Long-lived hyperpolarized molecules for magnetic resonance produced using parahydrogen

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Magnetic Resonance Imaging (MRI) is an impressively powerful diagnostic method. At the same time, however, it is very insensitive because of the low thermal polarization of nuclear spins. Consequently, direct observation of molecular targets or molecular transformations (metabolism) in vivo by MRI is difficult. Hyperpolarization (HP) techniques have demonstrated dramatic enhancement of the MR signal which allows real-time metabolic imaging. The goal of the project is to identify, optimize and apply new classes of hyperpolarized molecular agents for MRI. As a result, new hyperpolarized agents will become available for molecular imaging at much lower cost than before. Both German and Russian research teams have more than 10 years experience in this field, - an expertise that is reflected by a total of >60 articles on this topic, two of which were published together.Each team provides a unique and complementary expertise that is necessary for this strongly interdisciplinary project: the Russian team is focused on the chemical aspects, including the synthesis of new substrates, catalysts and analyses of hydrogenation reaction pathways. The German team is focused on the physical aspects, including the theoretical description of hyperpolarization phenomena, the polarizer hardware as well as the development of NMR and MRI pulse sequences and in vivo application. In this joint project, we propose to advance the parahydrogen HP methods known as Signal Amplification By Reversible Exchange (SABRE) and its new variant SABRE-RELAY, which enables the pH2-HP of a new class of biomolecules in their native state that was not possible before (e.g. amino acids). Specifically, we will (i) develop the theory for SABRE-RELAY, (ii) synthesize the following labeled molecules: 13C acetate, 13C-vinyl acetate, alanine-15N, aspartic acid-15N, glutamic acid-15N, glycine-15N, valine-15N, phenylalanine-15N for PHIP and SABRE-RELAY experiments, (iii) quantitatively analyze the reaction pathways involved in generation of HP for these molecules, (iv) find the optimal hyperpolarization strategies for PHIP, SABRE and SABRE-RELAY at low and high magnetic fields for the synthesized molecules in organic solvents, water, cell media and blood, (v) investigate the lifetime of hyperpolarization in different conditions and in long lived spin states, (vi) adapt pulse sequences for in vivo imaging of HP molecules and (vii) investigate approaches for purification of homogeneous HP sample from dissolved metal-organic complexes, and, ultimately (viii) apply the newly developed HP agents and methods in animal experiments in vivo.