Heart Imaging Agents: A Structural-Mechanistic Study

心脏显像剂：结构机制研究

• 批准号: 7665581
• 负责人: DAVID M RAFFEL
• 金额: $ 38.26万
• 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/7665581
• 关键词: Adrenal Glands; Area; Biodistribution; Biological Assay; 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; Octopamine; Parkinson Disease; Patients; Pharmacotherapy; Positron-Emission Tomography; Property; Protocols documentation; Radiolabeled; Rattus; Series; Structure; Study models; Techniques; Testing; Time; Tracer; Vertebral column; Vesicle; Work; analog; base; clinical application; density; effective therapy; guanoxan; heart imaging; improved; in vivo; meetings; meta-hydroxyephedrine; metabolic abnormality assessment; metaiodobenzylguanidine; neuronal transport; noradrenaline transporter; novel; phenethylguanidine; public health relevance; 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用于使用闪烁图成像对心脏交感神经功能无创评估的放射性示踪剂的开发。我们的实验室以前已经开发了几个成功的心脏交感神经元示踪剂，包括用于SPECT成像的[123i]元二苯甲苯胺（MIBG）和用于宠物成像的[11C] Meta-Hydroxyephedrine（HED）和[11C] Epinephrine（Epi）。所有这些示踪剂迅速将其作为去甲肾上腺素转运蛋白（Net）的底物迅速运输到心脏交感神经元中，然后通过囊泡单胺转运蛋白（VMAT2）将其摄入囊泡。尽管这些药物的快速神经元摄取导致了高质量的心脏图像，但它们的神经元摄取率是如此之快，以至于其动力学的隔室建模失败。这也导致示踪剂保留率对神经损失不敏感，直到这些损失变得严重。我们认为，只有使用具有最佳信息的新的，更多信息的示踪剂，可以克服精确定量的障碍，这些动力学具有最佳的动力学用于示踪动力学分析。这样的示踪剂将提供更准确，更敏感的区域神经密度的度量，从而在引起神经损害的疾病过程中较早地检测神经，例如糖尿病自主神经病和心力衰竭。在为患者提供有效的疗法以停止或反向神经支配的疗法方面，早期检测可能在临床上很重要。在最后一个项目期间，我们假设放射标记的净底物必须具有两个动力学特性，才能成为示踪剂动力学分析的“理想”：（1）通过有效的vesicular vesicular vesicular储存时间，神经元摄取速率较慢，并且（2）一个非常长的神经元保留时间。我们进一步假设，可以在许多已知的鸟嘌呤中找到具有这些特性的示踪剂，这些鸟甲肾上腺素对交感神经元产生有效的药理作用。对11C-苯基鸟苷的研究产生了具有所需动力学特性的几种化合物。 N- [11C]甘烷基 - （GMO）成为最有前途的11C标记剂，同时以4-氟和6-氟洛洛罗 - 氟甲苯 - 羟基苯基鸟苷的鼓励结果令人鼓舞结果，这些甲基类鸟嘌呤（4f-mhpg，6f-mhpg，6f-mhpg）支持这些成型的成型，以增强这些成型。在当前的提案中，一个主要目标是对Micropet进行转基因生物的成像研究，以评估其对人类定量宠物研究的适用性。第二个主要目标是准备和评估18F标记的4F-MHPG和6F-MHPG。同样，基于2-（2-吡啶基）乙基鸟胺和鸟氧烷的放射性标记的鸟可以的工作将扩展到两个新系列。这些新系列包括带环氟取代的结构，这是开发最佳18F标记示踪剂的持续努力的一部分。示踪性生物评估方法将包括对分离的大鼠心脏的动力学研究，大鼠的生物分布和代谢研究，细胞中净和VMAT2转运动力学的测定，以及猴子的代谢和微核研究。这项对11C和18F-瓜胺的系统研究应导致开发具有最佳动力学的示踪剂，以用PET量化心脏交感神经密度。公共卫生相关性的许多疾病，包括糖尿病，心力衰竭，心脏病发作（梗塞）和帕金森氏病都会对心脏神经造成严重损害，这可能导致心脏突然死亡。该项目的主要目的是开发核医学成像研究，医生可以使用这些研究来拍摄这些疾病患者心脏神经损害的照片。这些成像研究将有助于医生了解心脏神经如何在疾病中受损，还可以用来研究神经损伤是否可以停止或使用新药物疗法逆转。