Use of bile acid derivatives conjugated with metal ion chelated complexes for the diagnostic assessment of microvascular permeability

Abstract

The use of contrast agents of molecular weight lower than 5000 Dalton and including at least one residue of a biliary acid for the preparation of diagnostic contrast compositions for the microvascular permeability assessment is disclosed.

1 . Use of a contrast agent of molecular weight lower than 5000 Dalton and including in its structure at least one residue of a biliary acid for the preparation of diagnostic contrast compositions for the assessment of microvascular permeability.  
     
     
         2 . Use of a contrast agent according to  claim 1  wherein the molecular weight of said agent is between 4500 and 500 Dalton.  
     
     
         3 . Use of a contrast agent according to  claim 1  wherein the molecular weight of said agent is between 3000 and 500 Dalton.  
     
     
         4 . Use of a contrast agent according to  claim 1  wherein said contrast agent further includes in its structure one or two chelated complex units of bi or trivalent paramagnetic metal ions or a salt thereof with a physiologically compatible organic base selected from primary, secondary, tertiary amines or basic amino acid, or with an inorganic base whose cations are selected from sodium, potassium, magnesium, calcium or mixtures thereof.  
     
     
         5 . Use of a contrast agent according to  claim 4  further characterized in that it includes in its structure only one chelated complex unit.  
     
     
         6 . Use of contrast agents according to  claim 4  further characterized in that it includes in its structure two chelated complex units.  
     
     
         7 . Use of contrast agents according to  claim 4  wherein the chelating unit of the chelated complex consists of a polyaminopolycarboxylic acid residue.  
     
     
         8 . Use of contrast agents according to  claim 4  wherein the paramagnetic bi or trivalent metal ions chelated to the chelating units are selected from the group consisting of gadolinium (III), iron (III), iron (II), manganese (II), manganese (III), chromium (III), copper (II), dysprosium (III), ytterbium (III), terbium (III) and europium (III).  
     
     
         9 . Use of a contrast agent according to  claim 1  wherein the biliary acid residue is selected from biliary acids obtained by bioconversion or synthetic modification of the cholesterol.  
     
     
         10 . Use of a contrast agent according to  claim 9  wherein the biliary acid residue is a residue deriving from cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, lithocholic acids, as such or as a derivative thereof, including either those in which the hydroxy groups are functionalized or the taurine and glycine conjugated to the carboxy group at the 24-position of the cholane skeleton.  
     
     
         11 . Use of a contrast agent according to  claim 1  for the diagnostic assessment of the microvessels integrity.  
     
     
         12 . Use of a contrast agent according to  claim 1  for the determination of the microvascular permeability.  
     
     
         13 . Use of a contrast agent according to  claim 1  for the determination of the fractional plasma volume of a human or animal body tissue.  
     
     
         14 . Use of a contrast agent according to  claim 1  for the preparation of contrast compositions for the definition of a human or animal body tissue pathologic condition correlating microvascular permeability and fractional plasma volume characteristics.  
     
     
         15 . Use of a contrast agent according to  claim 14  for the diagnostic assessment of the angiogenesis.  
     
     
         16 . Use of a contrast agent according to  claim 14  to determine the histopathologic grade of a tumor mass.  
     
     
         17 . Use of a contrast agent according to  claim 14  to perform the diagnostic assessment of inflammatory states.  
     
     
         18 . Use of a contrast agent according to  claim 14  to perform the diagnostic assessment of myocardial and cerebral ischemic states.  
     
     
         19 . Use of a contrast agent according to  claim 15  to monitor the malignancy response to an angiogenesis inhibitor.  
     
     
         20 . Use of a contrast agent according to  claim 19  wherein the angiogenesis inhibition is performed with a human anti-VEGF monoclonal antibody.  
     
     
         21 . Use of a contrast agent according to  claim 15  to monitor the malignancy response to chemotherapy or radiation therapy.  
     
     
         22 . Use of a contrast agent according to  claim 1  for the preparation of contrast compositions for the definition of a human or animal body tissue physiological condition correlating microvascular permeability and fractional plasma volume characteristics.  
     
     
         23 . Use of a contrast agent according to  claim 22  to perform the definition of embryogenesis, wound healing, corpus luteum formation and growth.  
     
     
         24 . Use of a contrast agent according to  claim 1  wherein the diagnostic imaging step is performed by use of M.R.I.  
     
     
         25 . Use of a contrast agent according to  claim 24  wherein the diagnostic imaging is performed by use of the Contrast Enhanced Dynamic Magnetic Resonance Imaging (DCE MRI) technique.  
     
     
         26 . Use of a contrast agent according to  claim 24  wherein the agent is the gadolinium complex of the [3β(S),5β,12α]-3-[[4-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]-4-carboxy-1-oxobutyl]amino]-12-hydroxycholan-24-oic acid.  
     
     
         27 . Use of the contrast agent according to  claim 26  wherein said agent is under the form of trisodium salt.  
     
     
         28 . A diagnostic method of assessing microvascular permeability in a tissue or body region, said method comprising: 
 (a) administering to a subject in need of visualization a contrast agent of molecular weight lower than 5000 Dalton and including in its structure at least one residue of a biliary acid,    (b) monitoring the enhancement in said tissue or body region by use of Magnetic Resonance Imaging, and    determining the microvascular permeability in said tissue or body region based on rate of the enhancement increase.    
     
     
         29 . The method according to  claim 28  wherein the molecular weight of said agent is between 4500 and 500 Dalton.  
     
     
         30 . The method according to  claim 29  wherein the molecular weight of said agent is between 3000 and 500 Dalton.  
     
     
         31 . The method according to  claim 28  wherein said contrast agent further includes in its structure one or two chelated complex units of bi or trivalent paramagnetic metal ions or a salt thereof with a physiologically compatible organic base selected from primary, secondary, tertiary amines or basic amino acid, or with an inorganic base whose cations are selected from sodium, potassium, magnesium, calcium or mixtures thereof.  
     
     
         32 . The method according to  claim 31  wherein the contrast agent includes in its structure one chelated complex unit.  
     
     
         33 . The method according to  claim 31  wherein the contrast agent includes in its structure two chelated complex units.  
     
     
         34 . The method according to  claim 31  wherein the chelating unit of the chelated complex consists of a polyaminopolycarboxylic acid residue.  
     
     
         35 . The method according to  claim 31  wherein the paramagnetic bi or trivalent metal ions chelated to the chelating units are selected from the group consisting of gadolinium (III), iron (III), iron (II), manganese (II), manganese (III), chromium (III), copper (II), dysprosium (III), ytterbium (III), terbium (III) and europium (III).  
     
     
         36 . The method according  claim 28  wherein the biliary acid residue is from biliary acids obtained by bioconversion or synthetic modification of the cholesterol.  
     
     
         37 . The method of  claim 36  wherein the biliary acid residue is a residue deriving from cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, lithocholic acids,  
       
         
           
           
               
               
           
         
         both unfunctionalized, and functionalized at the positions having the hydroxy group as the reactive group, independently of the stereochemistry of the final products, as well as the conjugate of thereof acid group at the 24 position with taurine and glycine.  
       
     
     
         38 . The method of  claim 37  wherein the bile acid functional derivative is selected from the following group:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . The method according to  claim 28  for the diagnostic assessment of the microvessels integrity.  
     
     
         40 . The method according to  claim 28  for the determination of the microvascular permeability.  
     
     
         41 . The method according to  claim 28  for the determination of a fractional plasma volume of a human or animal body tissue.  
     
     
         42 . The method according to  claim 28  wherein the method defines a human or animal body tissue pathologic condition correlating microvascular permeability and fractional plasma volume characteristic.  
     
     
         43 . The method according to  claim 42  for the diagnostic assessment of the angiogenesis.  
     
     
         44 . The method according to  claim 42  to determine the histopathologic grade of a tumor mass.  
     
     
         45 . The method according to  claim 42  wherein the method provides diagnostic assessment of inflammatory states.  
     
     
         46 . The method according to  claim 42  to perform a diagnostic assessment of myocardial or cerebral ischemic states.  
     
     
         47 . The method according to  claim 43  to monitor the malignancy response to an angiogenesis inhibitor.  
     
     
         48 . The method according to  claim 47  wherein the angiogenesis inhibition is performed with a human anti-VEGF monoclonal antibody.  
     
     
         49 . The method according to  claim 43  to monitor the malignancy response to chemotherapy or radiation therapy.  
     
     
         50 . The method according to  claim 42  to define embryogenesis, wound healing, corpus luteum formation and growth.  
     
     
         51 . The method according to  claim 28  wherein the diagnostic imaging is performed by magnetic resonance imaging.  
     
     
         52 . The method according to  claim 51  wherein the diagnostic imaging is performed by Contrast Enhanced Dynamic Magnetic Resonance Imaging (DCE MRI).  
     
     
         53 . The method according to  claim 50  wherein the agent is the gadolinium complex of the [3β(S),5β,12α]-3-[[4-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]-4-carboxy-1-oxobutyl]amino]-12-hydroxycholan-24-oic acid.  
     
     
         54 . The method according to  claim 53  wherein said agent is in the form of a trisodium salt.