Open Access Dissertation
Date of Award
Eduard Y. Chekmenev
PARAHYDROGEN HYPERPOLARIZED MULTI-NUCLEAR CONTRAST AGENTS FOR POTENTIAL MRI APPLICATIONS
NUWANDI M. ARIYASINGHA
Advisor: Dr. Eduard Chekmenev
Major: Chemistry (Physical)
Degree: Doctor of Philosophy
There have been numerous studies to develop fast, cost effective hyperpolaried (HP) contrast agents with higher polarization values that can be potentially employed for magnetic resonance clinical imaging. Some of the currently used contrast agents are based on 129Xe hyperpolarized nucleus. However, one of the problems associated with this approach, is the high cost of the produced hyperpolarized contrast agents. In addition, the other important practical problem is that the currently used clinical MRI scanners are mostly designed for proton detection as opposed to the highly specialized MRI scanners designed for research purposed with 13C, 129Xe, etc. detection capability. Therefore, it is important to investigate the possibility of using proton-hyperpolarized hydrocarbon molecules for their utility as MRI contrast agents that can be visualized with currently available MRI scanners. One key interest in MRI research is the development of inhalable contrast agents that can be employed to a patient on a single breath hold for pulmonary image acquisition. These images can be used to probe lung functions (ventilation and diffusion) therefore identifying any abnormalities and diseases such as chronic obstructive pulmonary disease (COPD) and emphysema in early stages of these diseases, when intervention can significantly improve patients’ outcomes.
One first overarching goal of this work was to prepare cost-effective, bio-compatible, sufficiently long-lived contrast agents using scalable hyperpolarization methods relying on parahydrogen as a source of hyperpolarization. These agents can potentially be employed as inhalable contrast agents on clinically available MRI instruments with proton detection capability. I demonstrated that HP propane can be produced via propylene hydrogenation with 100% chemical conversion thus can be employed as a successful inhalable HP contrast agent with high polarizations values. Moreover, long-lived spin states (LLS) of HP propane can be created via both propylene and cyclopropane hydrogenation methods. Large animal model such as sheep will be performed to further study HP propane’s ability as an inhalable HP agent during the next three years. The study of inhalable contrast agents was extended to other molecules like, previously used anesthetic diethyl ether proving that long lived spin states of HP diethyl ether can also be generated at low magnetic fields. This demonstration proves that proton LLS of HP gases is a general phenomenon. Moreover, a low cost, high throughput preparation method of HP diethyl ether was demonstrated. A thorough kinetic study was conducted to show that highest polarization values (~8 %) were feasible and complete chemical conversion of ethyl vinyl ether to HP diethyl ether is achieved within a few seconds. Future developments of decreasing the flammability of diethyl ether can lead to its biomedical application as an HP MRI contrast agent.
The other interest is the preparation of injectable contrast agents (intravenous (IV) contrast agents) in order to image metabolism or abnormalities of organs/ tissues. Currently, hyperpolarized contrast agents for metabolism interrogation are based on the hyperpolarized 13C nucleus. The goal of my work is to employ hyperpolarized 15N nucleus in FDA-approved drugs. As opposed to 13C, 15N offers the advantages of lower cost and longer lifetime of hyperpolarized state in vivo.
Therefore, the second goal is the efficient preparation of injectable MRI contrast agents, which can be used to probe metabolism and related abnormalities. e.g. metronidazole, which is a commonly used FDA-approved antibiotic. In-tumor hypoxia has been correlated with poor outcome in many cancers. Therefore, 15N-hyperpolarized metronidazole was investigated towards its feasibility as a potential contrast agent to probe hypoxia using MRI. Quasi-resonance signal amplification by reversible exchange (QUASR-SABRE) method showed successful polarization values (2-fold higher than those in SABRE-SHEATH (SABRE in shield enables alignment transfer to heteronuclei) approach) for metronidazole antibiotic thus indicating a more effective polarization transfer method via SABRE hyperpolarization technique. This finding gives hope for achieving near-unity polarization values using QUASR- SABRE approach for a broad spectrum of biomolecules making them promising candidates of hypoxia sensing probe and probes for potentially for other applications.
In addition to the above motioned goals, there is also a need to understand approaches of successful polarization transfer methods from protons into hetero-nucleus in order to be able to improve the detection schemes of HP contrast agents. I investigated these approaches in my work using fluorinated N-heterocyclic molecules. I demonstrated successful polarization transfer from p-H2 derived hydrides to 19F nuclei via weak five-bond H-F spin-spin couplings.
Furthermore, radio amplification of stimulated radiation (RASER) activity is reported for low concentrated (~40 mM) substrate molecules using a commercial bench-top NMR spectrometer (at 1.4 T) without an RF pulse under both adiabatic longitudinal transport after dissociation endengers net alignment (ALTADENA) and parahydrogen synthesis allows dramatically enhanced nuclear alignment (PASADENA) conditions, enabling a wide range of potential applications including MR imaging, quantum computing and beyond.
Ariyasingha Uragoda Wiyannalage, Nuwandi Maduranga, "Parahydrogen Hyperpolarized Multi-Nuclear Contrast Agents For Potential Mri Applications" (2020). Wayne State University Dissertations. 2479.