Esterase-sensitive hyperpolarized 13C probes for simultaneous imag

用于同时成像的酯酶敏感超极化 13C 探针

• 批准号: 10292460
• 负责人: Chalermchai Khemtong
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292460
• 关键词: Acetates; Acidity; Acids; Anhydrides; Biological Markers; Blood; Blood Circulation; Butyrates; Carbon; Carbonates; Cardiovascular Diseases; Chemicals; Clinical; Development; Diabetes Mellitus; Diagnosis; Disease; Energy Metabolism; Enzymes; Esters; Goals; Gold; Heart; Homeostasis; Hydrolysis; Image; Imaging Device; Impairment; Injections; Ischemia; Kidney; Kinetics; Label; Lead; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Diseases; Metabolism; Modality; Molecular; Mus; Myocardial Ischemia; Nuclear; Organ; Phosphorylation; Plasma; Positron-Emission Tomography; Production; Prognosis; Pyruvate; Rattus; Regulation; Relaxation; Research; Series; Signal Transduction; Techniques; Testing; Time; Tissue Viability; Tissue imaging; Tissues; Whole Blood; acute toxicity; acyl group; base; carbonate dehydratase; chemical stability; diagnostic tool; esterase; experimental study; fluorodeoxyglucose; functional group; hexokinase; imaging agent; imaging modality; imaging probe; improved; in vivo; in vivo imaging; metabolic imaging; non-invasive imaging; novel; preference; success; temporal measurement; time use; tool; tumor; uptake

PROJECT SUMMARY: Abnormal metabolism is associated with a number of metabolic diseases such as cancer, diabetes, and cardiovascular diseases. Important markers for the altered metabolic states include changes in fuel preferences and loss of acidity regulations in tissues. To date, routine assessments of energy metabolism and acidity in viable tissues remain a challenge. Sensitive imaging modalities that can provide accurate characterization of these important biomarkers are therefore highly desirable. In this application, we aim to establish a series of hyperpolarized (HP) 13C-enriched molecules that can be activated by an endogenous enzyme esterase to produce both pH and metabolic imaging probes in tissues. Successful development of these HP 13C-enriched compounds will allow for tissue acidity and metabolic information to be simultaneously characterized following an injection of a single imaging probe. Molecular candidates for these applications must be chemically stable, can be highly polarized by dynamic nuclear polarization (DNP), have long 13C T1’s, and be highly sensitive to esterase hydrolysis. Once hydrolyzed, the molecules must quickly decompose to form a pair of pH imaging probes, HP 13CO2 and HP H13CO3-, as well as a HP 13C-enriched metabolic substrate such as 13C- pyruvate. Here, we propose a series of ethyl alkyl mixed anhydride carbonate compounds with 13C- enrichments at both the carbonate and carboxyl carbons. These carbon centers have long T1 making them suitable for HP 13C imaging applications. Moreover, these small organic molecules are expected to be efficiently polarized by DNP with significantly improved 13C MR imaging sensitivity. Last but not least, the ester functional group in these mixed anhydrides is expected to be highly susceptible to hydrolysis by esterase. Once injected into the circulation, we expect that these HP 13C-mixed anhydride carbonates will be rapidly hydrolyzed by esterase producing monoacyl carbonate molecules. These intermediates are expected to decompose, producing HP 13CO2 and a HP 13C-enriched metabolic substrate for pH measurement and metabolism analysis in tissues, respectively. In Aim 1 of this study, we will synthesize 13C-enriched ethyl acyl mixed anhydride carbonates with 13C-acetate, 13C-pyruvate, or 13C-butyrate as the acyl moiety. HP 13C parameters such as T1, signal enhancement and chemical stability of these compounds will also be evaluated. In Aim 2, we will investigate the production of HP 13CO2/H13CO3- and HP 13C metabolic substrate by esterase hydrolysis in solutions of isolated esterase, isolated rat plasma, blood, and homogenates of rat liver and heart tissues. Finally, we will evaluate the acute toxicity as well as the in vivo imaging efficacy of these HP 13C probes in mice and rats (Aim 3). Successful execution of this study could lead to a series of HP 13C imaging probes that allow for simultaneous imaging of tissue pH and energy metabolism in tissues associated with metabolic diseases.

项目概要： 代谢异常与许多代谢疾病相关，如癌症、糖尿病和糖尿病。 心血管疾病代谢状态改变的重要标志包括燃料的变化 偏好和组织中酸度调节的丧失。迄今为止，对能源的常规评估 存活组织中的代谢和酸性仍然是一个挑战。敏感的成像模式， 因此，提供这些重要生物标志物的准确表征是非常需要的。在这 应用，我们的目标是建立一系列超极化（HP）13 C富集分子，可以 由内源性酶酯酶激活，产生pH和代谢成像探针， 组织中这些富含HP 13 C的化合物的成功开发将允许组织酸性， 在注射单次成像后同时表征代谢信息 探针这些应用的候选分子必须是化学稳定的，可以高度极化， 通过动态核极化（DNP），具有长的13 C T1，并且对酯酶高度敏感 水解一旦水解，分子必须迅速分解，形成一对pH成像 探针HP 13 CO2和HP H13 CO 3-，以及富含HP 13 C的代谢底物，如13 C- 丙酮酸在这里，我们提出了一系列具有13 C-的乙基烷基混合酸酐碳酸酯化合物， 在碳酸盐和羧基碳上富集。这些碳中心具有长T1制造 适用于HP 13 C成像应用。此外，这些小的有机分子预计 被DNP有效极化，具有显著提高的13 C MR成像灵敏度。最后但并非 至少，预期这些混合酸酐中的酯官能团高度易受 通过酯酶水解。一旦注入到循环中，我们预计这些HP 13 C-混合酸酐 碳酸酯将被酯酶迅速水解，产生单酰基碳酸酯分子。这些 预计中间产物会分解，产生HP 13 CO2和富含HP 13 C的代谢产物 分别用于组织中pH测量和代谢分析的底物。在本研究的目标1中， 我们将用13 C-乙酸酯，13 C-丙酮酸酯， 或13 C-丁酸酯作为酰基部分。HP 13 C参数，如T1、信号增强和化学 还将评价这些化合物的稳定性。在目标2中，我们将研究HP的生产 13 CO2/H13 CO 3-和HP 13 C代谢底物在分离的酯酶溶液中的酯酶水解， 分离的大鼠血浆、血液和大鼠肝脏和心脏组织的匀浆。最后，我们将评估 急性毒性以及这些HP 13 C探针在小鼠和大鼠中的体内成像功效（目的3）。 本研究的成功执行可能会导致一系列HP 13 C成像探头， 与代谢相关的组织中的组织pH和能量代谢的同时成像 疾病