Isotopically-labeled benzofuran compounds as imaging agents for amyloidogenic proteins

Abstract

Benzofuran compounds which contain at least one detectable label selected from the group consisting of 131 I, 123 I, 124 I, 76 Br, 75 Br, 18 F, 19 F, 11 C, 13 C, 14 C and 3 H are provided as amyloid imaging agents for detecting brain amyloid deposits as well as other amyloidogenic peptides associated with systemic or localized amyloidosis. Additionally, the compounds are useful for determining if patients, presenting with clinically confusing cases of dementia or presenting with mild cognitive impairment, have Alzheimer's disease. The compounds are additionally useful as surrogate markers for monitoring the efficacy of anti-amyloidosis therapies.

1 . An amyloid binding compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Y is H, NO 2 , —NR″ 3   + , F, Cl, Br, I, O—(CR″ 2 ) n —X, or —(CR″ 2 ) n —X;
 wherein
 X is F, Cl, Br or I; and 
 n is 1-5; 
 
 
 R′ is H or a lower alkyl group; 
 R″ is H or a lower alkyl group; 
 R 3 -R 10  are independently selected from the group consisting of H, F, Cl, Br, I, C 1 -C 5  alkyl, (CH 2 ) 1-3 —OR 11 , CF 3 , —(CH 2 ) 1-3 —X, —O—(CH 2 ) 1-3 —X, CN, —CO—R 11 , —N(R 11 ) 2 , —NR″ 3   + , —NO 2 , —CO—N(R 11 ) 2 , —O—(CO)—R 11 , OR 11 , SR 11 , COOR 11 , R ph , —CR 11 ═CR 11 —R ph  and —C(R 11 ) 2 —C(R 11 ) 2 —R ph , wherein
 X is F, Cl, Br or I; and 
 R ph  is phenyl optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, C 1 -C 5  alkyl, (CH 2 ) 1-3 —OR 11 , CF 3 , —(CH 2 ) 1-3 —X, —O—(CH 2 ) 1-3 —X, CN, —CO—R 11 , —N(R 11 ) 2 , —CO—N(R 11 ) 2 , —O—(CO)—R 11 , OR 11 , SR 11 , and COOR 11 , wherein each R 11  is independently H or C 1 -C 5  alkyl. 
 
 
     
     
         2 . The amyloid binding compound according to  claim 1 , wherein Y is H, NO 2 , —NR″ 3   + , F, Cl, Br, I, or —(CR″ 2 ) n —X. 
     
     
         3 . The amyloid binding compound according to  claim 2 , wherein R 3 -R 10  are independently selected from the group consisting of H, F, Cl, Br, I, —N(R 11 ) 2 , and OR 11 . 
     
     
         4 . The amyloid binding compound according to  claim 3 , wherein R 8  and R 9  are independently OR 11 . 
     
     
         5 . The amyloid binding compound according to  claim 4 , wherein each of R 7  and R 10  is H. 
     
     
         6 . The amyloid binding compound according to  claim 5 , wheren each of R 3 , R 4 , R 5 , and R 6  is H. 
     
     
         7 . The amyloid binding compound according to  claim 2 , wheren Y is selected from F, Cl, Br, I, and —NO 2 . 
     
     
         8 . The amyloid binding compound according to  claim 7 , wherein Y is F. 
     
     
         9 . The amyloid binding compound according to  claim 2 , wherein each of R 3 , R 4 , R 5 , and R 6 , R 7 , and R 10  is H, and R 8  and R 9  are independently OR 11 . 
     
     
         10 . The amyloid binding compound according to  claim 2 , wherein Y comprises the at least one the detectable label. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The amyloid binding compound according to  claim 1  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A pharmaceutical composition comprising
 (i) an effective amount of an amyloid binding compound according to  claim 1 ; and   (ii) a pharmaceutically acceptable carrier.   
     
     
         15 .- 33 . (canceled) 
     
     
         34 . A method of selectively binding an amyloid binding compound of  claim 1  or a pharmaceutically acceptable salt thereof to amyloid plaques but not neurofibrillary tangles in brain tissue which contains both, the method comprising contacting the amyloid plaques in in vitro binding or staining assays with a compound of  claim 1  at a concentration below about 10 nM. 
     
     
         35 . A method of selectively binding in vivo an amyloid binding compound of Formula (I) or a pharmaceutically acceptable salt thereof to amyloid plaques but not to neurofibrillary tangles in brain tissue which contains both, the method comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof such that the blood concentration of the administered compound remains below about 10 nM in vivo. 
     
     
         36 .- 73 . (canceled)