Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

奥豪瑟增强磁共振成像 (OMRI)

• 批准号: 10702359
• 负责人: Murali Krishna
• 金额: $ 113.36万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702359
• 关键词: Aftercare; Biochemical; Biochemical Pathway; CD3 Antigens; Carbohydrates; Cell Nucleus; Chemicals; Clinical Trials; Colorectal; Complex; Contrast Media; Copper; Dependence; Detection; Deuterium; Development; Devices; Diffusion Magnetic Resonance Imaging; Dimethyl Sulfoxide; Future; Guidelines; HT29 Cells; Human; Hydration status; Image; In Situ; Investigation; Iridium; Label; Ligation; Lipids; Liquid substance; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Measures; Metabolic; Metabolism; Methodology; Methods; Molecular; Molecular Probes; Monitor; NMR Spectroscopy; Nature; Nitrogen; Normal tissue morphology; Nuclear; Nuclear Magnetic Resonance; Nucleic Acids; Pancreas; Physiology; Proteins; Protons; Pyruvate; Reaction; Relaxation; Reporting; Residual state; Sampling; Signal Transduction; Sodium; Source; Structure; Techniques; Temperature; Time; Tissues; Tracer; Water; Xenograft procedure; aerobic glycolysis; alanine aminopeptidase; base; cancer imaging; catalyst; clinically relevant; cold temperature; comparative; cost; density; design; detection sensitivity; enzyme activity; imaging approach; imaging biomarker; in vivo; iron oxide; magnetic field; metabolic imaging; molecular imaging; mouse model; novel; pressure; real-time images; response; treatment effect; treatment response; tumor; tumor growth

Rational Probe Design: Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions, there is a demand for developing exogenous, i.e., artificially designed, DNP-NMR molecular probes; however, complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here, we report Ala-[1-(13)C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation, calculation, biochemical assessment, and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe, we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived, practical DNP-NMR molecular probes through structure-guided molecular design. Low cost hyperpolarizer: Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) is investigated to achieve rapid hyperpolarization of (13) C1 spins of [1-(13) C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co-ligation of DMSO and H2 O. Order-unity (13) C (50 %) polarization of catalyst-bound [1-(13) C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1-(13) C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39 % polarization is measured using a 1.4 T NMR spectrometer, and extrapolated to 50 % at the end of build-up in situ. The highest measured polarization of a 30-mM pyruvate sample, including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3 OD. Efficient (13) C polarization is also enabled by favorable relaxation dynamics in sub-microtesla magnetic fields, as indicated by fast polarization buildup rates compared to the T1 spin-relaxation rates (e. g., approximately 0.2 s(-1) versus approximately 0.1 s(-1) , respectively, for a 6 mM catalyst-[1-(13) C]pyruvate sample). Finally, the catalyst-bound hyperpolarized [1-(13) C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1-(13) C]pyruvate produced via comparatively fast and simple SABRE-SHEATH-based approaches. Parahydrogen generator: We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing, which can be pressurized to 35 atm. Parahydrogen fraction 48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts. Parahydrogen quantification was performed on the fly via benchtop NMR spectroscopy to monitor the signal from residual orthohydrogen-parahydrogen is NMR silent. This real-time quantification approach was also used to evaluate catalyst activation at up to 1.0 standard liter per minute flow rate. The reported inexpensive device can be employed for a wide range of studies employing parahydrogen as a source of nuclear spin hyperpolarization. To this end, we demonstrate the utility of this parahydrogen generator for hyperpolarization of concentrated sodium [1-(13)C]pyruvate, a metabolic contrast agent under investigation in numerous clinical trials. The reported pilot optimization of SABRE-SHEATH (signal amplification by reversible exchange-shield enables alignment transfer to heteronuclei) hyperpolarization yielded (13)C signal enhancement of over 14,000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% (13)C polarization-if near 100% parahydrogen would have been employed, the reported value would be tripled to (13)C polarization of 3.5%. Imaging markers from MRI using D2O: Purpose: Water is a substrate in many biochemical pathways. Systemic administration of deuterated water (D2O) results in deuterium incorporation into nucleic acids, carbohydrates, proteins, and lipids. Given their relatively high rates of proliferation and resultant deuterium enrichment we hypothesized that tumors would be more easily discerned from healthy tissues via deuterium MRI. Methods: We initiated D2O administration in two xenograft mouse models harboring either human colorectal, HT-29, or pancreatic, MiaPaca2, cancers. Results: After 14 days of in vivo tumor growth and 7 days of systemic labeling with D2O, a clear dMRI contrast was demonstrated between the xenografts and normal tissue. Conclusions: Our novel clinically relevant labeling-imaging approach enables non-radioactive sensitive tumor detection and supports the use of deuterium in cancer imaging.

合理的探针设计：动态核极化（DNP）是一项前沿技术，可以显著提高核磁共振(NMR)/磁共振成像（MRI）对分子的检测灵敏度。这种方法可以使用MRI实时成像体内动态代谢状态。为了扩大可靶向的代谢反应，需要开发外源的，即人工设计的DNP-NMR分子探针；然而，由于缺乏既定的设计指南，符合实际的DNP-NMR分子探针的要求是具有挑战性的。在这里，我们报道了Ala-[1-(13)C]Gly-d2-NMe2作为DNP-NMR分子探针用于体内检测氨基肽酶N活性。我们通过精确的结构研究、计算、生化评估和先进的分子设计，合理地开发了这种探针，以实现对体内酶活性的快速和可检测的反应。利用该探针，我们成功地检测了体内酶的活性。本报告提出了一种全面的方法，通过结构引导分子设计开发人工衍生的实用DNP-NMR分子探针。利用对氢作为核自旋序源，研究了低成本超极化剂：利用SHield取向转移可逆交换（SABRE-SHEATH）实现[1-(13)C]丙酮酸盐（13）C1自旋的快速超极化。丙酮酸与铱极化转移配合物的交换可以通过温度与DMSO和H2 o的共连接之间的敏感相互作用来调节。通过限制[1-(13)C]丙酮酸在较低温度下的化学交换，在不到30秒的时间内实现催化剂结合的[1-(13)C]丙酮酸的有序统一（13）C（50%）极化。在催化剂结合的丙酮酸酯上，使用1.4 T核磁共振光谱仪测量39%的极化，并在原位积累结束时推断为50%。当在cd3od中使用20 mM DMSO和0.5 M水时，30 mM丙酮酸样品（包括游离和结合的丙酮酸）的最高极化率为13%。有效的（13）C极化也是由亚微特斯拉磁场中有利的弛豫动力学实现的，与T1自旋弛豫速率相比，极化积累速度更快(例如，对于6mm催化剂-[1-(13)C]丙酮酸样品，极化积累速度约为0.2 s（-1)，而弛豫速率约为0.1 s(-1)）。最后，催化剂结合的超极化[1-(13)C]丙酮酸可以通过循环温度和/或优化水的数量来快速释放，为未来通过相对快速和简单的基于sabre - sheath的方法生产的超极化[1-(13)C]丙酮酸的生物医学应用铺平了道路。副氢发生器：我们报告了一个强大的和低成本的副氢发生器设计，采用液氮作为冷却剂。发电机的核心由充满催化剂的螺旋铜管组成，可加压至35atm。采用顺磁水合氧化铁催化剂，在77 K温度下，用三种几乎相同的生成装置获得了48%的副氢分数。利用台式核磁共振波谱仪在苍蝇上进行对氢定量，以监测残余正氢-对氢的核磁共振沉默信号。这种实时定量方法也用于评估催化剂在高达1.0标准升/分钟流速下的活化情况。所报道的廉价装置可广泛用于利用对氢作为核自旋超极化源的研究。为此，我们证明了这种对氢发生器在浓缩丙酮酸钠[1-(13)C]的超极化中的效用，丙酮酸钠是一种代谢造影剂，正在许多临床试验中进行研究。据报道，SABRE-SHEATH的先导优化（可逆交换屏蔽信号放大，使对准转移到异核）超极化在临床相关的1t磁场下产生（13）C信号增强超过14000倍，相当于大约1.2%的（13）C极化——如果使用接近100%的对氢，报道的值将增加两倍，达到3.5%的（13）C极化。目的：水是许多生化途径的底物。全身管理的氘水（D2O）导致氘掺入到核酸，碳水化合物，蛋白质和脂质。鉴于其相对较高的增殖率和由此产生的氘富集，我们假设通过氘磁共振成像更容易从健康组织中识别肿瘤。方法：我们在两种携带人类结直肠癌HT-29或胰腺癌MiaPaca2的异种移植小鼠模型中开始给药D2O。结果：经过14天的体内肿瘤生长和7天的全身D2O标记，异种移植物与正常组织的dMRI对比明显。结论：我们的新临床相关的标记成像方法可以实现非放射性敏感的肿瘤检测，并支持氘在癌症成像中的应用。