Curcumin Derivatives for Amyloid-Beta Plaque Imaging

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.

1 . A compound having the formula Ar 1 -L-Ar 2 , wherein:
 (a) 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 carbonyl or secondary alcohol and Ar 1  and Ar 2  are each independently alkyl amine-substituted aryl or heteroaryl groups; or   (b) 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 Ar 1  and Ar 2  are each independently alkyl amine-substituted aryl or heteroaryl groups.   
     
     
         2 . The compound according to  claim 1 , wherein L is —CH═CH—(CO)—CH═C(OH)—CH═CH— or —C═CH—(CO)—CH 2 —C(O)—CH═CH—. 
     
     
         3 . The compound according to  claim 2 , wherein Ar 1  and Ar 2  are independently selected from 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 3 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 5 , wherein Ar 1  and Ar 2  are independently selected from 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 6 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1 , wherein Ar 1  and Ar 2  are independently selected from 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein said compound is capable of binding amyloid beta plaques in both in vitro and in vivo settings. 
     
     
         10 . The compound according to  claim 1 , wherein said compound further comprises at least one fluorine atom that is an  18 F isotope. 
     
     
         11 . The compound according to  claim 1 , wherein said compound further comprises at least one fluorine atom that is an  19 F isotope. 
     
     
         12 . The compound according to  claim 1 , wherein said compound further comprises at least one carbon atom that is a  11 C isotope. 
     
     
         13 . A pharmaceutical injectable dosage, comprising the compound of  claim 1  and an injectable carrier system. 
     
     
         14 .- 26 . (canceled) 
     
     
         27 . A method for providing a positron emission tomography (PET) scan of a subject, comprising:
 (a) administering to a subject a  11 C or  18 F labeled derivative of the compound according to  claim 1 ; and   (b) imaging gamma rays emitted due to the compound within said subject in order to provide a PET scan of the compound contained in said subject.   
     
     
         28 . The method according to  claim 27 , wherein the presence, absence or level of said compound within the subject is indicative of a disease state. 
     
     
         29 . The method according to  claim 28 , wherein the disease state is Alzheimer's disease. 
     
     
         30 .- 32 . (canceled) 
     
     
         33 . An optical system for imaging an amyloid beta plaque, comprising:
 (a) a fluorescence excitation source configured to excite fluorescent emission of a compound according to  claim 1  when said compound binds amyloid beta plaque;   (b) a fluorescence light detector for detecting fluorescent light emitted by said compound; and   (c) an imaging means to provide an image of the compound which correlates to the presence of said amyloid beta plaque.   
     
     
         34 . The optical system according to  claim 33 , wherein the fluorescence excitation source comprises a laser or light-emitting diode. 
     
     
         35 . The optical system according to  claim 33 , wherein the fluorescence light detector comprises a charge coupled device (CCD) system or photographic film. 
     
     
         36 . The optical system according to  claim 33 , wherein the fluorescence excitation source and the fluorescence light detector are embodied in an endoscopic device, a catheter-based device, a diffuse optical tomographic imaging device, a phased array technology device, a confocal imaging device, or an intravital microscopy device. 
     
     
         37 .- 38 . (canceled)