Iron(III) MRI Contrast Complexes With pH-Dependent Relaxivity

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Solution Overview

Problem

Existing gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) pose toxicity risks due to incomplete excretion, leading to tissue deposition and side effects like nephrogenic systemic fibrosis, particularly in patients with compromised kidney function, and there is a need for gadolinium-free alternatives with pH-dependent resonance behavior for enhanced diagnostic capabilities.

Innovation Solution

Development of novel iron(III) complexes with specific ligands, such as those derived from cyclohexanediamine tetraacetic acid (CDTA), which exhibit improved heat and acid resistance, reduced osmolality, and pH-dependent relaxivity, suitable for use as contrast agents in MRI, including applications like Chemical Exchange Saturation Transfer (CEST) imaging.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If gadolinium-based contrast agents are used to improve MRI contrast, then T1 relaxation is accelerated and diagnostic signal increases, but gadolinium accumulates in tissues and causes toxicity

Engineering Contradiction:

ImproveMRI contrast signalVSAvoidgadolinium toxicity

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent changes the metal ion parameter from gadolinium to iron(III), fundamentally altering the contrast mechanism while avoiding gadolinium toxicity. The iron(III) complexes maintain T1 relaxation enhancement capability through different magnetic properties, achieving MRI contrast without the harmful accumulation associated with gadolinium

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs iron(III) which is naturally abundant and rapidly excreted by the body, replacing gadolinium that persists in tissues. The iron complexes act as temporary contrast agents that fulfill their diagnostic purpose and are then naturally eliminated without long-term accumulation

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Object-affected harmful factors

If iron complexes are used as contrast agents, then gadolinium-free alternative is provided with lower osmolality, but T1 relaxivity is lower requiring higher doses

Engineering Contradiction:

ImproveosmolalityVSAvoidcontrast agent dose

Core Design Contradiction:

Object-affected harmful factorsVSQuantity of substance

Solution Approach 1:

The patent creates composite iron(III) complexes with specifically designed ligands (such as CDTA derivatives) that optimize both the safety profile and contrast performance. The ligand structure is engineered to enhance the T1 relaxivity of the iron center while maintaining low osmolality, achieving a balance between dose requirement and safety

Inventive Principle:

Principle #40Composite materials

3Adaptability or versatility

If conventional contrast agents are used, then standard T1-weighted imaging is achieved, but pH-dependent resonance behavior is not utilized

Engineering Contradiction:

ImprovepH-dependent relaxivityVSAvoidtumor visualization

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent introduces dynamic pH-responsive behavior to the iron(III) complexes, where the T1 relaxivity changes in response to pH variations. This dynamic property allows the contrast agent to adapt its performance based on the local microenvironment, enhancing tumor visualization where pH differs from normal tissue

Inventive Principle:

Principle #15Dynamics

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 iron(III) complexes provide enhanced contrast effects in MRI by increasing T1- and T2-relaxivity based on pH, allowing for improved tumor and inflammation visualization and reduced acute toxicity, with potential for higher dose tolerance and functional coupling for biomolecule labeling.

Implementation Method 1

GBCA accelerates both the T1 relaxation (spin-lattice relaxation) as well as the T2 relaxation (spin-spin relaxation), wherein the T1 relaxation results in a diagnostically useful MRI signal increase

Methodology Applied

Scientific EffectT1 relaxation (spin-lattice relaxation):

Implementation Method 2

GBCA accelerates both the T1 relaxation (spin-lattice relaxation) as well as the T2 relaxation (spin-spin relaxation)

Methodology Applied

Scientific EffectT2 relaxation (spin-spin relaxation):

Data Source

PatentUS12465659B2Iron(III) complexes having new contrast agent properties, for magnetic resonance imaging

Publication Date: 2025.11.11 CHARITE UNIVS MEDIZIN BERLIN

AI summary

The invention provides novel iron(III) complexes with formulae (1) and (2). Furthermore, corresponding ligands with formulae (L1) and (L2) for the production of iron(III) complexes are disclosed.