Non-steroidal radiolabeled agonist/antagonist compounds and their use in prostate cancer imaging

Abstract

The present invention relates to a radiolabeled non-steroidal compound having the formula: where R 1 , R 2 , and R 3 , are the same or different and are a radioactive or nonradioactive halogen, a nitro, a cyano, a carbamoyl, a hydrogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a β-chloroethylamine; R 4 is a hydrogen, an alkyl, or is joined to R 5 ; R 5 is a radioactive or nonradioactive halogen, a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thio, a thioalkyl, or is joined to R 4 ; R 6 is a hydrogen, an alkyl, a halogen, or a haloalkyl; A 1 and A 2 are the same or different, and each is a direct link or an alkylene; X 1 is a radioactive or nonradioactive halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or alkylene; R 7 is a radioactive or nonradioactive halogen, a hydrogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an alkylsulphinyl, an arylsulphinyl, an alkylsulphonyl, an arylsulphonyl, an amino, an alkylimino, an alkylamido group, a radioactive or nonradioactive haloalkylamido group, a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.

What is claimed:  
     
         1 . A radiolabeled non-steroidal compound having the formula:  
       
         
           
           
               
               
           
         
       
       where 
 R 1 , R 2  and R 3 , are the same or different and are a radioactive or nonradioactive halogen, a nitro, a cyano, a carbamoyl, a hydrogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a β-chloroethylamine;  
 R 4  is a hydrogen, an alkyl, or is joined to R 5 ;  
 R 5  is a radioactive or nonradioactive halogen, a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thio, a thioalkyl, or is joined to R 4 ;  
 R 6  is a hydrogen, an alkyl, a halogen, or a haloalkyl;  
 A 1  and A 2  are the same or different, and each is a direct link or an alkylene;  
 X 1  is a radioactive or nonradioactive halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or alkylene;  
 R 7  is a radioactive or nonradioactive halogen, a hydrogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an alkylsulphinyl, an arylsulphinyl, an alkylsulphonyl, an arylsulphonyl, an amino, an alkylimino, an alkylamido group, a radioactive or nonradioactive haloalkylamido group, a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.  
 
     
     
         2 . A radiolabeled non-steroidal compound according to  claim 1 , wherein the compound is an androgen receptor ligand.  
     
     
         3 . A radiolabeled non-steroidal compound according to  claim 2 , wherein the compound is an androgen receptor antagonist.  
     
     
         4 . A radiolabeled non-steroidal compound according to  claim 2 , wherein the compound is an androgen receptor agonist.  
     
     
         5 . A radiolabeled non-steroidal compound according to  claim 1 , wherein the compound is a substantially pure R-enantiomer.  
     
     
         6 . A radiolabeled non-steroidal compound according to  claim 1 , wherein 
 R 1  is CF 3 ,    R 2  is CN or NO 2 ,    R 3  is H,    R 4  is H and R 5  is OH, or R 4  and R 5  are joined together as SCO,    R 6  is CH 3  or CF 3 ,    A 1  is an alkylene or a direct link,    A 2  is a direct link,    X 1  is CH 2 , S, or SO 2,  and    R 7  is a radioactive or nonradioactive halogen, or a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.    
     
     
         7 . A radiolabeled non-steroidal compound according to  claim 6 , wherein 
 R 2  is CN or NO 2 ,    R 4  is H,    R 5  is OH,    A 1  is a direct link,    X 1  is CH 2 , and    R 7  is a radioactive halogen.    
     
     
         8 . A radiolabeled non-steroidal compound according to  claim 6 , wherein 
 R 2  is CN,    R 4  is H,    R 5  is OH,    A 1  is an alkylene,    X 1  is S or SO 2,  and    R 7  is a phenyl group substituted with a radioactive halogen.    
     
     
         9 . A radiolabeled non-steroidal compound according to  claim 6 , wherein 
 R 2  is CN,    R 4  and R 5  are joined together as SCO,    A 1  is an alkylene,    X 1  is S or SO 2 , and    R 7  is a phenyl group substituted with a radioactive halogen.    
     
     
         10 . A composition comprising: 
 a radiolabeled non-steroidal compound and a pharmaceutically acceptable carrier;    wherein the radiolabeled non-steroidal compound has the formula:                          where    R 1 , R 2  and R 3 , are the same or different and are a radioactive or nonradioactive halogen, a nitro, a cyano, a carbamoyl, a hydrogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a β-chloroethylamine;    R 4  is a hydrogen, an alkyl, or is joined to R 5 ;    R 5  is a radioactive or nonradioactive halogen, a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thio, a thioalkyl, or is joined to R 4 ;    R 6  is a hydrogen, an alkyl, a halogen, or a haloalkyl;    A 1  and A 2  are the same or different, and each is a direct link or an alkylene;    X 1  is a radioactive or nonradioactive halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or alkylene;    R 7  is a radioactive or nonradioactive halogen, a hydrogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an alkylsulphinyl, an arylsulphinyl, an alkylsulphonyl, an arylsulphonyl, an amino, an alkylimino, an alkylamido group, a radioactive or nonradioactive haloalkylamido group, a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.    
     
     
         11 . A radiolabeled non-steroidal compound according to  claim 10 , wherein the compound is an androgen receptor ligand.  
     
     
         12 . A radiolabeled non-steroidal compound according to  claim 11 , wherein the compound is an androgen receptor antagonist.  
     
     
         13 . A radiolabeled non-steroidal compound according to  claim 11 , wherein the compound is an androgen receptor agonist.  
     
     
         14 . A radiolabeled non-steroidal compound according to  claim 10 , wherein the compound is a substantially pure R-enantiomer.  
     
     
         15 . A radiolabeled non-steroidal compound according to  claim 10 , wherein 
 R 1  is CF 3 ,    R 2  is CN or NO 2 ,    R 3  is H,    R 4  is H and R 5  is OH, or R 4  and R 5  are joined together as SCO,    R 6  is CH 3  or CF 3 ,    A 1  is an alkylene or a direct link,    A 2  is a direct link,    X 1  is CH 2 , S, or SO 2,  and    R 7  is a radioactive or nonradioactive halogen, or a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.    
     
     
         16 . A method of imaging for prostate cancer or other androgen receptor containing tissues in a patient comprising: 
 contacting an androgen receptor with a radiolabeled non-steroidal compound under conditions effective to bind the radiolabeled non-steroidal compound to the androgen receptor and    detecting the presence of any radiolabeled non-steroidal compound bound to the androgen receptor.    
     
     
         17 . A method according to  claim 16 , wherein said contacting comprises administering the radiolabeled non-steroidal compound to a patient.  
     
     
         18 . A method according to  claim 17 , wherein said administering is oral, parenteral, or topical.  
     
     
         19 . A method according to  claim 16 , wherein said detecting is selected from a group consisting of single-photon emission computed tomography and positron emission tomography.  
     
     
         20 . A method according to  claim 16 , wherein the radiolabeled non-steroidal compound has the formula:  
       
         
           
           
               
               
           
         
       
       where 
 R 1 , R 2  and R 3 , are the same or different and are a radioactive or nonradioactive halogen, a nitro, a cyano, a carbamoyl, a hydrogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a β-chloroethylamine;  
 R 4  is a hydrogen, an alkyl, or is joined to R 5 ;  
 R 5  is a radioactive or nonradioactive halogen, a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thio, a thioalkyl, or is joined to R 4 ;  
 R 6  is a hydrogen, an alkyl, a halogen, or a haloalkyl;  
 A 1  and A 2  are the same or different, and each is a direct link or an alkylene;  
 X 1  is a radioactive or nonradioactive halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or alkylene;  
 R 7  is a radioactive or nonradioactive halogen, a hydrogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an alkylsulphinyl, an arylsulphinyl, an alkylsulphonyl, an arylsulphonyl, an amino, an alkylimino, an alkylamido group, a radioactive or nonradioactive haloalkylamido group, or a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.  
 
     
     
         21 . A method according to  claim 20 , wherein 
 R 1  is CF 3 ,    R 2  is CN or NO 2 ,    R 3  is H,    R 4  is H and R 5  is OH, or R 4  and R 5  are joined together as SCO,    R 6  is CH 3  or CF 3 ,    A 1  is an alkylene or a direct link,    A 2  is a direct link,    X 1  is CH 2 , S, or SO 2,  and    R 7  is a radioactive or nonradioactive halogen, or a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.    
     
     
         22 . A precursor compound for producing a radiolabeled non-steroidal compound, the precursor compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2  and R 3 , are the same or different, and each is a hydrogen, a halogen, a nitro, a cyano, a carbamoyl, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, a β-chloroethylamine, a diazonium salt, a triazene group, a tertiary alklyl group, an oxy group, an alkoxy group, a stannoalkyl group, a stannoaryl group, an unsubstituted or substituted boronic acid, an alkyl silane group, a pentaflourosilicate group, an alkylgermano group, a halomercury group, a trifluoroacetylthallate group, or a thallium difluoride group;  
 R 4  is a hydrogen, an alkyl, or is joined to R 5 ;  
 R 5  is a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thiol, a thioalkyl, a halogen, or is joined to R 4  or X 1 ;  
 R 6  is a hydrogen, an alkyl; a halogen, or a haloalkyl;  
 A 1  and A 2  are the same or different, and each is a direct link or alkylene;  
 X 1  is a halogen, an oxygen, a sulfur, a sulphinyl, a sulfonyl, an amino, an alkylimino, an alkylene, or is joined to R 5  directly, through an oxirane ring, through an SO 2  group, or through an SO group;  
 R 7  is an aryl ring, substituted at different positions with a hydrogen, a halogen, a diazonium salt, a triazene group, a tertiary alkyl amino group, a nitro group, an oxy group, an alkoxy group, an amino group, an alkylamino group, a stannoalkyl group, a stannoaryl group, an unsubstituted or a substituted boronic acid, an alkyl silane group, a pentafluorosilicate group, an alkylgermano group, a halomercury group, a trifluoroacetyl thallate group, or a thallium difluoride group.  
 
     
     
         23 . A precursor compound according to  claim 22 , wherein 
 R 1  is CF 3 ,    R 2  is CN or NO 2 ,    R 3  is H,    R 4  is H,    R 5  is OH,    R 6  is CH 3  or CF 3 ,    A 1  is an alkylene,    A 2  is a direct link,    X 1  is S or SO 2 , and    R 7  is an aryl ring substituted with a triazene group, a stannoalkyl group, or a stannoaryl group.    
     
     
         24 . A method of producing a radiolabeled non-steroidal compound comprising: 
 providing a precursor compound according to claim  22 ;    providing a radioactive compound; and    reacting the precursor compound and the radioactive compound under conditions effective to produce a radiolabeled non-steroidal compound having the formula:                          where    R 1 , R 2  and R 3 , are the same or different and are a radioactive or nonradioactive halogen, a nitro, a cyano, a carbamoyl, a hydrogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a β-chloroethylamine;    R 4  is a hydrogen, an alkyl, or is joined to R 5 ;    R 5  is a radioactive or nonradioactive halogen, a hydrogen, a hydroxy, an alkyl, a haloalkyl, an alkoxy, an acyloxy, an amino, an alkylamino, a thio, a thioalkyl, or is joined to R 4 ;    R 6  is a hydrogen, an alkyl, a halogen, or a haloalkyl;    A 1  and A 2  are the same or different, and each is a direct link or an alkylene;    X 1  is a radioactive or nonradioactive halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or alkylene;    R 7  is a radioactive or nonradioactive halogen, a hydrogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an alkylsulphinyl, an arylsulphinyl, an alkylsulphonyl, an arylsulphonyl, an amino, an alkylimino, an alkylamido group, a radioactive or nonradioactive haloalkylamido group, a phenyl optionally substituted with a radioactive or nonradioactive halogen, a nitro group, an alkyl, a radioactive or nonradioactive haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a radioactive or nonradioactive haloalkylamino group, a radioactive or nonradioactive dihaloalkylamino group, a radioactive or nonradioactive bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a radioactive or nonradioactive haloacylamido group, a radioactive or nonradioactive bis(haloacyl)imido group, or a radioactive or nonradioactive alkylhaloacylamido group.    
     
     
         25 . A method according to  claim 24 , wherein R 7  of the precursor compound is a phenyl substituted with a triazene group or a stannoalkyl or a stannoaryl group.