Reduced metastable complex macrocyclic contrast agents

Abstract

Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclic GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+-based synthesis methods.

Claimed is: 
     
         1 . A contrast agent for enhancing a biologic image obtained by magnetic resonance imaging (MRI), the contrast agent being in an aqueous solution for injection, the contrast agent comprising:
 a plurality of Gd-DOTA complexes and meglumine; and   at most 100 ppm of free Gd 3+  ion,   wherein greater than 90% of the Gd-DOTA complexes are maximally stable complexes.   
     
     
         2 . The contrast agent of  claim 1 , wherein the maximally stable complexes consist of one water molecule in the coordination sphere. 
     
     
         3 . The contrast agent of  claim 1 , wherein the contrast agent is metastable free such that the contrast agent has less than 1 metastable complex for every 10 6  maximally stable complexes. 
     
     
         4 . The contrast agent of  claim 3 , wherein the metastable complexes comprise four carboxylates coordinated to the Gd 3+  ion and 4 or 5 water molecules in a coordination sphere of the complex. 
     
     
         5 . The contrast agent of  claim 1 , comprising: 3.7 ppm free Gd3+ ion or less after 30 minutes in vitro. 
     
     
         6 . The contrast agent of  claim 5 , comprising: 2.9 ppm free Gd3+ ion or less after 30 minutes in vitro. 
     
     
         7 . The contrast agent of  claim 6 , comprising: 2.1 ppm free Gd3+ ion or less after 30 minutes in vitro. 
     
     
         8 . The contrast agent of  claim 1 , comprising: 35.5 ppm free Gd3 +  ion or less after 30 minutes in vivo. 
     
     
         9 . The contrast agent of  claim 8 , comprising: 34.8 ppm free Gd3+ ion or less after 30 minutes in vivo. 
     
     
         10 . The contrast agent of  claim 9 , comprising: 34.1 ppm free Gd3+ ion or less after 30 minutes in vivo. 
     
     
         11 . The contrast agent of  claim 1 , comprising: 3.7 ppm free Gd3+ ion or less after 30 minutes in vitro and 35.5 ppm free Gd3+ ion or less after 30 minutes in vivo. 
     
     
         12 . A method for synthesizing a gadolinium-based contrast agent, the method comprising:
 performing a complexation reaction between Gd3+ and DOTA;   deprotonation of the [Gd—H(dota)] or [Gd—H 2 (dota)] +  metastables; and   adding meglumine after verification of full complexification.   
     
     
         13 . The method of  claim 12 , wherein the deprotonation of metastables is by hydroxide insertion. 
     
     
         14 . The method of  claim 12 , wherein the deprotonation of metastables is by nitrogen inversion.