Long-lived hyperpolarized molecules for magnetic resonance produced using parahydrogen

磁共振成像（MRI）是一种令人印象深刻的强大诊断方法。但同时，由于核自旋的低热极化，它是非常不敏感的。因此，通过MRI直接观察分子靶点或分子转化（代谢）是困难的。超极化（HP）技术已经证明了MR信号的显著增强，可以实现实时代谢成像。该项目的目标是鉴定，优化和应用新型的超极化分子剂用于MRI。因此，新的超极化试剂将以比以前低得多的成本用于分子成像。德国和俄罗斯的研究团队在这一领域都有超过10年的经验，这一专业知识反映在关于这一主题的总共60篇文章中，其中两篇是一起发表的。每个团队都提供了这个跨学科项目所必需的独特和互补的专业知识：俄罗斯团队专注于化学方面，包括新底物的合成，催化剂和氢化反应途径的分析。德国团队专注于物理方面，包括超极化现象的理论描述，偏振器硬件以及核磁共振和核磁共振脉冲序列的开发和体内应用。在这个联合项目中，我们提议推进被称为可逆交换信号放大（SABRE）的对氢HP方法及其新变体SABRE- relay，它使一类新的生物分子的ph -HP在其天然状态下是不可能的（例如氨基酸）。具体来说，我们将(i)发展SABRE-RELAY的理论，（ii）合成以下标记分子：对PHIP和SABRE- relay进行13C醋酸酯、13C醋酸乙烯酯、丙氨酸- 15n、天冬氨酸- 15n、谷氨酸- 15n、甘氨酸- 15n、缬氨酸- 15n、苯丙氨酸- 15n实验，（iii）定量分析这些分子生成HP的反应途径，（iv）对合成的分子在有机溶剂、水、细胞介质和血液中寻找PHIP、SABRE和SABRE- relay在低磁场和高磁场下的最佳超极化策略。(v)研究在不同条件和长寿命自旋状态下的超极化寿命，（vi）调整脉冲序列用于HP分子的体内成像，（vii）研究从溶解的金属有机配合物中纯化均匀HP样品的方法，并最终（viii）将新开发的HP试剂和方法应用于动物体内实验。

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.