Mn(II) MRI Contrast Agent Ligand Design for Kinetic Stability

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current MRI contrast agents based on Gd(III) ions have limitations, including potential toxicity due to the release of Gd ions, whereas Mn(II) ions, being endogenous, offer a safer alternative but require high kinetic stability to prevent neurotoxicity, which existing Mn(II) complexes fail to achieve effectively.

Innovation Solution

Development of novel substituted ethylenediaminetetraacetic acid bisamide derivatives that form uncharged complexes with Mn(II) ions, exhibiting high thermodynamic and kinetic stability, thereby minimizing the release of toxic metal ions, and are used as MRI contrast agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If Mn(II) complexes are used as MRI contrast agents, then toxicity is reduced compared to Gd(III) agents, but kinetic stability is insufficient leading to metal ion release and neurotoxicity

Engineering Contradiction:

ImprovetoxicityVSAvoidkinetic stability

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent modifies the ligand structure by introducing specific substituents (aromatic rings, saturated rings with hydroxyl groups, heterocycloalkyl rings) at the amide nitrogen positions of the CDTA backbone. These structural parameter changes enhance the kinetic stability of the Mn(II) complex without compromising its thermodynamic stability, thereby preventing metal ion release while maintaining low toxicity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite chelating ligand system combining CDTA backbone with various stabilizing moieties (aromatic rings, saturated rings, heterocycloalkyl rings). This composite structure provides both thermodynamic stability for low toxicity and kinetic stability to prevent dissociation, resolving the contradiction between these two requirements.

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If existing Mn(II) complexes are used, then endogenous metal ion benefits are achieved, but kinetic inertness is low causing metal ion dissociation

Engineering Contradiction:

ImprovebiocompatibilityVSAvoidkinetic inertness

Core Design Contradiction:

Adaptability or versatilityVSStability of the object's composition

Solution Approach 1:

The patent introduces specific structural parameters into the ligand molecule, including aromatic rings (5-6 membered), saturated rings (6-7 membered) with hydroxyl substitutions, and heterocycloalkyl rings with second heteroatoms. These parameter changes significantly enhance kinetic inertness while preserving the biocompatibility advantage of using endogenous Mn(II) ions.

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If Gd(III) based contrast agents are used, then diagnostic imaging performance is achieved, but toxicity concerns arise from Gd ion release

Engineering Contradiction:

Improvediagnostic imaging qualityVSAvoidGd ion toxicity

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the expensive and potentially toxic Gd(III) metal center with the endogenous, biocompatible Mn(II) ion. By combining this substitution with enhanced ligand design, the patent achieves comparable diagnostic performance without the long-term toxicity concerns associated with gadolinium accumulation.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent modifies the ligand parameters to specifically optimize Mn(II) complex stability and relaxivity properties. The introduced substituents (aromatic rings, saturated rings with hydroxyls, heterocycloalkyl rings) are designed to enhance both the stability and the MRI contrast performance, matching or exceeding Gd(III) agent performance while eliminating Gd toxicity.

Inventive Principle:

Principle #35Parameter changes

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 Mn(II) complexes demonstrate improved kinetic inertness, with negligible decomplexation and comparable relaxivity values to Gd(III)-based compounds, making them suitable for diagnostic imaging without the toxicity concerns associated with Gd-based agents.

Implementation Method 1

The intensity of the signal recorded in MRI stems, essentially, from the local value of the longitudinal relaxation rate 1/T1... Most contrast agents used in the clinical practice are complexes of paramagnetic Gd(III) ion... the Mn(II) cation has a great potential since it is an endogenous metal ion

Methodology Applied

Scientific EffectParamagnetic relaxation enhancement:

Data Source

PatentEP3262033B1Ethylenediaminetetraacetic acid bis(AMIDE) derivatives and their respective complexes with mn(II) ion for use as MRI contrast agent

Publication Date: 2020.08.26 BRACCO IMAGING SPA

AI summary

The present invention relates to novel substituted ethylenediaminetetraacetic acid bisamide derivatives, their complexes with Mn(II) ion and the use thereof as contrast agents for Magnetic Resonance Imaging (MRI) analysis.