Heart Imaging Agents: A Structural-Mechanistic Study

描述（由申请人提供）：这个项目的主要重点是开发放射性示踪剂，用于使用扫描成像技术对心脏交感神经功能进行无创评估。我们的实验室之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[123I]间碘苄基胍（MIBG）和用于PET成像的[11C]间羟基麻油（HED）和[11C]肾上腺素（EPI）。所有这些示踪剂都作为去甲肾上腺素转运体（NET）的底物迅速转运到心脏交感神经元，然后由囊泡单胺转运体（VMAT2）进入囊泡。虽然这些药物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，以至于它们的动力学的区室建模失败。这也导致示踪剂保留措施对神经损失不敏感，直到这些损失变得严重。我们相信，准确定量的这一障碍只能通过新的动力学优越的、信息更丰富的示踪剂来克服，这些示踪剂具有最佳的动力学分析。这种示踪剂将提供更准确和敏感的区域神经密度测量，允许在引起神经损伤的疾病（如糖尿病自主神经病变和心力衰竭）的过程中更早地检测到失神经。在为患者提供有效的治疗来停止或逆转去神经支配方面，早期发现去神经支配可能具有重要的临床意义。在上一个项目期间，我们假设放射性标记的NET底物必须具有两种动力学特性，才能“理想”地进行示踪剂动力学分析：(1)较慢的神经元摄取速率；(2)通过有效的囊泡储存，神经元保留时间很长。我们进一步假设具有这些特性的示踪剂可以在已知的对交感神经元发挥有效药理作用的许多胍中找到。对11c -苯乙基胍的研究得到了几种具有期望动力学性质的化合物。N-[11C]鸟酰-()-间章鱼胺（GMO）成为最有前途的11C标记剂，而4-氟和6-氟-间羟基苯乙基胍（4F-MHPG, 6F-MHPG）的令人鼓舞的结果支持这些化合物发展成为18f标记的示踪剂。在目前的提案中，一个主要目标是用微PET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估18f标记的4F-MHPG和6F-MHPG。此外，关于放射性标记胍的工作将扩展到基于2-（2-吡啶基）乙基胍和鸟氧嘧啶的两个新系列。这些新系列包括环氟取代结构，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离体大鼠心脏的动力学研究、大鼠体内的生物分布和代谢研究、细胞内NET和VMAT2转运动力学的测定，以及猴子体内的代谢和微pet研究。这项对11C-和18f -胍类化合物的系统研究将导致一种具有最佳动力学的示踪剂的开发，用于PET量化心脏交感神经密度。众所周知，许多疾病，包括糖尿病、心力衰竭、心脏病发作（梗死）和帕金森病，都会对心脏神经造成严重损害，从而可能导致心源性猝死。该项目的主要目标是发展核医学成像研究，医生可以用它来拍摄这些疾病患者心脏神经受损的照片。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，也可以用来研究神经损伤是否可以通过新的药物治疗来停止或逆转。

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.