Hyperpolarized Lactate Contrast Agent for LDH Activity

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Solution Overview

Problem

Current methods for determining lactate dehydrogenase (LDH) activity, particularly in vivo, face limitations due to pyruvate inhibition and low detection of hyperpolarized 13C label in lactate, necessitating the development of alternative imaging agents and detection methods.

Innovation Solution

The use of hyperpolarized [13C, 2H]lactate, specifically [1-13C, 2-2H]lactate, to measure LDH-catalyzed exchange of deuterium label between labeled and unlabelled lactate, allowing for LDH activity determination through 13C-MR detection by monitoring the conversion and protonation state via phase modulation in heteronuclear 13C/1H spin echo experiments.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If pyruvate is used as hyperpolarized substrate to measure LDH-catalysed flux, then it polarizes readily to high levels and transport into the cell is fast, but the enzyme is inhibited by the high pyruvate concentrations used

Engineering Contradiction:

Improvehyperpolarized 13C label detectionVSAvoidLDH enzyme inhibition

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

Instead of using pyruvate as the hyperpolarized substrate (conventional approach), the invention inverts the approach by using lactate as the hyperpolarized substrate. This reversal allows measurement of LDH activity without enzyme inhibition, since lactate does not inhibit LDH even at high concentrations required for hyperpolarization.

Inventive Principle:

Principle #13The other way round (Inversion)

2Quantity of substance

If lactate is used to measure LDH-catalysed flux, then it is present naturally at much higher concentrations and transported into the cell very rapidly, but very little label is detected in pyruvate

Engineering Contradiction:

Improvelactate concentrationVSAvoidhyperpolarized 13C label detection in pyruvate

Core Design Contradiction:

Quantity of substanceVSMeasurement precision

Solution Approach 1:

The invention uses an isotopically labeled intermediate approach: hyperpolarized [1-13C]lactate is administered, and LDH activity is measured by detecting the appearance of 13C label in pyruvate and its subsequent metabolic products. The lactate-pyruvate metabolic conversion serves as the intermediary measurement point, allowing detection of LDH activity through product formation rather than direct substrate depletion.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If deuterium label exchange is measured between [13C, 2H]lactate and endogenous unlabelled lactate, then LDH activity can be determined through 13C-MR detection, but the method complexity increases

Engineering Contradiction:

ImproveLDH activity determinationVSAvoiddetection method

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention changes the detection parameter from direct 1H NMR observation of deuterium exchange to indirect 13C MR detection of the coupled carbon-deuterium system. By exploiting the 13C-2H spin coupling in the lactate molecule, the method translates deuterium exchange information into the more sensitive and bio-compatible 13C MR signal domain, improving reliability while managing complexity through parameter transformation.

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

This approach enables non-invasive, effective measurement of LDH activity in vivo and in vitro, overcoming the limitations of pyruvate inhibition and low label detection, with hyperpolarized [13C, 2H]lactate providing a safe and efficient imaging medium due to its high concentration and rapid metabolism.

Implementation Method 1

measuring the LDH-catalyzed exchange of deuterium label between the [13C, 2H]lactate and endogenous unlabelled lactate

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

measure exchange of the C2 deuterium label with proton in hyperpolarised [1-13C, 2-2H]lactate, or other 2H and 13C-labeled lactate isotopomers that are deuterium labelled at the C2 position, and is dependent on the rate of lactate transport into the cell, the endogenous lactate concentration and LDH activity

Methodology Applied

Scientific EffectIsotope exchange:

Implementation Method 3

hyperpolarized imaging agent and to a method of 13C-MR detection

Methodology Applied

Scientific EffectNuclear magnetic resonance:

Implementation Method 4

hyperpolarized [13C, 2H]lactate, specifically [1-13C, 2-2H]lactate, to measure LDH-catalyzed exchange of deuterium label

Methodology Applied

Scientific EffectHyperpolarization:

Implementation Method 5

monitoring the conversion and protonation state via phase modulation in heteronuclear 13C/1H spin echo experiments

Methodology Applied

Scientific EffectPhase modulation: Phase Modulation

Data Source

PatentUS9259490B2Hyperpolarized lactate contrast agent for determination of LDH activity

Publication Date: 2016.02.16 GE HEALTHCARE LTD

AI summary

A hyperpolarized MR imaging medium and a method of 13C-MR detection using a hyperpolarized MR imaging medium for the determination of lactate dehydrogenase (LDH) activity. The contrast media comprises hyperpolarized [13C, 2H]lactate.