Investigations of Signal-Enhanced Magnetic Resonance Contrast Agents
by Theresa Luca Katrin Hune
Date of Examination:2024-10-28
Date of issue:2025-05-22
Advisor:Dr. Stefan Glöggler
Referee:Prof. Dr. Martin Suhm
Referee:Prof. Dr. Christian Griesinger
Persistent Address:
http://dx.doi.org/10.53846/goediss-11263
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Abstract
English
The subject of this thesis is to extend the scope of magnetic resonance imaging (MRI) to the visualization and characterization of metabolic activities. The inherent insensitivity of conventional MRI limits its applicability to the visualization of signals originating from water and fatty tissue within the body. This problem is overcome by the application of hyperpolarization techniques that have the potential to enhance MR signals by several orders of magnitudes. The application of signal enhancement to small molecules such as metabolites enables their use as biocompatible contrast agents for the characterization of their metabolism in vivo. The presented work focuses on the feasibility of parahydrogen-based signal enhancement methods for in vivo application in medical studies and its potential with regard to the clinical translation. First, a proof-of-concept study in a murine model of human melanoma is presented. The previously reported procedure for the hyperpolarization of [1-13C]-pyruvate for application in vitro is adapted for application in mouse studies. A novelty is the use of fully deuterated [1-13C]-pyruvate-d3, to asses the influence of deuteration on the relaxation time and polarization value. The solution of hyperpolarized [1-13C]-pyruvate-d3 was injected into tumor-bearing mice and the quick conversion of the hyperpolarized pyruvate into lactate due to the Warburg effect was observed. This was subsequently used to localize the tumor in vivo. Continuing, the rate of metabolic conversion of the injected pyruvate is used to detect diet induced changes in energy metabolism. A longitudinal study of the influence of a Western diet on the pyruvate metabolism in mice is described. Mice fed a diet high in fat and fructose were injected hyperpolarized [1-13C]-pyruvate at ages of 3, 6 and 13 months. The resulting conversion rates from pyruvate to lactate and alanine were compared to a control group and showed to be significantly reduced. To gain a deeper understanding of the different metabolic processes occurring within distinct organs, a method for differentiation is presented, aimed to provide additional insights especially in the context of organ crosstalk. The approach was designed to deliver information on the metabolism of the injected pyruvate in two separate organs of the same animal. To exemplify the approach, the conversion of pyruvate to lactate was measured in the liver and brain of three mice fed a high-fat diet. Each mouse received two injections with half the dose each so that the measurements of the metabolism in each organ were recorded separately. This was possible due to the fast throughput of parahydrogen-induced hyperpolarization. An extension of the hyperpolarization protocol to [2-13C]-pyruvate as a potential way for the investigation of mitochondrial metabolism is presented subsequently. Lastly, a small excursus describes the hyperpolarization of deuterium instead of hydrogen. The heavier homologue of hydrogen has received much less attention in literature than its lighter counterpart. These investigations mainly focus on non-hydrogenative hyperpolarization, especially the partially negative line (PNL) generated by ortho-enriched deuterium.
Keywords: Hyperpolarization; Magnetic Resonance; Parahydrogen; Pyruvate; PHIP; Metabolism
