Hyperpolarized 89Y complexes as potential in vivo imaging agents

描述(申请人提供)：磁共振成像(MRI)已经成为最重要的临床成像手段，但由于其固有的低灵敏度，不太适合用于分子和代谢成像。溶液相核动力极化技术可以将标准核磁共振实验的灵敏度提高5000到25000倍。这种灵敏度的提高使得对1H以外的其他核进行分子/功能成像成为可能。来自任何超极化原子核的信号将根据自旋-晶格弛豫时间(T1)衰减，可以预期~5t1有一个可检测到的核磁共振信号。这对可以成像的生化过程造成了限制，并激励了对长T1代理人的搜索。在常见的自旋1/2核磁共振活性核中，89Y(III)具有最长的T1弛豫时间(高达600秒)，这使得超极化的Y-成为一种潜在的活体成像和光谱探针。我们的初步数据表明，Y(III)-络合物可以用目前可用的商业硬件进行超极化。这个项目的目标是证明超极化Y-复合体的体内成像是可能的。我们将首先建立89Y的DNP超极化的最佳条件(具体目标1)。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)配合物并进行超极化处理。将测定配合物的极化增强效应和T_1‘S(具体目标2)。我们将为大鼠建造一个双调谐89Y/1H线圈，并开发一种方案来成像超极化Y(III)螯合物的生物分布。样品将在Hypersense“DNP偏振器中超极化，体内成像实验将在4.7T(特定目标3)下进行。89Y(III)对其化学环境的极端敏感性可用于设计灵敏的探针，以成像和绘制体内的生理参数，如pH、温度和其他代谢指标。公共卫生相关溶液阶段核动态极化核磁共振技术将标准核磁共振实验的灵敏度提高了5000到25000倍，使核磁共振成像成为可能，而不是1H。这项提议的目的是证明在体内成像超极化的Y-89-络合物是可能的。潜在的应用包括设计和合成灵敏的探针来成像和绘制体内的生理参数，如pH、温度、氧化还原状态和葡萄糖水平。

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.