Diagnostic imaging contrast agents with extended blood retention

Abstract

The present invention relates to contrast agents for diagnostic imaging with prolonged blood retention. In particular, this invention relates to novel compounds that are characterized by an image enhancing moiety (IEM); a protein plasma binding moiety (PPBM); and a blood half-life extending moiety (BHEM). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for blood half-life extension and contrast enhancement of diagnostic imaging.

1 . A composition of matter having the following formula:  
         IEM-[L m -{BHEMs-PPBM 0 } p ] q    or a pharmaceutically acceptable salt thereof, 
 wherein m, s, o, and p are one;  
 wherein q is one or two;  
 wherein IEM is an image enhancing moiety;  
 wherein L is an organic linker connecting the IEM to the BHEM;  
 wherein BHEM is a blood half-life extending moiety;  
 wherein PPBM is an HSA binding moiety;  
 wherein IEM is selected from the following:  
                     
 wherein R 1 -R 11  is —[L m —{BHEM s -PPBM o } p ] q  and the R 1 -R 11  groups that are not —[L m —{BHEM s -PPBM o } p ] q  are hydrogen;  
 wherein R 12 , R 13 , and R 14  can be the same or different and are selected from the group consisting of —[L m —{BHEM s -PPBM o } p ] q , O 31  and NH 2 ;  
 wherein R 15  is H, CH 2 CH(OH)CH 3 , hydroxyl alkyl, or CH 2 COR 12 ;  
 wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III);  
 wherein L is a linker consisting of 1 to 4 —CH 2 — groups; and  
 wherein said BHEM moiety comprises urea, amine, amide, sulfonamide, or carbamate.  
   
     
     
         2 . The composition of  claim 1 , wherein said IEM moiety is:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 1 , wherein said composition is a pharmaceutically acceptable salt, wherein said pharmaceutically acceptable salt is selected from the group consisting of: 
 (a) N-methyl-D-glucamine (b) calcium, (c) sodium, and (d) mixtures thereof.    
     
     
         4 . The composition of  claim 3 , wherein said salt is sodium.  
     
     
         5 . The composition of  claim 3 , wherein said salt is N-methyl-glucamine.  
     
     
         6 . The composition of  claim 3 , wherein said salt is a mixture of sodium and N-methyl-glucamine.  
     
     
         7 . The composition of  claim 1 , wherein said M is Gd(III).  
     
     
         8 . The composition of  claim 1 , wherein said BHEM moiety is carbamate.  
     
     
         9 . The composition of  claim 1 , wherein said BHEM moiety is amide.  
     
     
         10 . A pharmaceutical composition comprising the composition according to  claim 1  and a carrier, adjuvant, or vehicle.  
     
     
         11 . The pharmaceutical composition of  claim 10 , further comprising a free organic ligand or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A method of MR imaging of a mammal, said method comprising the steps of: 
 a) administering to said mammal a composition according to  claim 1;  and    b) subjecting said mammal to MR imaging.    
     
     
         13 . The method of  claim 12 , wherein said mammal is a human.  
     
     
         14 . The method of  claim 12 , wherein said MR imaging comprises imaging at least a portion of the vasculature of said mammal.  
     
     
         15 . The method of  claim 12 , wherein a portion of said imaging occurs 10 minutes or later after administration of said composition.  
     
     
         16 . The method of  claim 12 , wherein said composition is administered to said mammal at a concentration between 0.001 to about 1 mmol/kg body weight.  
     
     
         17 . The method of  claim 12 , wherein said imaging of said mammal comprises imaging a tumor of said mammal.  
     
     
         18 . The method of  claim 12 , wherein said imaging of said mammal comprises imaging the brain of said mammal.  
     
     
         19 . The method of  claim 18 , wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.  
     
     
         20 . The method of  claim 18 , wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.  
     
     
         21 . A method for examining vasculature of a tissue comprising HSA in a mammal, said method comprising: 
 a) administering to said mammal a composition according to  claim 1;  and    b) obtaining an MR image of said vasculature of said tissue.    
     
     
         22 . The method of  claim 21 , wherein said step b) comprises obtaining multiple images of said tissue.  
     
     
         23 . The method of  claim 21 , further comprising, prior to step a), obtaining an MR image of said tissue.  
     
     
         24 . The method of  claim 22  or  23 , further comprising comparing two or more of said images of said tissue.  
     
     
         25 . The method of  claim 21 , wherein said mammal is a human.  
     
     
         26 . A method for examining perfusion in a tissue comprising HSA in a mammal, said method comprising: 
 a) administering to said mammal a composition according to  claim 1;  and    b) obtaining an MR image of said tissue of said mammal.    
     
     
         27 . The method of  claim 26 , wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.  
     
     
         28 . The method of  claim 26 , wherein said step b) comprises obtaining multiple images of said tissue.  
     
     
         29 . The method of  claim 26 , further comprising, prior to step a), obtaining an MR image of said tissue.  
     
     
         30 . The method of  claim 28  or  29 , further comprising comparing two or more of said images of said tissue.  
     
     
         31 . The method of  claim 26 , wherein said mammal is a human.  
     
     
         32 . The method of  claim 21  or  26 , wherein said tissue comprises a stenosis.  
     
     
         33 . A method of monitoring a human's brain during cognitive events, said method comprising: 
 a) administering to said human a composition according to  claim 1;  and    b) obtaining an MR image of said brain of said human.    
     
     
         34 . The method of  claim 33 , wherein said step b) comprises obtaining multiple images of said brain.  
     
     
         35 . The method of  claim 33 , further comprising, prior to step a), obtaining an MR image of said brain.  
     
     
         36 . The method of  claim 34  or  35 , further comprising comparing two or more of said images of said brain.  
     
     
         37 . The method of  claim 33 ,  34 , or  35 , wherein said obtaining occurs during a cognitive event.  
     
     
         38 . The method of  claim 33 ,  34 , or  35 , wherein said obtaining occurs before or after a cognitive event.  
     
     
         39 . A method for determining blood volume in a tissue comprising HSA in a mammal, said method comprising: 
 a) administering to said mammal a composition according to  claim 1;  and    b) obtaining an MR image of said tissue.    
     
     
         40 . The method of  claim 39 , wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.  
     
     
         41 . The method of  claim 39 , wherein said step b) comprises obtaining multiple images of said tissue.  
     
     
         42 . The method of  claim 39 , further comprising, prior to step a), obtaining an MR image of said tissue.  
     
     
         43 . The method of  claim 41  or  42 , further comprising comparing two or more of said images of said tissue.