Bimodal Ligands for Rapid Metal Complexation and Stability

Solution Overview

Problem

Current bifunctional ligands for radioimmunotherapy, magnetic resonance imaging, and iron depletion therapy face challenges such as slow complexation kinetics, instability, and non-specific distribution, limiting their clinical effectiveness in binding radioactive metals and achieving targeted treatment or imaging.

Innovation Solution

Development of NETA and DEPA analogues with specific donor groups and metal ion complexes, along with conjugates for biomolecules, to enhance complex stability and tissue specificity, including the design of bifunctional ligands like C-NE3TA and 3P-2C-NETA for improved binding and targeting capabilities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If C-DOTA is used as a bifunctional ligand, then complex stability with metals is improved, but complexation kinetics become too slow for clinical application

Engineering Contradiction:

Improvecomplex stabilityVSAvoidcomplexation kinetics

Core Design Contradiction:

Stability of the object's compositionVSSpeed

Solution Approach 1:

The ligand is divided into two functional segments: a macrocyclic portion (providing stability) and an acyclic portion (providing rapid kinetics). This segmentation allows each part to optimize its function independently, resolving the contradiction between stability and kinetics.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent merges the macrocyclic DOTA structure with an acyclic DTPA-like tail to create a hybrid bifunctional ligand. This combination integrates the stability benefits of macrocyclic complexes with the rapid binding kinetics of acyclic ligands.

Inventive Principle:

Principle #5Merging (Combining)

2Speed

If 1B4M-DTPA is used as a bifunctional ligand, then complexation kinetics are rapid, but complex stability becomes clinically unacceptable

Engineering Contradiction:

Improvecomplexation kineticsVSAvoidcomplex stability

Core Design Contradiction:

SpeedVSStability of the object's composition

Solution Approach 1:

The ligand is divided into two functional segments: a macrocyclic portion (providing stability) and an acyclic portion (providing rapid kinetics). This segmentation allows each part to optimize its function independently, resolving the contradiction between stability and kinetics.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent merges the macrocyclic DOTA structure with an acyclic DTPA-like tail to create a hybrid bifunctional ligand. This combination integrates the stability benefits of macrocyclic complexes with the rapid binding kinetics of acyclic ligands.

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If conventional bifunctional ligands are used for targeted therapy, then metal binding is achieved, but tissue specificity and in vivo stability are insufficient

Engineering Contradiction:

Improvein vivo stabilityVSAvoidnon-specific distribution

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The ligand design incorporates local quality modifications through specific spatial arrangement of donor atoms and functional groups, creating regions of high affinity for target metals while maintaining overall in vivo stability and reducing non-specific binding.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates a composite ligand system combining macrocyclic and acyclic moieties with specific functional groups, achieving enhanced in vivo stability and tissue specificity through the synergistic properties of the composite structure.

Inventive Principle:

Principle #40Composite materials

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 new ligands demonstrate enhanced complex stability, rapid complexation kinetics, and improved in vivo stability, enabling more effective diagnostic imaging and targeted therapy with reduced toxicity and improved tissue specificity.

Implementation Method 1

substituted 1,4,7-triazacyclononane-N,N′,N′′-triacetic acid and 1,4,7,10-tetraazacyclicododecane-N,N′,N′′,N′′′-tetraacetic acid compounds with a pendant donor groups... metal complexes thereof

Methodology Applied

Scientific EffectCoordination chemistry: Chemical Bonding

Data Source

PatentUS10556873B2Bimodal ligands with macrocyclic and acyclic binding moieties, complexes and compositions thereof, and methods of using

Publication Date: 2020.02.11 CHONG HYUN-SOON PHD

AI summary

Substituted 1,4,7-triazacyclononane-N,N′,N″-triacetic acid and 1,4,7,10-tetraazacycicododecane-N,N′,N″,N′″-tetraacetic acid compounds with a pendant amino or hydroxyl group, metal complexes thereof, compositions thereof, and methods of making and use in diagnostic imaging and treatment of cellular disorders.