Cleavable Agents for Hyperpolarized MRI Substrates
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Solution Overview
Problem
Conventional MRI techniques face low detection sensitivity, limiting their ability to image substances other than high-concentration species like water, and existing hyperpolarization methods, such as SABRE, are restricted to substrates with sp1 or sp2-hybridized N or S atoms, excluding many potential biomarkers and molecules of interest.
Innovation Solution
Development of a new class of cleavable agents with a catalyst-binding moiety and a hyperpolarized payload that can undergo reversible binding to SABRE catalysts, allowing for rapid hyperpolarization via para-H2 and subsequent bond cleavage to generate agents with different sensing properties, enabling the creation of a wide range of hyperpolarized substrates for MRI applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional MRI techniques are used, then imaging of high-concentration species like water is achieved, but detection sensitivity remains low for other substances
Solution Approach 1:
The patent applies hyperpolarization to dramatically change the spin population distribution parameter of target molecules, achieving orders-of-magnitude sensitivity enhancement. This allows detection of low-concentration metabolites and other substances that are invisible to conventional MRI, thereby improving both detection sensitivity and the range of imaged substances simultaneously
2Productivity
If SABRE hyperpolarization is applied to substrates with sp1 or sp2-hybridized N or S atoms, then rapid hyperpolarization is achieved, but substrate scope is limited
Solution Approach 1:
The patent segments the substrate into two functional parts: a catalyst-binding moiety containing sp1 or sp2-hybridized N or S atoms that binds to the SABRE catalyst for rapid hyperpolarization, and a payload portion containing the target metabolite or molecule of interest. This segmentation allows the catalyst-binding moiety to enable fast hyperpolarization while the payload portion can be any molecule of interest, thereby achieving both rapid hyperpolarization and broad substrate scope
Solution Approach 2:
The catalyst-binding moiety acts as an intermediary that mediates between the SABRE catalyst and the payload. It provides the necessary sp1 or sp2-hybridized N or S atoms for catalyst binding and hyperpolarization, while being connected to the payload through a cleavable bond. This intermediary enables the catalyst to hyperpolarize the binding moiety, which then transfers or releases the hyperpolarized state to the payload upon bond cleavage
3Measurement precision
If direct SABRE hyperpolarization is attempted on carboxylic acid derivatives, then metabolic imaging capability is improved, but direct binding to SABRE catalyst is not achieved
Solution Approach 1:
For carboxylic acid derivatives, the patent uses a catalyst-binding moiety as an intermediary that contains sp1 or sp2-hybridized N or S atoms for SABRE catalyst binding. This binding moiety is connected to the carboxylic acid derivative payload through a cleavable bond, enabling the catalyst to bind and hyperpolarize the complex, which then releases the hyperpolarized carboxylic acid derivative upon bond cleavage for metabolic imaging
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
This approach enhances MRI detection sensitivity by enabling the rapid and cost-effective generation of hyperpolarized substrates, expanding the range of molecules that can be imaged and paving the way for biomedical applications with improved speed and cost efficiency.
Implementation Method 1
SABRE uses a catalyst to co-locate parahydrogen (para-H2)—a cheap and easy-to-produce source of nuclear spin order—and a target substrate within a transient complex, allowing spin order to transfer to substrate spins via scalar couplings
Implementation Method 2
Hyperpolarization can combat this problem by generating highly non-equilibrium nuclear spin population distributions, thereby providing orders-of-magnitude improvements in MR detection sensitivity for select substances
Implementation Method 3
depressurizing a container containing the hyperpolarized cleavable agent to cause rapid hydrolytic, aminolytic, or enzymatic cleavage of the bond between the heterocyclic moiety and the carboxylic acid or carboxylic acid precursor moiety
Implementation Method 4
depressurizing a container containing the hyperpolarized cleavable agent to cause rapid hydrolytic, aminolytic, or enzymatic cleavage of the bond between the heterocyclic moiety and the carboxylic acid or carboxylic acid precursor moiety
Implementation Method 5
depressurizing a container containing the hyperpolarized cleavable agent to cause rapid hydrolytic, aminolytic, or enzymatic cleavage of the bond between the heterocyclic moiety and the carboxylic acid or carboxylic acid precursor moiety
Data Source
AI summary
The present disclosure is directed to a cleavable agent for enhanced magnetic resonance generally corresponding to the formula Y-L-R, wherein Y represents a catalyst-binding moiety having at least one isotopically labeled heteroatom, L represents a cleavable bond, and R represents a hyperpolarized payload having at least one isotopically labeled carbon. Also disclosed herein is a method of cleaving the cleavable agent for enhanced magnetic resonance.