Magnetic resonance imaging agents for the detection of physiological agents

Abstract

The invention relates to novel magnetic resonance imaging contrast agents and methods of detecting physiological signals or substances.

1 . A composition comprising at least one MRI agent having the formula:  
       
         
           
           
               
               
           
         
         wherein   is a polymer;  
         M is a chelator comprising a paramagnetic metal ion, or a salt thereof;  
         n is an integer of at least one;  
         R 26  a first linker;  
         R 27  is an optional second linker; and  
         wherein upon interaction of said peptide blocking moiety with a target protease, the T 1  of said MRI agent is decreased.  
       
     
     
         2 . A composition according to  claim 1 , having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A composition according to  claim 1  wherein R 26  is a cleavable linker.  
     
     
         4 . A composition according to  claim 3  is a wherein said cleavable linker is a protease labile linker.  
     
     
         5 . A composition according to  claim 3  wherein said cleavable linker is an esterase labile linkage.  
     
     
         6 . A composition according to  claim 1  or  2  wherein said polymer further comprises a targeting moiety.  
     
     
         7 . A composition according to  claim 1  wherein said chelator is DOTA.  
     
     
         8 . A composition according to  claim 1  wherein said target protease is selected from the group consisting of serine proteases, cysteine proteases, aspartyl proteases and matrix metalloproteases (MMPs).  
     
     
         9 . A composition according to  claim 8  wherein said cysteine proteases are selected from the group consisting of cathepsins, calpains, caspases, and interleukin-converting enzyme (ICE).  
     
     
         10 . A composition according to  claim 8  wherein said serine proteases are selected from the group consisting of trypsin, chymotrypsin, and tissue plasminogen activator and (tPA).  
     
     
         11 . A composition according to  claim 8  wherein said metalloproteases are selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-9, and MMP-10.  
     
     
         12 . A composition according to  claim 1  wherein said paramagnetic metal ion is selected from the group consisting of gadolinium (Gd3+), iron III (Fe+3), manganese II (Mn+2), yttrium III (Y+3), dysprosium (Dy+3), and chromium (Cr(III)).  
     
     
         13 . A method comprising administering a composition according to  claim 1  to a tissue, cell or patient, under conditions whereby said peptide blocking moiety interacts with a target protease in said tissue, cell or patient such that the T 1  of said MRI agent is decreased, and, acquiring a magnetic resonance image of said cell, tissue or patient.  
     
     
         14 . A method according to  claim 13  wherein R 26  is a cleavable linker.  
     
     
         15 . A method according to  claim 14  wherein said cleavable linker is a protease labile linker.  
     
     
         16 . A method according to  claim 14  wherein said cleavable linker is an esterase labile linkage.  
     
     
         17 . A method according to  claim 14  wherein said polymer further comprises a targeting moiety.  
     
     
         18 . A method according to  claim 14 , wherein said chelator is DOTA.  
     
     
         19 . A method according to  claim 13 , wherein said target protease is selected from the group consisting of serine proteases, cysteine proteases, aspartyl proteases and metalloproteases (MMPs).  
     
     
         20 . A method according to  claim 19 , wherein said cysteine proteases are selected from the group consisting of cathepsins, calpains, caspases, and interleukin-converting enzyme (ICE).  
     
     
         21 . A method according to  claim 19 , wherein said serine proteases are selected from the group consisting of trypsin, chymotrypsin, and tissue plasminogen activator and (tPA).  
     
     
         22 . A method according to  claim 19 , wherein said MMPs are selected from the group consisting of metalloprotease-1 (MMP), MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-9, and MMP-10.