta plaque present in the subject.

12. The method according to claim 6, wherein step (c) is performed using a light detection or image recording component comprising a charge coupled device (CCD) system or photographic film.