Hydroxamic Acid Macrocyclic Chelators With Pendant Moieties

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Solution Overview

Problem

Current chelating agents used in radioimmunotherapy face challenges such as rapid metal ion loss, non-selective binding, and toxicity concerns, particularly with regards to lanthanide and actinide radiometal cations that tend to deposit in bone, leading to bone marrow suppression.

Innovation Solution

Development of a new class of metal chelating agents with bridging and pendant chelating moieties linked via a scaffold, which are designed to rapidly metallate and form highly stable complexes with +3 and +4 metals at physiological pH, while being resistant to oxidation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If DOTA-like macrocyclic chelating agents are used to form stable metal complexes, then complex stability is improved, but complexation requires harsher conditions such as high temperatures

Engineering Contradiction:

Improvecomplex stabilityVSAvoidcomplexation temperature

Core Design Contradiction:

Stability of the object's compositionVSTemperature

Solution Approach 1:

The patent modifies the chelating agent structure by introducing pendant chelating moieties with specific pKa values that enable rapid metalation at physiological pH and temperature, eliminating the need for harsh heating conditions while maintaining complex stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite chelating structure combining bridging chelating moieties (providing structural framework) with pendant chelating moieties (providing rapid metalation capability), where the synergistic interaction between different functional groups achieves both stability and mild reaction conditions

Inventive Principle:

Principle #40Composite materials

2Speed

If acyclic chelating agents like DTPA are used for rapid metalation, then association kinetics are improved, but selectivity toward specific metal ions deteriorates

Engineering Contradiction:

Improvemetalation rateVSAvoidmetal ion selectivity

Core Design Contradiction:

SpeedVSReliability

Solution Approach 1:

The patent introduces pendant chelating moieties with specific pKa values (6-9) that create localized high-affinity binding sites for target metal ions, enabling rapid and selective metalation without compromising overall complex stability

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

By adjusting the pKa of pendant chelating groups to be between 6-9, the patent optimizes the balance between rapid association kinetics and high selectivity, allowing the chelating agent to preferentially bind specific metal ions at physiological pH

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If conventional chelating agents are used, then metal ion binding is achieved, but metal ion loss occurs leading to bone deposition and bone marrow suppression

Engineering Contradiction:

Improvemetal ion bindingVSAvoidbone marrow suppression

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent inverts the conventional approach by designing chelating agents that form extremely stable complexes under physiological conditions, preventing metal ion release and subsequent bone deposition, thereby converting a potentially harmful process into a controlled therapeutic outcome

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention creates chelating agents with optimized pharmacokinetics that maintain stable metal complexes during the therapeutic window, allowing the complex to be cleared from the body after delivering its therapeutic effect, preventing long-term accumulation and bone marrow toxicity

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

4Stability of the object's composition

If chelating agents with high metal affinity are used, then complex stability is improved, but the agents may deplete essential biological metal ions causing health problems

Engineering Contradiction:

Improvecomplex stabilityVSAvoidbiological metal ion depletion

Core Design Contradiction:

Stability of the object's compositionVSObject-generated harmful factors

Solution Approach 1:

The patent fine-tunes the pKa values of pendant chelating groups to create a selective binding window that favors pathological metal ions (such as radiometals) over essential biological metal ions, maintaining complex stability while avoiding depletion of physiological metals

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 new chelating agents achieve rapid and selective binding of metal ions, minimizing premature release in vivo and enhancing the stability and specificity of radiodiagnostics and therapeutics.

Implementation Method 1

The chelating agents of the invention have numerous favorable properties, which are not generally available, either alone or in combination, in macrocyclic chelating agents. For instance, exemplary compounds of the invention metallate rapidly.

Methodology Applied

Scientific EffectChelation: Chemical Bonding

Implementation Method 2

Exemplary metal chelates of the chelating agents of the invention are also resistant to oxidation by O2, ubiquitous in the atmosphere and in living organisms.

Methodology Applied

Scientific EffectOxidation resistance: Oxidation

Data Source

PatentUS20250170284A1Hydroxamic Acid Macrocyclic Agents With Pendant Chelating Moieties And Complexes Thereof

Publication Date: 2025.05.29 LUMIPHORE INC

AI summary

The invention provides metal chelating agents and metal complexes of these agents of use in therapeutic and diagnostic applications.