Low detection sensitivity of conventional MRI/MRS remains an Achilles Heel that can preclude a number of otherwise promising approaches. For example, using MRI to detect and track metabolic markers could be a powerful way to screen and diagnose diseases and gauge response to treatment, but relatively low concentrations can make it difficult to observe such substances in vivo. However, a number of approaches have been developed that can achieve highly non-equilibrium nuclear spin population distributions in select systems-thereby improving the MR sensitivity of such "hyperpolarized" (HP) species by orders of magnitude. For example, in traditional PHIP (or, ParaHydrogen Induced Polarization) the pure anti-phase spin order of parahydrogen (pH2) is exploited as a source of spin polarization by using it to hydrogenate unsaturated chemical bonds in molecular precursors. Alternatively, in a new PHIP approach called SABRE (Signal Amplification by Reversible Exchange), spin order may be transferred from pH2 to target molecules during the lifetime of transient complexes ostensibly without permanent chemical change. Importantly, organometallic catalysts are required for both PHIP approaches. Either way, PHIP offers a number of unique advantages, including the ability to generate HP organic molecules with much greater speed and lower costs compared to other possible methods. However, the biomedical application of PHIP is constrained by a number of key technical limitations-particularly the nature of the available PHIP catalysts (including the difficulty of separating them from the created HP agents), as well as the efficiency and scope of the underlying reactions. Thus, our objective is to develop new approaches that will dramatically improve the applicability of PHIP for biomedical research and ultimately, clinical use. More specifically, our efforts will concern the synthesis, evaluation and MR demonstration of new heterogeneous catalysts for traditional PHIP and SABRE;hyperpolarization of aqueous agents will be a point of emphasis in both cases. These experiments will be supported by the construction and implementation of an automated PHIP/SABRE polarizer with in situ MR detection (adapted from the established Vanderbilt design, but modified for heterogeneous catalysis work). We will demonstrate the creation and use of HP aqueous organic agents free from contamination from the catalysts-which otherwise presents a major obstacle to expanding the biomedical and clinical applicability of PHIP. Overall, our collaboration's research aims to develop the capability of PHIP for mass-scale production of pure HP substances for numerous MRI/MRS applications, including the production of metabolic MRI contrast agents for screening and tracking the response to treatment of various cancers and other illnesses.
Using MRI to detect and track metabolic markers could be a powerful way to screen and diagnose diseases and gauge response to treatment;however, the low concentrations of such molecules in the body (compared to water, the normal MRI signal source) make it very difficult to observe such substances under ordinary circumstances. The main focus of the proposal is the development of new approaches to create and use organic molecules that have been hyperpolarized, a trait which endows them with MR signal strength that is orders of magnitude greater than normal (enough to be imaged by both conventional and low-field MRI scanners). New catalytic materials will be developed that will allow parahydrogen to be the polarization source in this process, thereby creating pure hyperpolarized MRI contrast agents in a manner that is much cheaper and faster than other methods-and ultimately allowing real-time imaging of metabolic processes in the body.
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|Shchepin, Roman V; Barskiy, Danila A; Coffey, Aaron M et al. (2016) Efficient Synthesis of Molecular Precursors for Para-Hydrogen-Induced Polarization of Ethyl Acetate-1-(13) C and Beyond. Angew Chem Int Ed Engl 55:6071-4|
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