Imaging Agents for Detecting Neurological Disorders

Abstract

Imaging agents of formula (I) and methods for detecting neurological disorders comprising administering to a patient in need compounds of formula (I) capable of binding to tau proteins and β-amyloid peptides are presented herein. The invention also relates to methods of imaging Aβ and tau aggregates comprising introducing a detectable quantity of pharmaceutical formulation comprising a radiolabeled compound of formula (I) and detecting the labeled compound associated with amyloid deposits and/or tau proteins in a patient. These methods and compositions enable preclinical diagnosis and monitoring progression of AD and other neurological disorders.

What is claimed: 
     
         1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         A is a bond, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 4 )alkene, or (C 2 -C 4 )alkyne; 
         Z is aryl selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein
 X 1  and X 13  are each independently C, CH, N, O, or S; 
 X 2 -X 12  and X 14 -X 17  are each independently C, CH or N; 
 Y 1  is N, O, or S; 
 R 1 -R 2  are each independently H, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, —(O—CH 2 —CH 2 ) n — (PEG), monoalkylamino, dialkylamino, monoarylamino, diarylamino, NR 10 COOalkyl, NR 10  COOaryl, NR 10  COalkyl, NR 10  CO aryl, COOalkyl, COOaryl, COalkyl, COaryl, aryl, or saturated heterocyclyl, wherein the last seventeen groups are unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, alkoxy, R 10 , a radiolabel and alkyl substituted with a radiolabel; or R 1  and R 2  together form a five- or six-membered saturated or unsaturated ring which optionally contains an additional heteratom in the ring which is selected from N, O, and S, the ring being unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, alkoxy, R 10 , a radiolabel and alkyl substituted with radiolabel; 
 R 3 -R 9  are each independently H, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, —(O—CH 2 —CH 2 ) n —, monoalkylamino, dialkylamino, monoarylamino, diarylamino, NR 10 COOalkyl, NR 10  COOaryl, NR 10  COalkyl, NR 10  CO aryl, COOalkyl, COOaryl, COalkyl, COaryl, aryl, or heterocyclyl, wherein the last seventeen groups are unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, alkyl, haloalkyl, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, alkoxy, R 10 , a radiolabel and alkyl substituted with a radiolabel; 
 R 10  is H, alkyl, alkene, aryl unsubstituted or substituted with halogen, hydroxyl, cyano, nitro, amino, —OSO 2 alkyl, —OSO 2 aryl, —OSi(alkyl) 3 , —OTHP or a radiolabel; 
 n is 1, 2, or 3; 
 m is 0 or 1; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein at least one of R 1 -R 9  comprises a radiolabel selected from the group consisting of  11 C,  13 N,  15 O,  18 F,  123 I,  124 I,  125 I,  131 I,  76 Br  77 Br. 
     
     
         3 . The compound of  claim 2 , wherein the radiolabel is  18 F. 
     
     
         4 . The compound of  claim 1 , wherein A is a bond. 
     
     
         5 . The compound of  claim 1 , wherein A is C 2  alkyne. 
     
     
         6 . The compound of  claim 5 , wherein Z is 
       
         
           
           
               
               
           
         
         wherein at least one of X 9 -X 13  is nitrogen and m is 1. 
       
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 4 , wherein Z is 
       
         
           
           
               
               
           
         
         and at least one of X 9 -X 16  is nitrogen and m is 1. 
       
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 8 , wherein Z is quinoline. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . The compound of  claim 5 , wherein Z is 
       
         
           
           
               
               
           
         
         and wherein at least one X 9 -X 16  is nitrogen and m is 1. 
       
     
     
         14 - 16 . (canceled) 
     
     
         17 . A pharmaceutical diagnostic formulation for detecting neurological disorders comprising a radiolabeled compound of  claim 2  or a pharmaceutically acceptable salt thereof in a suitable vehicle or diluent. 
     
     
         18 . The pharmaceutical diagnostic formulation of  claim 17  for detection of amyloid peptides. 
     
     
         19 . The pharmaceutical diagnostic formulation of  claim 17  for detection of tau proteins of neurofibrillary tangles. 
     
     
         20 . The pharmaceutical diagnostic formulation of  claim 17  wherein the neurological disorder is Alzheimer's disease. 
     
     
         21 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein A is C 2  alkene. 
     
     
         32 . The compound of  claim 13 , wherein Z is quinoline. 
     
     
         33 . The compound of  claim 10 , wherein R 1  is monoalkylamino, wherein the monoalkylamino is unsubstituted or substituted by a radical selected from the group consisting of halogen, hydroxyl, alkoxy, R 10 , and a radiolabel. 
     
     
         34 . The compound of  claim 10 , wherein R 1  is dialkylamino, wherein the dialkylamino is unsubstituted or substituted by a radical selected from the group consisting of halogen, hydroxyl, alkoxy, R 10 , and a radiolabel. 
     
     
         35 . The compound of  claim 1 , which is selected from the group consisting of:
 2-(1-Methyl-1H-indol-5-yl)quinoline   
       
         
           
           
               
               
           
         
         N-(3-Fluoropropyl)-4-(quinolin-2-ylethynyl)aniline 
       
       
         
           
           
               
               
           
         
         N,N-dimethyl-4-[(E)-2-quinoxalin-2-ylvinyl]aniline 
       
       
         
           
           
               
               
           
         
         N-Methyl-4-(quinolin-3-yl)aniline 
       
       
         
           
           
               
               
           
         
         2-Fluoro-4-(6-methoxyquinolin-2-yl)-N-methylaniline 
       
       
         
           
           
               
               
           
         
         N,N-Dimethyl-4-(quinolin-7-yl)aniline 
       
       
         
           
           
               
               
           
         
         N-(2-fluoroethyl)-N-methyl-4-[(E)-2-quinazolin-2-ylvinyl]aniline 
       
       
         
           
           
               
               
           
         
         N,N-Dimethyl-4-(quinolin-6-ylethynyl)aniline 
       
       
         
           
           
               
               
           
         
         2-(4-(4-(2-Fluoroethyl)piperizin-1-yl)-6-methoxyquinoline 
       
       
         
           
           
               
               
           
         
       
       and
 4-(6-Methoxyquinolin-2-yl)-N-methylaniline 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A compound which is 2-(4-(4-(2-(2-fluoroethoxy)ethyl)piperazin-1-yl)phenyl)-6-methoxyquinoline 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         37 . A method for detecting neurological disorders in a patient, comprising administering an effective amount of the compound of  claim 2 . 
     
     
         38 . The method of  claim 37 , wherein the neurological disorder is Alzheimer's disease (AD). 
     
     
         39 . The method of  claim 37 , further comprising measuring the affinity of the compound for senile plaques. 
     
     
         40 . The method of  claim 37 , further comprising measuring the affinity of the compound for tau aggregates. 
     
     
         41 . The method of  claim 39 , wherein the detection is performed using gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy. 
     
     
         42 . The method of  claim 41 , wherein the detection by gamma imaging is PET or SPECT. 
     
     
         43 . The method of  claim 40 , wherein the detection is performed using gamma imaging, magnetic resonance imaging, magnetic resonance spectroscopy or fluorescence spectroscopy. 
     
     
         44 . The method of  claim 43 , wherein the detection by gamma imaging is PET or SPECT