Compounds and amyloid probes thereof for therapeutic and imaging uses

Abstract

The present invention provides compounds and amyloid probes thereof that allow for an antemortem method of diagnosing AD and quantitating the extent or progression of amyloid deposits (plaques) by in vivo imaging of amyloid and/or amyloid deposits in the regions of the brain. Preferably, an amyloid probe of the invention can cross the blood-brain barrier and distinguish AD brain from normal brain. An amyloid probe can be administered to a patient in amounts suitable for in vivo imaging of amyloid deposits. Amyloid probes of the invention can also be used to detect and quantitate amyloid deposits in diseases including, without limitation, Down's syndrome, familial AD and homozygotes for the apolipoprotein E4 allele. In one aspect, the compounds may be used in the treatment or prophylaxis of diseases that include, without limitation, AD and type 2 diabetes mellitus. The compounds and amyloid probes of the invention include analogs, salts, pharmaceutical compositions, derivatives, prodrugs, racemic mixtures or tautomeric forms thereof.

1 . An amyloid binding compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , alkyl, alkenyl, alkynyl, alkoxy, monoalkylamine, dialkylamine, hydroxyalkyl, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycles, heteroaryl, aralkyl, carboxy, esterified carboxy, amidate carboxy, OR 6 , NR 5 R 6  or R 6 , 
 R 2  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , alkyl, alkenyl, alkynyl, alkoxy, monoalkylamine, dialkylamine, hydroxyalkyl, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycles, heteroaryl, aralkyl, carboxy, esterified carboxy, amidate carboxy, OR 6 , NR 5 R 6  or R 6 , 
 R 3  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , alkyl, alkenyl, alkynyl, alkoxy, monoalkylamine, dialkylamine, hydroxyalkyl, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycles, heteroaryl, aralkyl, carboxy, esterified carboxy, amidate carboxy, OR 6 , NR 5 R 6  or R 6 , 
 R 4  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , alkyl, alkenyl, alkynyl, alkoxy, monoalkylamine, dialkylamine, hydroxyalkyl, haloalkyl, alkylthio, alkylsulfonyl, aryl, heterocycles, heteroaryl, aralkyl, carboxy, esterified carboxy, amidate carboxy, OR 6 , NR 5 R 6  or R 6 , 
 R 5  is C n H 2n+1  or —CH 2 —CH═CH—I and R 6  is C n H 2n+1 , —[CH 2 —CH 2 —O] m —R 5 , where n and m are independently 0, 1, 2, 3, 4, 5, 6 or 7, 
 X is O or S, 
 Y is CH or N, and 
 Z is CH or N. 
 
   
   
       2 . An amyloid binding compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , OR 6 , NR 5 R 6  or R 6 , 
 R 2  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , OR 6 , NR 5 R 6  or R 6 , 
 R 3  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , OR 6 , NR 5 R 6  or R 6 , 
 R 4  is H, F, Cl, Br, I, NO 2 , CN, CF 3 , OR 6 , NR 5 R 6  or R 6 , 
 R 5  is C n H 2n+1  or —CH 2 —CH═CH—I and R 6  is C n H 2n+1 , —[CH 2 —CH 2 —O] m —R 5 , where n and m are independently 0, 1, 2, 3, 4, 5, 6 or 7, 
 X is O or S, 
 Y is CH or N, and 
 Z is CH or N. 
 
   
   
       3 . The amyloid binding compound of  claim 1 , wherein the compound comprises the formula 
     
       
         
         
             
             
         
       
     
   
   
       4 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       5 . An amyloid probe comprising the compound of  claim 1 , wherein the compound comprises a detectable label. 
   
   
       6 . The amyloid probe of  claim 5 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently comprises  131 I,  124 I,  125 I,  3 H,  123 I,  18 F,  19 F,  11 C,  75 Br,  13 C,  13 N,  15 O,  76 Br. 
   
   
       7 . A pharmaceutical composition comprising the probe of  claim 5  and a pharmaceutically acceptable carrier. 
   
   
       8 . A method of detecting the presence and/or location of an amyloid deposit in a subject, the method comprising the steps of:
 administering an effective amount of the probe of  claim 5  to the subject; and   detecting the binding of the probe in the subject, wherein the binding of the probe indicates the presence and/or location of an amyloid deposit in the subject.   
   
   
       9 . The method of  claim 8 , wherein the amyloid deposit is located in the brain of the subject. 
   
   
       10 . The method of  claim 8 , wherein detection is by gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy. 
   
   
       11 . The method of  claim 10 , wherein detection by gamma imaging is by PET or SPECT. 
   
   
       12 . A method of detecting the presence and/or location of an amyloid deposit in biopsy or post-mortem tissue from a subject, the method comprising the steps of:
 incubating the tissue with a solution comprising the probe of  claim 5 ; and   detecting the binding of the probe in the tissue, wherein the binding of the probe indicates the presence and/or location of an amyloid deposit in the tissue.   
   
   
       13 . The method of  claim 12 , wherein the tissue is from the brain of the subject. 
   
   
       14 . The method of  claim 12 , wherein detection is by gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy. 
   
   
       15 . The method of  claim 14 , wherein detection by gamma imaging is by PET or SPECT.