Heart Imaging Agents: A Structural-Mechanistic Study

描述(申请人提供)：该项目的主要焦点一直是开发放射性示踪剂，利用核素成像对心脏交感神经功能进行非侵入性评估。我们实验室以前已经成功地开发了几种用于心脏交感神经元的示踪剂，包括用于SPECT成像的[123I]间碘苯甲基胍(MIBG)和用于PET成像的[11C]间羟基麻黄碱(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)的底物快速转运到心脏交感神经元中，然后被囊泡性单胺转运体(VMAT2)摄取成囊泡。虽然这些药物的神经元快速摄取会产生高质量的心脏图像，但它们的神经元摄取速度如此之快，以至于无法对其动力学进行分室建模。这也导致示踪剂保留的测量对神经丢失不敏感，直到这些丢失变得严重。我们相信，只有具备最优动力学的新示踪剂才能克服准确定量的障碍，这些示踪剂具有更丰富的信息。这种示踪剂将提供更准确和更灵敏的区域神经密度测量方法，使在导致神经损害的疾病(如糖尿病自主神经病变和心力衰竭)的病程中更早检测到失神经。在为患者提供停止或逆转去神经的有效治疗方面，早期发现去神经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净底物必须具备两个动力学性质，才能在示踪动力学分析中达到“理想”：(1)较慢的神经元摄取速率；(2)通过有效的囊泡储存，具有非常长的神经元滞留时间。我们进一步假设，在许多已知的对交感神经元产生强大药理作用的胍类化合物中，可以找到具有这些特性的示踪剂。对11C-苯乙基胍的研究得到了几个具有所需动力学性质的化合物。N-[11C]鸟嘌呤-间八胺(GMO)是最有前途的11C标记剂，而4-氟和6-氟间羟基苯乙基胍(4F-MHPG，6F-MHPG)则支持这些化合物发展成为18F标记示踪剂。在目前的提案中，一个主要目标是用微型PET在猴子身上进行转基因的成像研究，以评估其是否适合于人类的定量PET研究。第二个主要目标是制备和评价18F标记的4F-MHPG和6F-MHPG。此外，放射性标记的胍的工作将延伸到两个新的系列，基于2-(2-吡啶基)乙基胍和金刚烷基。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大鼠离体心的动力学研究，大鼠的生物分布和代谢研究，细胞内Net和VMAT2运输动力学的分析，以及猴子的代谢和microPET研究。对~(11)C-和~(18)F-胍的系统研究应能开发出一种具有最佳动力学的示踪剂，用于用正电子发射计算机断层扫描定量心脏交感神经密度。公共卫生相关性许多疾病，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，这可能会导致心源性猝死。该项目的主要目标是开发核医学成像研究，医生可以利用这些研究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药疗法来阻止或逆转。

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.