Investigations of New Magnetic Resonance Contrast Agents
by Lisa Maria Fries
Date of Examination:2025-10-20
Date of issue:2025-11-26
Advisor:Dr. Stefan Glöggler
Referee:Prof. Dr. Marina Bennati
Referee:Prof. Dr. Christian Griesinger
Persistent Address:
http://dx.doi.org/10.53846/goediss-11647
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Abstract
English
Magnetic resonance spectroscopy (MRS) and imaging (MRI) are powerful noninvasive techniques for probing biochemical composition and anatomy. However, the inherently low sensitivity of these magnetic resonance techniques confines routine applications to conventional proton (1H) MRI of water and fat, with detection of other biologically relevant molecules hampered by strong background signals. Heteronuclear MRI expands the magnetic resonance toolbox by targeting nuclei beyond 1H that do not suffer from strong endogenous background signals, thereby enabling specific detection. Unlike conventional 1H MRI that mainly reflects total metabolite pools, this approach permits noninvasive tracking of dynamic metabolic fluxes and biodistribution. For 13C , the low natural abundance and sensitivity are overcome using hyperpolarization, which boosts signal intensity by several orders of magnitude and permits real-time in vivo metabolic measurements. Deuterium, while not hyperpolarized, offers short relaxation times for rapid signal averaging and can be referenced to the natural abundance of HDO water, enabling quantitative hotspot mapping. The first part of this thesis focuses on hyperpolarized 13C magnetic resonance. Distinct metabolic conversion patterns between pancreatic and colon tumor xenografts in mice were revealed by localized 13C MRS, which enabled determination of pyruvate to lactate and pyruvate to alanine conversion rate constants using hyperpolarized [1-13C]pyruvate. Building on this, the influence of extracellular acidosis on pancreatic cancer metabolism was investigated by comparing acid adapted and control Panc02 tumors. Tumors adapted to acidic pH exhibited significantly higher glycolytic activity in vivo, as indicated by increased lactate production measured with hyperpolarized 13C magnetic resonance. Next, the focus shifted from intracellular metabolism to vascular imaging. For this purpose, a novel 13C -labeled angiographic agent, [1-13C]N-acetyl-alanine ethyl ester, was synthesized. As an endogenous metabolic end product, N-acetyl-alanine offers excellent biocompatibility for angiographic imaging. Hyperpolarization and imaging protocols were optimized, and single-shot 13C RARE imaging enabled high-resolution mapping of murine vascular structures with excellent temporal and spatial detail. The second part of this thesis explores deuterium MRI as a complementary modality. Deuterated particle imaging was developed using a new class of 2H-enriched imaging agents: fully acetylated PAMAM generation 5 dendrimers with deuterated methyl groups, yielding nanopolymers with exceptionally high 2H loading. High submillimeter resolution 2H MRI enabled quantitative renal uptake mapping in mice, with endogenous HDO serving as an internal reference. In a separate murine inflammation model, DPI revealed pronounced lymphatic accumulation of the dendrimers in the inflamed leg, demonstrating both anatomical and functional imaging capabilities. Together, these projects showcase a comprehensive approach to advancing molecular imaging: from real-time metabolic measurements, to angiography, to quantitative anatomical and functional imaging. The strategic combination of molecular design and sequence optimization opens new pathways for metabolic imaging in vivo, establishing a foundation for future clinical translation of heteronuclear MRI.
Keywords: Magnetic Resonance; Hyperpolarization; Parahydrogen; Deuterium MRI; Metabolism
