1,4-bis-(2-hydroxy-benzyl)-1,4,7-triazacyclononane derivatives and similar compounds as ligands in iron(III) complexes for use as MRI contrast agents
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Solution Overview
Problem
Current MRI contrast agents based on Gd(III) complexes pose concerns regarding kidney function retention, environmental impact, and stability issues, while Fe(III) complexes lack high relaxivity, kinetic inertness, and redox stability for wide-ranging MRI applications.
Innovation Solution
Development of novel 1,4-bis-(2-hydroxy-benzyl)-1,4,7-triazacyclononane derivatives that form Fe(III) complexes with high relaxivity, kinetic inertness, and stability to reduction, suitable for use as MRI contrast agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Fe(III) complexes are used as MRI contrast agents, then alternative to Gd(III) agents is provided, but they lack high relaxivity and kinetic inertness
Solution Approach 1:
The patent modifies the ligand structure by introducing specific substituents (R1, R2, R3, Y1, Y2, Y3, L1, L2, L3, Z1, Z2, Z3) at defined positions on the macrocyclic framework, changing the chemical parameters of the complex to achieve both high relaxivity and kinetic inertness simultaneously
Solution Approach 2:
The patent creates a composite structure combining a macrocyclic ligand framework with specific aromatic substituents containing hydroxyl and carboxyl groups, forming a Fe(III) complex that integrates multiple functional moieties to achieve both stability and high relaxivity
2Reliability
If Fe(III) complexes are used as MRI contrast agents, then alternative to Gd(III) agents is provided, but they lack stability to reduction
Solution Approach 1:
The patent creates a chemically inert coordination environment around the Fe(III) center through the macrocyclic ligand structure, protecting the iron from reduction by endogenous antioxidants while maintaining high contrast effectiveness
Solution Approach 2:
The patent converts the potential harm of Fe(III) reduction into a benefit by designing a ligand system that prevents reduction, thereby avoiding Fenton reaction and maintaining both redox stability and contrast effectiveness
3Quantity of substance
If Gd(III) complexes are used as MRI contrast agents, then high relaxivity is achieved, but concerns arise regarding kidney function retention and environmental impact
Solution Approach 1:
The patent extracts the Fe(III) ion from the problematic Gd(III) complex system while retaining the essential macrocyclic ligand structure, thereby achieving high relaxivity without the kidney retention and environmental issues associated with gadolinium
Solution Approach 2:
The patent changes the paramagnetic metal center parameter from Gd(III) to Fe(III) while optimizing the ligand structure to maintain high relaxivity, thereby eliminating harmful effects while preserving contrast effectiveness
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 Fe(III) complexes exhibit a balanced profile of high relaxivity, kinetic inertness, and stability, providing effective contrast for MRI without the drawbacks of Gd(III) agents.
Implementation Method 1
accelerate the relaxation rates (R1 and R2) of proximate tissue water protons in regions of agent accumulation
Data Source
AI summary
The invention relates to the novel compounds of formula (I) as well as ions, stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts thereof, or mixtures of the same. The compounds of formula (I) are ligands that are able to chelate Fe(III) ions, thereby generating Fe(III) complexes, which are particularly suitable in diagnostic imaging, for example as contrast agents for magnetic resonance imaging (MRI), due to their high relaxivity, thermodynamic stability, kinetic inertness and redox stability.