Amyloid plaque aggregation inhibitors and diagnostic imaging agents

Abstract

This invention relates to a method of imaging amyloid deposits and to labeled compounds, and methods of making labeled compounds useful in imaging amyloid deposits. This invention also relates to compounds, and methods of making compounds for inhibiting the aggregation of amyloid proteins to form-amyloid deposits, and a method of delivering a therapeutic agent to amyloid deposits.

What is claimed is: 
     
       1. A pharmaceutical composition, comprising a compound of Formula III′ and a pharmaceutically acceptable excipient or diluent, wherein a the compound of Formula III′ is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 A, B, and D are CH or N, 
 provided that at least no more than two of A, B, and D is N; 
 R 3  is Br, I, F,  125 I,  131 I,  123 I,  18 F,  76 Br,  77 Br, haloalkyl, Sn(alkyl) 3  or -L-Ch; 
 R 1  and R 2  are independently selected from the group consiting of hydrogen, C 1-4  alkyl, C 2-4  aminoalkyl, C 1-4  haloalkyl, haloarylalkyl, and -L-Ch, or R 1  and R 2  are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S, or NR 5  in said ring, where 
 R 5  is hydrogen or C 1-4  alkyl; 
 L is —(CH 2 ) n —, or —(CH 2 ) n —C(O)— where 
 n is 0-5; and 
 Ch is a tetradentate ligand capable of complexing with a metal; 
 with the proviso that only one of R 1 , R 2 , and R 3  can be is -L-Ch. 
 
     
     
       2. A The pharmaceutical composition of  claim 1 , wherein A and B are CH; and
 D is N. 
 
     
     
       3. A The pharmaceutical composition of  claim 1 , wherein A and D are CH; and
 B is N. 
 
     
     
       4. A The pharmaceutical composition of  claim 1 , wherein B and D are CH; and
 A is N. 
 
     
     
       5. A The pharmaceutical composition of  claim 2 , wherein R 1  and R 2  are independently hydrogen or C 1-4  alkyl. 
     
     
       6. A The pharmaceutical composition of  claim 5 , wherein R 1  and R 2  are both methyl. 
     
     
       7. A The pharmaceutical composition of  claim 6 , wherein R 3  is Br, I, F,  125 I,  131 I,  123 I,  18 F,  76 Br,  77 Br,  18 F/fluoro(C 1-5 )alkyl or Sn(alkyl) 3 . 
     
     
       8. A The pharmaceutical composition of  claim 7 , wherein R 3  is  18 F/fluoromethyl,  18 F/fluoroethyl,  18 F/fluoropropyl,  18 F/fluorobutyl, or  18 F/fluoropentyl. 
     
     
       9. A The pharmaceutical composition of  claim 2 , wherein R 3  is L-Ch. 
     
     
       10. A The pharmaceutical composition of  claim 9 , wherein Ch is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and 
       
         
           
           
               
               
           
         
       
       and 
       n is zero. 
     
     
       11. A The pharmaceutical composition of  claim 10 , wherein Ch is: 
       
         
           
           
               
               
           
         
       
     
     
       12. A The pharmaceutical composition of  claim 11 , wherein R 1  and R 2  are independently hydrogen or C 1-4  alkyl. 
     
     
       13. A The pharmaceutical composition of  claim 12 , wherein R 1  and R 2  are both methyl. 
     
     
       14. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of Formula III′, wherein a the radiolabeled compound of Formula III′ is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 A, B, and D are CH or N, 
 provided that at least no more than two of A, B and D is N; 
 R 3  is  125 I,  131 I,  123 I,  18 F,  76 Br,  77 Br,  18 F(C 1-5 )alkyl or -L-Ch; 
 R 1  and R 2  are independently selected from the group consiting of hydrogen, C 1-4  alkyl, C 2-4  aminoalkyl, C 1-4  haloalkyl, haloarylalkyl, and -L-Ch, or R 1  and R 2  are taken together with the nitrogen to which they are attached to form a 5- to 7-member heterocyclic ring optionally having O, S or NR 5  in said ring, where 
 R 5  is hydrogen or C 1-4  alkyl; 
 L is —(CH 2 ) n —, or —(CH 2 ) n —C(O)— where 
 n is 0-5; and 
 Ch is a tetradentate ligand complexed with a radiolabeled metal; 
 with the proviso that only one of R 1 , R 2 , and R 3  can be is -L-Ch. 
 
     
     
       15. A method of inhibiting reducing amyloid plaque aggregation in a mammal, comprising administering a composition of  claim 1  in an amount effective to inhibit reduce amyloid plaque aggregation. 
     
     
       16. A method of imaging amyloid deposits, comprising:
 a. introducing into a mammal a detectable quantity of a diagnostic composition of  claim 14 ; and 
 b. allowing sufficient time for the radiolabeled compound to become associated with amyloid deposits; and 
 c. detecting the radiolabeled compound associated with one or more amyloid deposits.