Heart Imaging Agents: A Structural-Mechanistic Study

心脏显像剂：结构机制研究

• 批准号: 7524384
• 负责人: DAVID M RAFFEL
• 金额: $ 38.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 2012-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524384
• 关键词: Adrenal Glands; Area; Biodistribution; Biological Assay; Bos taurus; Carbon; Cardiac; Cattle; Cells; Chromaffin granule; Classification; Clinical; Clinical Research; Data; Denervation; Detection; Development; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Discipline of Nuclear Medicine; Disease; Early Diagnosis; Ensure; Epinephrine; Fluorine; Glioma; Goals; Guanidines; Heart; Heart failure; Human; Human Cloning; Image; In Vitro; Infarction; Investigation; Kinetics; Label; Laboratories; Light; Macaca mulatta; Measurement; Measures; Metabolism; Methods; Modeling; Monkeys; Myocardial Infarction; Nerve; Neurons; Noise; Norepinephrine; Numbers; Octopamine; Parkinson Disease; Patients; Pharmacotherapy; Positron-Emission Tomography; Property; Protocols documentation; Public Health; Radiolabeled; Rate; Rattus; Series; Structure; Study models; Techniques; Testing; Time; Tracer; Vesicle; Work; analog; base; clinical application; density; desire; guanidinium; guanoxan; heart imaging; improved; in vivo; meta-hydroxyephedrine; metabolic abnormality assessment; metaiodobenzylguanidine; neuronal transport; noradrenaline transporter; novel; phenethylguanidine; radiotracer; single photon emission computed tomography; sudden cardiac death; uptake; vesicular monoamine transporter

DESCRIPTION (provided by applicant): The main focus of this project has been the development of radiotracers for the noninvasive assessment of cardiac sympathetic nerve function using scintigraphic imaging. Our laboratory has previously developed several successful tracers for cardiac sympathetic neurons, including [123I]meta-iodobenzylguanidine (MIBG) for SPECT imaging and [11C]meta-hydroxyephedrine (HED) and [11C]epinephrine (EPI) for PET imaging. All of these tracers are rapidly transported into cardiac sympathetic neurons as substrates of the norepinephrine transporter (NET), and then taken up into vesicles by the vesicular monoamine transporter (VMAT2). While the rapid neuronal uptake of these agents results in high quality heart images, their neuronal uptake rates are so fast that compartmental modeling of their kinetics fails. This also causes measures of tracer retention to be insensitive to nerve losses until those losses become severe. We believe this obstacle to accurate quantification can only be overcome with new kinetically superior, more information-rich tracers that possess optimal kinetics for tracer kinetic analyses. Such tracers would provide more accurate and sensitive measures of regional nerve density, allowing detection of denervation earlier in the course of diseases that cause nerve damage, such as diabetic autonomic neuropathy and heart failure. Early detection of denervation may be clinically important in terms of providing patients with effective therapies to halt or reverse denervation. In the last project period, we hypothesized that a radiolabeled NET substrate must possess two kinetic properties to be `ideal' for tracer kinetic analyses: (1) a slower neuronal uptake rate, and (2) a very long neuronal retention time, through efficient vesicular storage. We had further hypothesized that a tracer with these properties could be found among the many guanidines known to exert potent pharmacological effects on sympathetic neurons. Studies of 11C-phenethylguanidines yielded several compounds with the desired kinetic properties. N-[11C]guanyl-( )-meta-octopamine (GMO) emerged as the most promising 11C-labeled agent, while encouraging results with 4-fluoro- and 6-fluoro-meta-hydroxyphenethylguanidine (4F-MHPG, 6F-MHPG) support the development of these compounds into 18F-labeled tracers. In the current proposal, a major goal is to perform imaging studies of GMO in monkeys with microPET to assess its suitability for quantitative PET studies in humans. A second major goal is to prepare and evaluate 18F-labeled 4F-MHPG and 6F-MHPG. Also, work on radiolabeled guanidines will extend to two new series based on 2-(2-pyrindinyl)ethylguanidine and guanoxan. These new series include structures with ring fluorine substitutions as part of ongoing efforts to develop an optimal 18F-labeled tracer. Tracer bioevaluation methods will include kinetic studies in isolated rat heart, biodistribution and metabolism studies in rats, assays of NET and VMAT2 transport kinetics in cells, and metabolism and microPET studies in monkeys. This systematic study of 11C- and 18F-guanidines should result in the development of a tracer with optimal kinetics for quantifying cardiac sympathetic nerve density with PET. PUBLIC HEALTH RELEVANCE Many diseases, including diabetes, heart failure, heart attacks (infarction) and Parkinson's disease are known to cause severe damage to the nerves of the heart, which may contribute to sudden cardiac death. The main goal of this project is to develop nuclear medicine imaging studies that can be used by doctors to take pictures of the damage to the nerves of the heart in patients with these diseases. These imaging studies will help doctors understand how the nerves of the heart are damaged in diseases, and also can be used to study if the nerve damage can be stopped or reversed with new drug therapies.

描述（由申请人提供）：该项目的主要重点是开发放射性示踪剂，用于使用放射性成像对心脏交感神经功能进行无创评估。我们的实验室以前已经开发了几种成功的心脏交感神经元示踪剂，包括用于SPECT成像的[123 I]间碘苄胍（MIBG）和用于PET成像的[11 C]间羟麻黄碱（HED）和[11 C]肾上腺素（EPI）。所有这些示踪剂作为去甲肾上腺素转运体（NET）的底物被快速转运到心脏交感神经元中，然后被囊泡单胺转运体（VMAT 2）摄取到囊泡中。虽然这些试剂的快速神经元摄取导致高质量的心脏图像，但它们的神经元摄取速率如此之快，以至于其动力学的房室模型失败。这也导致示踪剂保留的测量对神经损失不敏感，直到这些损失变得严重。我们相信，这种准确定量的障碍只能用新的动力学上级，更丰富的信息，具有最佳动力学示踪剂动力学分析的示踪剂来克服。这种示踪剂将提供更准确和灵敏的局部神经密度测量，允许在引起神经损伤的疾病过程中更早地检测去神经支配，例如糖尿病自主神经病变和心力衰竭。去神经支配的早期检测在为患者提供有效治疗以停止或逆转去神经支配方面可能具有临床重要性。在最后一个项目期间，我们假设放射性标记的NET底物必须具有两个动力学特性才能“理想”用于示踪剂动力学分析：（1）较慢的神经元摄取速率，以及（2）通过有效的囊泡储存，具有非常长的神经元保留时间。我们进一步假设，在已知对交感神经元产生强效药理作用的许多胍类物质中，可以找到具有这些特性的示踪剂。11 C-苯乙基胍的研究产生了几种化合物所需的动力学性能。N-[11 C]胍基-（）-间-章鱼胺（GMO）成为最有前途的11 C标记剂，而4-氟-和6-氟-间-羟基苯乙基胍（4F-MHPG，6 F-MHPG）的令人鼓舞的结果支持将这些化合物开发成18F标记的示踪剂。在当前的提案中，一个主要目标是使用microPET对猴子的转基因生物进行成像研究，以评估其对人类定量PET研究的适用性。第二个主要目标是制备和评价18F标记的4F-MHPG和6 F-MHPG。此外，放射性标记的胍的工作将扩展到两个新的系列的基础上2-（2-吡啶基）乙基胍和guanoxan。这些新系列包括具有环氟取代的结构，作为开发最佳18F标记示踪剂的持续努力的一部分。示踪剂生物评价方法将包括在离体大鼠心脏中的动力学研究、在大鼠中的生物分布和代谢研究、在细胞中的NET和VMAT 2转运动力学测定以及在猴中的代谢和microPET研究。11 C-和18F-胍的系统研究应导致开发具有最佳动力学的示踪剂，用于用PET定量心脏交感神经密度。许多疾病，包括糖尿病、心力衰竭、心脏病发作（梗塞）和帕金森氏病，已知会对心脏神经造成严重损害，这可能导致心脏性猝死。该项目的主要目标是开发核医学成像研究，可供医生用于拍摄这些疾病患者心脏神经损伤的照片。这些成像研究将帮助医生了解心脏神经在疾病中是如何受损的，也可用于研究神经损伤是否可以通过新的药物疗法停止或逆转。