Bioactivated diagnostic imaging contrast agents

Abstract

The present invention relates to improved diagnostic agents for Magnetic Resonance Imaging and optical imaging. In particular, this invention relates to MRI and optical imaging agents that allow for the sensitive detection of a specific bioactivity within a tissue. These agents are prodrug contrast agents which are bioactivated in vivo in the presence of the specific bioactivity. This invention also relates to pharmaceutical compositions comprising these agents and to methods of using the agents and compositions comprising the agents.

1 . A method of imaging a tumor using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following formula:      IEM-PBM-[L] q -[MS-MM] p      wherein q is 0 or 1;    wherein p is 1;    wherein L comprises a physiologically compatible linker moiety which links the PBM and [MS-MM] moieties;    wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic number 21-29, 42, 44, or 57-83;    wherein said —PBM moiety is selected from the group consisting of:                          wherein one aryl ring of said —PBM is substituted with said [L] q -[MS-MM] p  moiety;    wherein R can be a linear or branched aliphatic group, an aryl group, or a cycloalkyl group;    wherein the wavy line signifies the attachment site for the IEM;    wherein said —PBM moiety is conjugated to said IEM via a covalent bond to a methylene carbon of said chelating agent of said IEM;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         2 . A method of imaging sites of active inflammation using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following formula:      IEM-PBM-[L] q -[MS-MM] p      wherein q is 0 or 1;    wherein p is 1;    wherein L comprises a physiologically compatible linker moiety which links the PBM and [MS-MM] moieties;    wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic number 21-29, 42, 44, or 57-83;    wherein said —PBM moiety is selected from the group consisting of:                          wherein one aryl ring of said —PBM is substituted with said —[L] q -[MS-MM] p  moiety;    wherein R can be a linear or branched aliphatic group, an aryl group, or a cycloalkyl group;    wherein the wavy line signifies the attachment site for the IEM;    wherein said —PBM moiety is conjugated to said IEM via a covalent bond to a methylene carbon of said chelating agent of said IEM;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         3 . A method of imaging arterial plaques using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following formula:      IEM-PBM-[L] q -[MS-MM] p      wherein q is 0 or 1;    wherein p is 1;    wherein L comprises a physiologically compatible linker moiety which links the PBM and [MS-MM] moieties;    wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic number 21-29, 42, 44, or 57-83;    wherein said —PBM moiety is selected from the group consisting of:                          wherein one aryl ring of said —PBM is substituted with said —[L] q -[MS-MM] p  moiety;    wherein R can be a linear or branched aliphatic group, an aryl group, or a cycloalkyl group;    wherein the wavy line signifies the attachment site for the IEM;    wherein said —PBM moiety is conjugated to said IEM via a covalent bond to a methylene carbon of said chelating agent of said IEM;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         4 . A method of imaging a tumor using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein one aryl ring of said structure is substituted with a [L] q -[MS-MM] p  moiety, wherein q is one or two and p is one;    wherein X is CH 2 , O, or NH;    wherein L comprises a physiologically compatible linker moiety which links said one substituted aryl ring with said —[MS-MM] p  moiety;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         5 . A method of imaging a site of active inflammation using magnetic resonance imagaing, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein one aryl ring of said structure is substituted with a [L] q -[MS-MM] p  moiety, wherein q is one or two and p is one;    wherein X is CH 2 , O, or NH;    wherein L comprises a physiologically compatible linker moiety which links said one substituted aryl ring with said —[MS-MM] p  moiety;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         6 . A method of imaging arterial plaques using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein one aryl ring of said structure is substituted with a [L] q -[MS-MM] p  moiety, wherein q is one or two and p is one;    wherein X is CH 2 , O, or NH;    wherein L comprises a physiologically compatible linker moiety which links said one substituted aryl ring with said —[MS-MM] p  moiety;    wherein said MS moiety is an amide bond;    wherein said MM moiety is a peptide consisting of two or three amino acids;    and pharmaceutically acceptable salts thereof; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         7 . The method of any one of claims  1 - 6 , wherein said MM moiety is a peptide consisting of two Arg, Lys, or tm-Lys amino acids, or mixtures thereof.  
     
     
         8 . The method of any one of claims  1 - 6 , wherein said MM moiety is -Arg-tmLys-tmLys.  
     
     
         9 . The method of any one of claims  1 - 6 , wherein said MM moiety is Ile-Arg-Lys  
     
     
         10 . The method of any one of claims  1 - 6 , wherein said chelating agent is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         wherein the wavy line signifies the attachment site for the —PBM-[L] q -[MS-MM] p  moiety.  
       
     
     
         11 . The method of any one of claims  1 - 6 , wherein said paramagnetic metal ion is selected from the group consisting of: 
 (a) Gd(III),    (b) Mn(II),    (c) Fe(III),    (d) Cu(II),    (e) Cr(III), and    (f) Eu(III).    
     
     
         12 . The method of any one of claims  1 - 6 , wherein said pharmaceutically acceptable salt is an N-methyl-D-glucamine, calcium, or sodium salt.  
     
     
         13 . The method of any one of claims  1 - 6 , wherein said compound has the structure of Prodrug Compound 2:  
       
         
           
           
               
               
           
         
       
       or Prodrug Compound 10:  
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of imaging a tumor using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein X is CH 2 , O, or NH; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         15 . A method of imaging a site of active inflammation using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein X is CH 2 , O, or NH; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         16 . A method of imaging arterial plaques using magnetic resonance imaging, said method comprising: 
 a) administering to a mammal a compound having the following structure:                          wherein said IEM comprises a complex between:    (1) a chelating agent selected from the group consisting of DTPA, DOTA, DTPA-BMA, and HP-DO3A, and    (2) one or more paramagnetic metal ions (M) with atomic numbers 21-29, 42, 44, or 57-83;    wherein X is CH 2 , O, or NH; and    b) subjecting said mammal to magnetic resonance imaging.    
     
     
         17 . The method of any one of claims  14 - 16 , wherein said compound has the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of any one of claims  14 - 16 , wherein said paramagnetic metal ion is selected from the group consisting of: 
 (a) Gd(III),    (b) Mn(II),    (c) Fe(III),    (d) Cu(II),    (e) Cr(III), and    (f) Eu(III).    
     
     
         19 . The method of any one of claims  14 - 16 , wherein said compound has the following structure:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of any one of claims  1 ,  4 , or  14 , wherein said tumor is located in the breast, lung, pancreas, or prostate.  
     
     
         21 . The method of  claim 20 , wherein said tumor is located in the prostate.  
     
     
         22 . The method of any one of claims  1 ,  4 , or  14 , wherein said tumor is malignant.  
     
     
         23 . The method of any one of claims  2 ,  5 , or  15 , wherein said sites of inflammation are associated with arthritis.  
     
     
         24 . The method of  claim 23 , wherein said arthritis is rheumatoid arthritis.  
     
     
         25 . The method of any one of claims  3 ,  6 , or  16 , wherein said arterial plaques are associated with atherosclerosis.  
     
     
         26 . The method of any one of claims  3 ,  6 , or  16 , wherein said arterial plaques comprise unstable plaques.  
     
     
         27 . The method of any one of claims  1 - 6  or  14 - 16 , wherein said magnetic resonance imaging is conducted 15 minutes after administration of said compound.