Gadolinium Chelate Relaxivity via Hydroxyl Pendant Arms
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Solution Overview
Problem
Current MRI contrast agents, particularly those containing Gd(III) ions, face challenges in achieving high relaxivity, which limits their diagnostic efficacy and requires higher doses and longer imaging times.
Innovation Solution
Development of novel tetraaza macrocyclic ligands with pendant arms containing hydroxyl residues and suitable substituents, which form chelated complexes with paramagnetic metal ions like Gd(III), enhancing relaxivity and stability, thereby improving MRI contrast.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional Gd(III) chelates are used as MRI contrast agents, then diagnostic imaging can be performed, but relaxivity is insufficient requiring higher doses and longer imaging times
Solution Approach 1:
The patent modifies the chemical structure of the chelating ligand by introducing pendant arms with hydroxyl groups at specific positions (e.g., -CH(OH)R, -CH(OH)CH2OH, -C(OH)(R)2 groups). These structural parameter changes increase the number of water protons in the inner coordination sphere of the Gd(III) ion, thereby enhancing relaxivity and allowing lower doses to achieve the same diagnostic effect
Solution Approach 2:
The invention creates composite chelate structures combining the DO3A macrocyclic core with various pendant arm functionalities (hydroxyl groups, amino groups, carboxyl groups). This composite approach integrates multiple functional groups into a single chelating agent, improving both relaxivity and stability while maintaining the ability to chelate Gd(III) ions effectively
2Measurement precision
If higher doses of contrast agent are administered to improve relaxivity, then imaging quality may be enhanced, but acquisition time increases
Solution Approach 1:
By changing the structural parameters of the chelate (adding pendant arms with hydroxyl groups), the patent increases the relaxivity per unit dose. This allows achieving the same signal enhancement at lower doses, thereby reducing the time required for image acquisition while maintaining diagnostic quality
3Ease of manufacture
If conventional chelating ligands are used, then synthesis is straightforward, but relaxivity and stability are limited
Solution Approach 1:
The patent segments the chelating ligand into distinct functional modules: the DO3A macrocyclic core provides stability and Gd(III) binding, while pendant arms with specific functional groups (hydroxyl, amino, carboxyl) provide enhanced relaxivity. This modular segmentation allows systematic optimization of each component's contribution to overall performance
Solution Approach 2:
The invention applies local quality modifications by introducing specific functional groups at specific positions on the pendant arms. For example, hydroxyl groups at positions 3 and/or 7 of the DO3A ring, or specific substituents R1-R6 in the pendant arms, locally enhance water proton interaction and relaxivity without compromising the overall stability of the chelate structure
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 novel complexes demonstrate significantly higher relaxivity compared to existing agents, allowing for reduced doses and shorter imaging times while maintaining diagnostic quality, with minimal protein binding and improved thermal stability.
Implementation Method 1
The intensity of the signal recorded in MRI imaging stems, essentially, from the local value of the longitudinal relaxation rate 1/T1... Gd(III) is highly paramagnetic with seven unpaired electron and a long electronic relaxation time, making it an excellent candidate as a relaxation agent
Implementation Method 2
Contrast agents for use in the MRI imaging technique typically include a paramagnetic metal ion which is complexed with a cyclic or acyclic chelating ligand... the tetradentate macrocyclic ligand DO3A... complexed therewith
Data Source
AI summary
The present invention relates to new class of functionalized macrocycles capable of chelating paramagnetic metal ions, their chelated complexes with metal ions and the use thereof as contrast agents, particularly suitable for Magnetic Resonance Imaging (MRI) analysis.5