Heart Imaging Agents: A Structural-Mechanistic Study

心脏显像剂：结构机制研究

• 批准号: 6988482
• 负责人: DAVID M RAFFEL
• 金额: $ 37.16万
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988482
• 关键词: Macaca mulatta; autonomic nervous system; bioimaging /biomedical imaging; heart imaging /visualization /scanning; heart innervation; laboratory rat; neuroimaging; neuronal transport; positron emission tomography; radiotracer; technology /technique development

DESCRIPTION (provided by applicant): The primary goal of this project has been to develop radiotracers for the noninvasive assessment of cardiac sympathetic innervation. To this end, our laboratory has developed several successful radiotracers for imaging cardiac sympathetic neurons, including radioiodinated meta iodobenzylguanidine (MIBG), 11C]meta-hydroxyephedrine (HED) and [11C]epinephrine (EPI). All of these tracers are avidly taken up into cardiac sympathetic nerves by the neuronal norepinephrine transporter (NET) and stored in vesicles by the vesicular monoamine transporter (VMAT2). However, while the very rapid neuronal uptake of these agents provides high quality images, it also makes tracer kinetic analyses problematic. The major goal of this proposal is to develop kinetically superior, more information-rich tracers that possess optimal kinetic properties for quantitative analyses. Such tracers would provide more sensitive and accurate measures of nerve density than are currently possible. This would allow detection of early denervation in patients with diseases such as diabetic autonomic neuropathy and heart failure, before nerve losses become severe. Early detection of nerve losses may be critically important in providing effective therapies to halt or reverse cardiac denervation. We hypothesize that a radiolabeled NET substrate must possess 2 kinetic properties to be 'ideal' for tracer kinetic analyses: (1) a slow neuronal uptake rate, and (2) a very long neuronal retention time, through rapid and efficient vesicular storage. We further hypothesize that a tracer with these properties can be found among the many guanidines known to exert potent pharmacological effects on sympathetic neurons. A radiosynthetic method for incorporating carbon-11 into guanidines will be used to synthesize and evaluate 2 series of [11C]guanidines as sympathetic nerve tracers with improved kinetics. Radiolabeling with a N-[11C]guanyl moiety instead of a N-[11C]methyl group offers several advantages, including higher polarity, resistance to metabolism, and stability in blood. Series I is comprised of [11C]phenethylguanidines. Pilot studies show that several [11C]phenethylguanidines possess the desired slow neuronal uptake rate and long neuronal retention time. In an effort to develop an [18F] guanidine with ideal kinetics, Series II consists of ring-fluorinated phenethylguanidines. These will be evaluated with HC-labeling before 18F-labeling the best agents. Bioevaluation of [11C]guanidines will start with kinetic studies in the isolated rat heart and cellular studies of NET and VMAT2 transport kinetics. The biodistribution of promising compounds will be measured in rats. Finally, microPET imaging in monkeys will be performed with the best tracers. This systematic study of [11C]guanidines should result in the development of a tracer with optimal kinetics for quantifying cardiac sympathetic nerve density with PET.

描述（由申请人提供）：该项目的主要目标是开发用于对心脏交感神经的无创评估的放射性示例。为此，我们的实验室开发了几种成功的放射性示踪剂，用于成像心脏交感神经元，包括放射性碘化的二苯甲烷基鸟嘌呤（MIBG），11C] Meta-Hydroxyephedrine（HED）和[11C] Epinephrine（EPI）。所有这些示踪剂都被神经元去甲肾上腺素转运蛋白（NET）广泛地吸收到心脏交感神经中，并通过囊泡单胺转运蛋白（VMAT2）储存在囊泡中。但是，尽管这些药物的神经元摄取非常快速，但它也使示踪剂动力学分析有问题。该提案的主要目标是开发具有最佳信息动力学特性的动力学上更高，更多的信息轨迹。这样的示踪剂将提供比目前可能更敏感和准确的神经密度测量方法。这将允许在神经丧失严重之前检测到糖尿病自主神经病和心力衰竭等疾病患者的早期神经支配。在提供有效的疗法以停止或逆转心脏神经保护方面，对神经丧失的早期发现可能至关重要。我们假设放射性标记的净底物必须具有2种动力学特性，以便于示踪剂动力学分析：（1）通过快速有效的囊泡储存速度缓慢的神经元摄取率，以及（2）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甲衍定物中找到具有这些特性的示踪剂，该鸟甲肾上腺素对交感神经元产生有效的药理作用。将碳-11掺入鸟甲啶中的一种放射合成方法将用于合成和评估2系列的[11C]鸟可以作为具有改进动力学的交感神经示踪剂。用N- [11C]鸟苷部分而不是N- [11C]甲基的放射性标记具有多种优势，包括更高的极性，对代谢的抗性和血液稳定性。 I系列由[11C]苯乙鸟苷组成。试点研究表明，几种[11C]苯乙鸟苷具有所需的缓慢神经元摄取率和长长的神经元保留时间。为了开发具有理想动力学的[18F]鸟选择素，II系列由环氟苯基鸟苷组成。在18F标记最好的代理之前，将通过HC标记进行评估。 [11C]鸟苷的生物评估将从分离的大鼠心脏和净和VMAT2转运动力学的细胞研究中进行动力学研究。有希望化合物的生物分布将在大鼠中测量。最后，将使用最好的示踪剂进行猴子中的微型图像。这项对[11C]鸟嘌呤的系统研究应导致开发具有最佳动力学的示踪剂，以量化使用PET的心脏交感神经密度。