RADIOLABELLED mGluR2 PET LIGANDS

Abstract

The present invention relates to novel, selective, radiolabelled mGluR2 ligands which are useful for imaging and quantifying the metabotropic glutamate receptor mGluR2 in tissues, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue, cells or a mammal, in vitro or in vivo and to precursors of said compounds.

1 - 19 . (canceled) 
     
     
         20 . A compound according to Formula (I) 
       
         
           
           
               
               
           
         
         wherein, 
         X is CH or N, 
         R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl; 
         R 2  is selected from the group of consisting of H, Cl, and —OCH 3 ; and 
         R 3  is selected from the group consisting of —NHCH 3 , CH 3 , and F; 
         wherein at least one atom is radiolabelled, or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The compound of  claim 20 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of (a), (b), (c) and (d), wherein (a), (b), (c) and (d) are respectively: 
       
         
           
           
               
               
           
         
       
       and R 3  is as defined in  claim 20 . 
     
     
         22 . The compound of  claim 20 , wherein R 3  is selected from the group consisting of —NH[ 11 C]CH 3 , [ 11 C]CH 3 , and  18 F. 
     
     
         23 . The compound of  claim 20 , wherein the compound is of Formula [ 11 C]-(I-a) 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of (a), (b), and (c), wherein (a), (b), and (c) are respectively: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 20 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A pharmaceutical composition comprising: a therapeutically effective amount of the compound of  claim 20 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The pharmaceutical composition according to  claim 25 , wherein the diluent is a sterile solution. 
     
     
         28 . A method of imaging mGlu2 receptor in a tissue, cells or a mammal, comprising:
 contacting with or providing a detectable amount of a compound or a pharmaceutically acceptable salt thereof of Formula (I)   
       
         
           
           
               
               
           
         
       
       to a tissue, cells or mammal wherein,
 X is CH or N, 
 R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl, 
 R 2  is selected from the group of consisting of H, Cl, and —OCH 3 , and 
 R 3  is selected from the group consisting of —NHCH 3 , CH 3 , and F, 
 wherein at least one atom is radiolabelled; and 
 detecting the labelled compound associated with the mGlu2 receptor. 
 
     
     
         29 . The method of  claim 28 , further comprising:
 quantifying the mGlu2 receptor based on detection of the labelled compound.   
     
     
         30 . The method of  claim 28 , further comprising:
 determining mGlu2 receptor site occupancy by other non-radiolabelled compounds.   
     
     
         31 . The method of  claim 28 , wherein the compound is detected by positron-emission tomography. 
     
     
         32 . A compound having the Formula (P-I), (P-II), or (P-III) 
       
         
           
           
               
               
           
         
         wherein 
         X is CH or N, 
         R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl; 
         R 2  is selected from the group consisting of H, Cl, and —OCH 3 ; and 
         Boc is tert-butyloxycarbonyl. 
       
     
     
         33 . The compound of  claim 32 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of (a), (b), and (c), wherein (a), (b), and (c) are respectively: 
       
         
           
           
               
               
           
         
       
     
     
         34 . A process for the preparation of a compound of Formula [ 11 C]-(I-a), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting a compound of Formula (P-III) 
 
       
         
           
           
               
               
           
         
       
       with [ 11 C]CH 3 I under appropriate conditions, followed by Boc cleavage under appropriate conditions, to yield the compound of Formula [ 11 C]-(I-a) 
       wherein,
 X is CH or N, 
 R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl; 
 R 2  is selected from the group of consisting of H, Cl, and —OCH 3 ; and 
 Boc is tert-butyloxycarbonyl. 
 
     
     
         35 . A process for the preparation of a compound of Formula [ 18 F]-(I-c), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting a compound of Formula (P-I) 
 
       
         
           
           
               
               
           
         
       
       with  18 F − /4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane in the presence of K 2 C 2 O 4  or KHCO 3  to yield the compound of Formula [ 18 F]-(I-c), 
       wherein,
 X is CH or N, 
 R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl; 
 R 2  is selected from the group of consisting of H, Cl, and —OCH 3 . 
 
     
     
         36 . A process for the preparation of a compound of Formula [ 18 F]-(I-b), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting a compound of Formula (P-II), 
 
       
         
           
           
               
               
           
         
       
       with [ 11 C]CH 3 I to yield a compound of Formula [ 18 F]-(I-b), 
       wherein,
 X is CH or N, 
 R 1  is selected from the group consisting of CF 3 , SF 5 , and Cl; 
 R 2  is selected from the group of consisting of H, Cl, and —OCH 3 . 
 
     
     
         37 . A compound having the formula, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition comprising: a therapeutically effective amount of the compound of  claim 37 , and a pharmaceutically acceptable carrier or excipient. 
     
     
         39 . A method for the treatment of a subject having a central nervous system conditions or a diseases selected from the group consisting of mood disorders; delirium, dementia, amnestic substance-related disorders; schizophrenia, schizophrenia spectrum, psychotic disorders other than schizophrenia or schizophrenia spectrum disorders; somatoform disorders, somatic symptom, disorders related to somatoform disorder; hypersomnic sleep disorder and hypersomnolence disorder comprising: administering to the subject in need of treatment for said central nervous system disorder a therapeutically effective amount of the compound of  claim 37 . 
     
     
         40 . The method of  claim 37 , wherein the condition or diseases is a mood disorder. 
     
     
         41 . The method of  claim 37 , wherein the condition or diseases is dementia.