Cyclic Gd(III) Complex for Stable Liver-Targeted MRI Contrast
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Solution Overview
Problem
Current commercial Gd-based MRI contrast agents for liver imaging suffer from poor stability and targetability, leading to high health risks due to large Gd residue.
Innovation Solution
A cyclic Gd(III) complex with a specific chemical structure, incorporating lipophilic groups and a chiral group, is developed to enhance stability and targetability, utilizing a preparation method involving nucleophilic substitution, hydrolysis, condensation, and complexation reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If linear Gd-DTPA derivatives are used as MRI contrast agents, then detection sensitivity is improved, but stability deteriorates causing large Gd residue and health risks
Solution Approach 1:
The patent changes the fundamental structural parameter of the Gd complex from linear to cyclic configuration. This structural parameter change transforms the stability characteristic while maintaining the MRI contrast enhancement function, thereby resolving the contradiction between detection sensitivity and stability.
Solution Approach 2:
The patent employs composite ligand systems combining macrocyclic frameworks with specific substituent groups (e.g., carboxylic acid groups, hydroxyl groups) to create a stable cyclic Gd complex. This composite approach ensures both high stability through the macrocyclic structure and effective MRI contrast through the functional groups.
2Adaptability or versatility
If conventional Gd-based contrast agents are used, then liver imaging capability is provided, but targetability deteriorates resulting in poor liver-specific accumulation
Solution Approach 1:
The patent introduces specific local functional groups (carboxylic acid groups at positions 2 and 6, hydroxyl groups) to the cyclic Gd complex structure. These local modifications enable selective interaction with liver tissues and gallbladder, achieving targetability while maintaining overall liver imaging capability.
Solution Approach 2:
The patent modifies the chemical and physical parameters of the Gd complex by introducing lipophilic groups and specific functional groups that enhance liver uptake. This parameter modification enables the complex to be actively transported into liver cells via OATP transporters, achieving superior targetability.
3Reliability
If cyclic Gd complex structure is adopted, then stability is improved with no metal ion release, but complexity of preparation increases
Solution Approach 1:
The patent segments the complex preparation process into distinct modular steps: synthesis of the cyclic ligand framework, introduction of functional groups, complexation with Gd³⁺ ion, and purification. This segmentation makes the complex preparation more manageable and reproducible while maintaining the high stability of the cyclic structure.
Solution Approach 2:
The patent employs preliminary synthesis of the cyclic ligand structure with pre-installed functional groups before Gd complexation. This preliminary action simplifies the overall process by preparing stable building blocks that can be easily combined with the metal ion under mild conditions, reducing the complexity of the final preparation.
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 cyclic Gd(III) complex exhibits excellent stability and targetability, with no detectable metal ion release over a year, making it suitable for high-field MRI as a liver and gallbladder-specific contrast agent, outperforming existing agents like Primovist and Gd-DOTA.
Implementation Method 1
Magnetic resonance imaging (MRI) is a technology in which an electromagnetic signal (EMS) is acquired through magnetic resonance of atomic nuclei under the action of a magnetic field
Implementation Method 2
mixing a compound with a structure shown in formula A-1, DO3A, potassium carbonate, and acetonitrile to allow a nucleophilic substitution reaction to obtain a compound with a structure shown in formula A-2
Implementation Method 3
mixing the compound with a structure shown in formula A-2 obtained in step (1), tetrahydrofuran (THF), methanol, and a lithium hydroxide aqueous solution to allow a hydrolysis reaction to obtain a first reaction precursor
Implementation Method 4
mixing the first reaction precursor obtained in step (2) with 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), dichloromethane (DCM), an amine, and diisopropylethylamine (DIPEA) to allow a condensation reaction to obtain a compound with a structure shown in formula A-3
Implementation Method 5
The cyclic Gd(III) complex provided by the present disclosure can be used as an MRI contrast agent targeting the liver and gallbladder, with excellent stability and targetability
Data Source
AI summary
The present disclosure provides a cyclic Gd (III) complex with a chemical structure shown in formula I, where a ring structure of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is used as a parent ring, lipophilic groups R′ and R″ in formula I are respectively introduced to a α-position of phenylacetic acid (PAA) and a benzene ring structure, and a chiral group R in formula I is introduced to a DOTA macrocycle position. The chiral group R can increase the rigidity of a macrocyclic structure and improve the stability of the complex, and the lipophilic groups R′ and R″ can bind to hepatocellular organic anion transporting polypeptides (OATPs), thereby greatly improving the distribution of the cyclic Gd (III) complex as a contrast agent in the liver and gallbladder, that is, thereby providing excellent targetability.