Hyperpolarized 89Y complexes as potential in vivo imaging agents

描述（由申请人提供）：磁共振成像（MRI）已成为最重要的临床成像方式，但由于其固有的低灵敏度，它不太适合分子和代谢成像。溶液相核动态极化（DNP）技术可以将标准NMR实验的灵敏度提高5000至25000倍。这种灵敏度的增加使得有可能对1H以外的其他核进行分子/功能成像。来自任何超极化核的信号将根据自旋-晶格弛豫时间（T1）衰减，并且可以预期具有~ 5 T1的可检测NMR信号。这对可以成像的生化过程造成了限制，并激发了对长T1试剂的研究。在常见的自旋1/2 NMR活性核中，89 Y（III）具有最长的T1弛豫时间（高达600秒），使得超极化钇-89作为潜在的体内成像和光谱探针具有吸引力。我们的初步数据表明，Y（III）配合物可以超极化与目前可用的商业硬件。本项目的目标是证明超极化Y-复合物的成像在体内是可能的。我们将首先建立89 Y（特定目标1）的DNP超极化的最佳条件。将制备两个开链（DTPA，TTHA）和四个大环配体[DOTA，PCTA，DOTP，DOTA（AmP）4]的Y（III）配合物并超极化。将测定复合物的极化增强和T1（具体目标2）。我们将建立一个双调谐89 Y/1H线圈的大鼠和开发一个协议，以图像的超极化Y（III）螯合物的生物分布。样品将在Hypersense“DNP偏振器中超偏振，并在4.7T下进行体内成像实验（特定目标3）。89 Y（III）对其化学环境的极端敏感性可用于设计敏感探针，以成像和绘制生理参数，如pH值、温度和体内代谢的其他指标。溶液相核动态极化（DNP）核磁共振（NMR）技术将标准NMR实验的灵敏度提高了5000至25000倍，使1H以外的核的MRI成像成为可能。本提案的目的是证明成像超极化钇-89-配合物是可能的在体内。潜在的应用包括敏感探针的设计和合成，以成像和映射生理参数，如pH值，温度，氧化还原状态和体内葡萄糖水平。

DESCRIPTION (provided by applicant): Magnetic resonance imaging (MRI) has become arguably the most important clinical imaging modality but it is less well suited for molecular and metabolic imaging because of its inherently low sensitivity. Solution phase nuclear dynamic polarization (DNP) technology can increase the sensitivity of standard NMR experiments by factors of 5000 to 25000. Such increases in sensitivity make it possible to perform molecular/functional imaging of other nuclei than 1H. The signal coming from any hyperpolarized nucleus will decay according to the spin-lattice relaxation time (T1) and one can anticipate having a detectable NMR signal for ~5T1. This poses a limitation on the biochemical processes that could be imaged and motivates the search for long T1 agents. Among the common spin 1/2 NMR active nuclei 89Y(III) has the longest T1 relaxation time (up to 600 seconds) rendering hyperpolarized yttrium-89 attractive as a potential in vivo imaging and spectroscopy probe. Our preliminary data indicated that Y(III)-complexes can be hyperpolarized with currently available commercial hardware. The goal of this project is to demonstrate that imaging of hyperpolarized Y- complexes is possible in vivo. We will first establish the optimal conditions for the DNP hyperpolarization of 89Y (Specific Aim 1). Y(III) complexes of two open chain (DTPA, TTHA) and four macrocyclic ligands, [DOTA, PCTA, DOTP, DOTA(AmP)4] will be prepared and hyperpolarized. Polarization enhancements and T1's of the complexes will be determined (Specific Aim 2). We will build a dual-tuned 89Y/1H coil for rats and develop a protocol to image the biodistribution of hyperpolarized Y(III) chelates. The samples will be hyperpolarized in the Hypersense " DNP polarizer and the in vivo imaging experiments will be performed at 4.7T (Specific Aim 3). The extreme sensitivity of 89Y(III) to its chemical environment could be exploited in the design of sensitive probes to image and map physiological parameters such as pH, temperature, and other indices of metabolism in vivo. PUBLIC HEALTH RELEVANCE Solution phase nuclear dynamic polarization (DNP) nuclear magnetic resonance (NMR) technology increases the sensitivity of standard NMR experiments by factors of 5000 to 25000 making MRI imaging of nuclei other than 1H feasible. The goal of this proposal is to demonstrate that imaging hyperpolarized yttrium-89-complexes is possible in vivo. Potential applications include the design and synthesis of sensitive probes to image and map physiological parameters such as pH, temperature, redox state and glucose levels in vivo.