PET Imaging Probes Targeting Cardiac Parasympathetic Innervation

针对心脏副交感神经支配的 PET 成像探针

• 批准号: 9537670
• 负责人: DAVID M RAFFEL
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9537670
• 关键词: Acetylcholinesterase; Acetylcholinesterase Inhibitors; Adrenergic Agents; Affinity; Animals; Area; Arrhythmia; Autonomic Dysfunction; Autoradiography; Binding; Brain; Carbon; Cardiac; Cause of Death; Choline; Choline O-Acetyltransferase; Cicatrix; Clinical; Clinical Trials; Denervation; Development; Disease; Effectiveness; Enzymes; Fluorine; Goals; Heart; Heart Arrest; Heart Atrium; Heart Diseases; Heart failure; Image; Implantable Defibrillators; Kinetics; Label; Lead; Life; Measurement; Measures; Medical Imaging; Metabolism; Michigan; Myocardial; Myocardial Infarction; Myocardial tissue; Nerve; Neurons; Neurotransmitters; PET/CT scan; Patients; Play; Population; Positron-Emission Tomography; Process; Radiolabeled; Radionuclide Imaging; Rattus; Resistance; Resolution; Risk; Risk stratification; Role; Scientist; Series; Signal Transduction; Structure; Sudden Death; Sympathectomy; System; Tachycardia; Tacrine; Techniques; Testing; Tissues; Tracer; Treatment Efficacy; Universities; Ventricular Arrhythmia; Vesicle; acetylcholine transporter; afferent nerve; analog; base; choline analog; choline transporter; cholinergic; cholinergic neuron; density; digital; donepezil; heart function; heart imaging; imaging probe; imaging study; improved; in vitro Assay; insight; lipophilicity; meta-hydroxyephedrine; metaiodobenzylguanidine; nanomolar; nerve supply; neuroimaging; neuromechanism; neuronal transport; non-invasive imaging; nonhuman primate; novel; novel therapeutics; patient stratification; radiotracer; relating to nervous system; respiratory; risk minimization; success; therapy design; tool; uptake; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Adrenergic Agents; Affinity; Animals; Area; Arrhythmia; Autonomic Dysfunction; Autoradiography; Binding; Brain; Carbon; Cardiac; Cause of Death; Choline; Choline O-Acetyltransferase; Cicatrix; Clinical; Clinical Trials; Denervation; Development; Disease; Effectiveness; Enzymes; Fluorine; Goals; Heart; Heart Arrest; Heart Atrium; Heart Diseases; Heart failure; Image; Implantable Defibrillators; Kinetics; Label; Lead; Life; Measurement; Measures; Medical Imaging; Metabolism; Michigan; Myocardial; Myocardial Infarction; Myocardial tissue; Nerve; Neurons; Neurotransmitters; PET/CT scan; Patients; Play; Population; Positron-Emission Tomography; Process; Radiolabeled; Radionuclide Imaging; Rattus; Resistance; Resolution; Risk; Risk stratification; Role; Scientist; Series; Signal Transduction; Structure; Sudden Death; Sympathectomy; System; Tachycardia; Tacrine; Techniques; Testing; Tissues; Tracer; Treatment Efficacy; Universities; Ventricular Arrhythmia; Vesicle; acetylcholine transporter; afferent nerve; analog; base; choline analog; choline transporter; cholinergic; cholinergic neuron; density; digital; donepezil; heart function; heart imaging; imaging probe; imaging study; improved; in vitro Assay; insight; lipophilicity; meta-hydroxyephedrine; metaiodobenzylguanidine; nanomolar; nerve supply; neuroimaging; neuromechanism; neuronal transport; non-invasive imaging; nonhuman primate; novel; novel therapeutics; patient stratification; radiotracer; relating to nervous system; respiratory; risk minimization; success; therapy design; tool; uptake

Cardiac autonomic dysfunction is well documented in many types of heart disease and is frequently associated with regional destruction of cardiac nerve populations. This can produce neural mechanisms that contribute to the genesis of cardiac arrhythmias, tachycardia and fibrillation, conditions which often lead to sudden death. This process involves not only the extrinsic sympathetic and parasympathetic nerves, but also afferent sensory nerves and a rich network of intrinsic cardiac nerves. Our lab at the University of Michigan has previously developed radiotracers for imaging sympathetic nerves, including [123I]metaiodobenzylguanidine ([123I]MIBG) for planar scintigraphy, [11C]meta-hydroxyephedrine ([11C]HED) for PET imaging, and recently 4-[18F]fluoro- meta-hydroxyphenethylguanidine ([18F]4F-MHPG) for quantifying regional sympathetic nerve density using tracer kinetic analysis. Clinical trials with [123I]MIBG and [11C]HED in heart failure have shown that higher levels of sympathetic denervation are associated with a greatly elevated risk of sudden death, thus neuronal imaging may improve risk stratification of patients being staged for implantable cardioverter defibrillators. Despite the successes in imaging sympathetic nerves, a current unmet need is a useful tracer for parasympathetic nerves. This has been an elusive goal for many reasons. Cholinergic parasympathetic nerves are primarily localized in atrial tissues, including the AV and SA nodes, small structures that are hard to image with PET due to the partial volume effect. Also, parasympathetic nerve density in the ventricles is much lower than the sympathetic nerves. Nevertheless, with the high spatial resolution of current PET/CT systems and advanced techniques such as cardiac and respiratory gating, it should be possible to image parasympathetic nerves if a tracer with high neuronal uptake and low non-specific binding can be found. In this study, we will evaluate two approaches to achieving this goal. First, we will test radiolabeled analogs of homocholine, a ‘false neurotransmitter’ that is transported into parasympathetic nerve terminals by the choline transporter (ChT), acetylated by choline acetyltranferase (ChAT) into acetylhomocholine, which is then stored in vesicles by the vesicular acetylcholine transporter (VAChT). An advantage of homocholine over other radiolabeled choline analogs for cardiac imaging is the resistance of acetylhomocholine to metabolism by acetylcholinesterase (AChE). The second approach will target AChE, which is expressed extraneuronally near cholinergic nerves. Specifically, 11C- and 18F-labeled analogs of a series of potent AChE inhibitors with sub-nanomolar binding affinities will be studied. Compared with many other AChE inhibitors (e.g., tacrine, donepezil), these N,N'-diphenethylsulfamides have much lower log P values, which should minimize non-specific binding in the heart. In vitro assays, digital autoradiography, and small animal PET studies in rats and non-human primates will be used to assess these two approaches. A PET tracer capable of imaging cardiac parasympathetic nerves would be a valuable clinical tool for assessing disease-induced damage to this important nerve population in patients with heart diseases.

心脏自主神经功能障碍在许多类型的心脏病中都有充分记录，并且经常相关 随着心脏神经种群的区域破坏。这可以产生有助于的神经机制 心律不齐，心动过速和纤颤的起源通常导致猝死。 这个过程不仅涉及外在交感神经和副交感神经系统，还涉及传入的感觉 神经和丰富的内在心脏神经网络。我们在密歇根大学的实验室以前 开发了用于成像交感神经的放射性示例，包括[123i] Metaiododobenzylguanidine（[[123i] MIBG） 对于平面闪烁显像，[11c]元羟基肾上腺素（[[11C] HED）用于PET成像，最近4-- [18F]氟 - 元羟基苯基鸟嘌呤（[18F] 4F-MHPG）用于使用区域交感神经密度来量化区域性交感神经密度 示踪剂动力学分析。 [123i] MIBG和[11C] HED的临床试验表明，较高的水平 交感神经的神经膜与突然死亡的风险大大相关，因此神经元成像 可能会改善针对植入式心脏扭曲器除颤器上演的患者的风险分层。尽管有 在成像交感神经方面取得了成功，当前的未满足需求是副交感神经的有用示踪剂。 由于许多原因，这是一个难以捉摸的目标。胆碱能副交感神经系统主要定位于 心房组织，包括AV和SA节点，小结构，由于 部分体积效应。同样，心室中的副交感神经密度远低于同情 神经。然而，使用当前的PET/CT系统和高级技术的高空间分辨率 例如心脏和呼吸道控门，如果示踪剂与副交感神经 可以找到高神经元摄取和低非特异性结合。在这项研究中，我们将评估两种方法 实现这一目标。首先，我们将测试同醇的放射性标记类似物，一种“假神经递质” 由胆碱化的胆碱转运蛋白（CHT）转运到副交感神经末端 乙酰基转造酶（CHAT）进入乙酰基胺胆碱，然后由囊泡乙酰胆碱储存在蔬菜中 转运蛋白（VACHT）。同醇比其他放射性标记的胆碱类似物的优势 成像是乙酰胆碱对乙酰胆碱酯酶（ACHE）对代谢的抗性。第二个 方法将靶向疼痛，该疼痛在胆碱能神经附近表达。具体来说，11c-和 将研究一系列具有亚纳摩尔结合亲和力的潜在ACHE抑制剂的标记类似物。 与许多其他ACHE抑制剂（例如，他的酸性抑制剂，多奈哌齐）相比，这些N，N'-二苯甲酰硫酰胺具有 较低的log P值，这应该最大程度地减少心脏中的非特异性结合。体外测定，数字 放射自显影以及对大鼠和非人类素数的小动物宠物研究将用于评估这些评估 两种方法。能够成像心脏副交感神经的宠物示踪剂将是有价值的临床 评估疾病引起的心脏病患者对这种重要神经人群损害的工具。