Synthesis of molecular probes for the hyperpolarization with parahydrogen
by Denis Moll
Date of Examination:2022-12-01
Date of issue:2023-11-28
Advisor:Dr. Stefan Glöggler
Referee:Dr. Stefan Glöggler
Referee:Prof. Dr. Johannes C. L. Walker
Persistent Address:
http://dx.doi.org/10.53846/goediss-10215
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Abstract
English
Nuclear magnetic resonance spectroscopy (NMR) and related nuclear magnetic resonance imaging (MRI) allow us to acquire information about molecules at an atomic level and thereby create images of human tissues and organs without destroying the molecules or the tissue itself nor exposing them to strong (X-ray or radioactive) radiation. Nuclei with magnetic moments arrange themselves along magnetic field lines when placed in an external magnetic field and can be excited by radio frequency pulses to produce a spectrum (NMR) or an image (MRI). However, neither of these technologies exploits their full potential. Even in state-of-the-art high-field magnets, only a fraction of the observable molecules contributes to the detected signal. This low so-called thermal polarization limits the technology's ability to look directly at changes at the molecular level under physiological conditions. However, scientific progress made it possible to increase the number of atoms contributing to the detected signal by clever manipulation of the magnetic moments, thus enabling an increase of intensity by up to 100,000-fold. The so-called hyperpolarization can be used to track even the smallest concentration of molecules. Therefore, imaging techniques could be used to investigate the influence of diseases on the human body without having to rely on long measurements or other methods. A widely used technique to bring molecules into this hyperpolarized state is called "parahydrogen-induced hyperpolarization" (PHIP). This involves the use of the nuclear spin isomer of a hydrogen molecule, known as parahydrogen (pH2), which hyperpolarizes an unsaturated, isotopically enriched molecule through chemical reaction. In case it is not possible to produce the desired product directly by hydrogenation, it is necessary to use an unsaturated side arm, which subsequently has to be cleaved by the use of further chemicals. The development of hyperpolarized metabolites, i. e. substances that are specific to the body, could make contrast agents available in the future that provide medical experts with information not only on the localization but also on the status of the disease. Metabolites are substances that are used in the body, for example to generate energy, and are thus part of processes that are essential for survival. Cancer or cardiovascular diseases are among the most frequent causes of death in western countries, and their mode of action has a considerable influence on human metabolism and blood circulation. The purpose of this work was to make biologically relevant substances that are not accessible for hyperpolarization using PHIP by direct. This included: 1) The proton-deuterium exchange on tracer molecules to extend their traceability. 2) The development of synthetic strategies to produce novel sidearms with specific properties and their coupling to metabolites. 3) The development of a labeling molecule for angiography. 4) The hyperpolarization and release of the metabolites to be observed in biocompatible solutions for analysis in magnetic resonance-based techniques. For this purpose, modifications were first performed on the important metabolic intermediate pyruvate. This molecule is formed during the digestion of glucose and represents a branch point of human metabolism. The interplay of new metabolic pathways starting from pyruvate are controlled as needed and are strongly influenced locally by diseases. The long-term goal is to use hyperpolarized pyruvate in imaging techniques to visualize the change in favoring certain pathways. Based on the quantification of these changes, access to differential diagnosis should be possible. To make pyruvate traceable in the human body for longer periods of time, new mild proton-deuterium exchange reactions were investigated to allow effective use of the substances isotopically labelled in the following. Deuterated pyruvate was subsequently coupled to a novel sidearm that, for the first time, allows the metabolite to be released without the use of additional chemicals after hyperpolarization. This new class of sidearm thus dramatically shortens the work-up time, thereby providing easier access to hyperpolarized materials. This sidearm, based on a 2-nitrobenzyl structure, was used to produce highly polarized molecules (over 60% proton polarization for 1-13C acetate, up to 30% proton polarization for 1-13C pyruvate) that could allow biological measurements even in aqueous solutions (13C polarizations up to 8% in water). In addition to the study of metabolic processes and their imaging, the development of new contrast agents for angiography, for example, are of great interest, especially in MRI. Gadolinium compounds, which have been commonly used up to now, are deposited in the brain, which is why their use has been severely restricted. Metabolic end products, which do not participate in any further metabolic processes but only circulate in the bloodstream until they are secreted, are particularly suitable for the purpose of angiography. One of these substances is an acetylated amino acid from protein degeneration, the acetyl-alanine. This endogenous substance was equipped with a vinyl group as a hyperpolarizable side arm. The subsequent hyperpolarization achieved the highest polarizations measured in injectable solutions for nitrogen-containing molecules using PHIP. With polarization values above 6%, applications in living organisms should be possible. Thus, N-acetyl-vinyl-alanine would offer a possible contrast agent for angiography by MRI.
Keywords: Hyperpolarization; organic chemistry; MRI contrast agent
