Gadolinium PCTA Complex Diastereoisomer Enrichment for Stability

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Solution Overview

Problem

Current gadolinium-based contrast agents for medical imaging face challenges such as undesired lanthanide release, leading to conditions like NSF, and cerebral deposition, due to insufficient thermodynamic and kinetic stabilities, particularly with PCTA-based chelating ligands which have lower stability constants compared to other macrocyclic chelates.

Innovation Solution

A novel process for preparing and purifying a complex of gadolinium with a PCTA-based chelating ligand, focusing on isomeric enrichment to predominantly produce the diastereoisomers II-RRR and II-SSS, enhancing thermodynamic and kinetic stability, and formulating with a free macrocyclic ligand like DOTA instead of a calcium complex to improve stability and reduce unwanted lanthanide release.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If PCTA-based chelating ligands are used to create gadolinium complexes, then the complexes are easier to synthesize chemically and have superior relaxivity (contrasting power), but they exhibit lower thermodynamic and kinetic stability leading to undesired lanthanide release and cerebral deposition

Engineering Contradiction:

Improveease of synthesisVSAvoidcomplex stability

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The invention changes the stereochemical parameters of the PCTA-based ligand by enriching for specific diastereoisomers (II-RRR and II-SSS) that exhibit enhanced thermodynamic and kinetic stability compared to racemic mixtures. This selective parameter modification maintains the ease of chemical synthesis while resolving the stability issue through controlled stereoisomeric composition

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite contrast agent system that combines the gadolinium-PCTA complex with a free macrocyclic ligand like DOTA. This composite formulation leverages the superior relaxivity of PCTA-based complexes while the free macrocyclic ligand acts as a stability-enhancing component that reduces lanthanide release through competitive complexation

Inventive Principle:

Principle #40Composite materials

2Quantity of substance

If PCTA-based chelating ligands are used to create gadolinium complexes, then the complexes have superior relaxivity (contrasting power), but they exhibit lower kinetic stability leading to cerebral deposition after repeated administrations

Engineering Contradiction:

Improvecontrasting powerVSAvoidkinetic stability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The invention modifies the kinetic stability parameter by selecting and enriching for specific diastereoisomers (II-RRR and II-SSS) of the PCTA-based ligand. These stereoisomers demonstrate enhanced kinetic inertness and resistance to gadolinium release compared to racemic mixtures, thereby preventing cerebral deposition while preserving the superior contrasting power

Inventive Principle:

Principle #35Parameter changes

3Duration of action of moving object

If gadolinium-based contrast agents are administered repeatedly for diagnostic examinations or treatment monitoring, then the efficacy of treatment monitoring is improved, but the risk of NSF and cerebral deposition increases due to cumulative lanthanide release

Engineering Contradiction:

Improvemonitoring capabilityVSAvoidlanthanide release

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The invention takes preliminary action by pre-formulating the contrast agent with optimized diastereoisomeric composition (enriched in II-RRR and II-SSS) and incorporating free macrocyclic ligands before administration. This preliminary stabilization prevents cumulative lanthanide release during repeated administrations, enabling long-term monitoring capability without increasing the risk of NSF or cerebral deposition

Inventive Principle:

Principle #10Preliminary action

4Reliability

If formulations include additional chelating agents to prevent lanthanide release, then the thermodynamic stability is improved, but the complexity of the formulation increases and trans-ligation reactions may occur

Engineering Contradiction:

Improvethermodynamic stabilityVSAvoidformulation complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention uses a free macrocyclic ligand (e.g., free DOTA) as an intermediary component in the formulation. This intermediary acts as a safety buffer that can bind released lanthanide ions through competitive complexation, preventing NSF and cerebral deposition. The approach maintains relatively simple formulations while the stereoisomeric enrichment reduces trans-ligation risks through enhanced intrinsic stability

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20240358863A1Complex of gadolinium and a chelating ligand derived from a diastereoisomerically enriched PCTA and preparation and purification process

Publication Date: 2024.10.31 GUERBET SA

AI summary

The present invention relates to a complex of formula (II) constituted of at least 90% of a diastereoisomeric excess comprising a mixture of isomers II-RRR and II-SSS of formulae:The present invention also relates to a process for preparing and purifying said complex of formula (II), and also to a composition comprising said complex.