Macrocyclic Gadolinium Chelates for Liver-Specific CT and MRI
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Solution Overview
Problem
There is a need for new macrocyclic gadolinium-based contrast agents (GBCAs) suitable for both magnetic resonance imaging (MRI) and computed tomography (CT), particularly for liver-specific imaging, that exhibit high water solubility, stability, high relaxivity, and complete excretion, while avoiding long-term retention in tissues and organs, and are well-tolerated.
Innovation Solution
Development of a new class of liver-specific metal chelate complexes, particularly with gadolinium, that form stable macrocyclic structures, allowing for high uptake in the liver, fast and complete excretion, and high relaxivity, suitable for both MRI and CT imaging.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear gadolinium-based contrast agents are used for MRI, then liver-specific imaging is achieved, but long-term retention in tissues and organs occurs
Solution Approach 1:
The patent changes the molecular structure parameter from linear to macrocyclic chelate configuration, which fundamentally alters the pharmacokinetic profile while maintaining liver-specific imaging capability through the same OATP transporter mechanism
Solution Approach 2:
The patent creates composite contrast agents combining macrocyclic gadolinium chelates with hepatobiliary phase imaging capabilities, merging the safety advantages of macrocyclic structures with the diagnostic utility of liver-specific agents
2Object-affected harmful factors
If macrocyclic gadolinium-based contrast agents are used, then stability and reduced retention are achieved, but liver-specific uptake is insufficient
Solution Approach 1:
The patent introduces liver-specific targeting moieties (such as glycine conjugates or other hepatobiliary phase agents) to the macrocyclic gadolinium chelate structure, creating localized recognition elements that enable specific uptake by hepatocytes via OATP transporters while the macrocyclic core maintains stability
Solution Approach 2:
The patent designs dual-function contrast agents that simultaneously provide the stability of macrocyclic structures and the liver-specific targeting capability, enabling one agent to perform both safety and diagnostic functions
3Measurement precision
If high concentration of contrast agent is used for CT imaging, then image quality is improved, but nephrotoxicity increases
Solution Approach 1:
The patent changes the contrast mechanism by using gadolinium-based agents with high relaxivity for MRI and alternative metal ions with high atomic numbers for CT, allowing effective imaging at lower concentrations compared to traditional iodinated contrast media
Solution Approach 2:
The patent emphasizes complete and rapid excretion of the contrast agent through renal pathways, ensuring that the agent is quickly eliminated from the body after performing its diagnostic function, thereby minimizing cumulative toxic effects on the kidneys
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new metal chelate complexes provide enhanced liver imaging capabilities with high tolerability, improved relaxivity, and complete excretion, addressing the limitations of existing linear GBCAs and extracellular CT contrast media.
Implementation Method 1
Paramagnetic contrast media shorten the T1 (longitudinal) and T2 (transversal) relaxation times of surrounding water protons to indirectly produce a signal-enhancing effect
Implementation Method 2
All x-ray contrast media approved for intravascular use are iodine-containing monomeric or dimeric substances... Gadolinium-based contrast agents... metal ion having at least the x-ray attenuation of iodine
Data Source
AI summary
The present invention relates to a new class of compounds of general formula (I), to the metal chelates with a metal ion suitable for computed tomography thereof, to the Gd3+ chelate complexes thereof, to methods of preparing said compounds, and to the use of said compounds as contrast agents in diagnostic imaging, such as in magnetic resonance imaging (MRI) and computed tomography (CT).