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

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很好的记录， 局部破坏心脏神经这可以产生神经机制，有助于 心律失常、心动过速和纤维性颤动的发生，这些情况常常导致猝死。 这一过程不仅涉及交感神经和副交感神经， 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之前 开发了用于交感神经成像的放射性示踪剂，包括[123 I]间碘苄胍（[123 I]MIBG） 用于平面血管造影，用于PET成像的[11 C]间羟麻黄碱（[11 C]HED），以及最近的4-[18 F]氟- 间羟基苯乙基胍（[18F]4F-MHPG），用于使用 示踪动力学分析[123 I]MIBG和[11 C]HED治疗心力衰竭的临床试验表明， 交感神经失神经支配与猝死的风险大大增加有关，因此神经元成像 可以改善植入式心律转复除颤器患者的风险分层。尽管 尽管在交感神经成像方面取得了成功，但目前未满足的需求是副交感神经的有用示踪剂。 这是一个难以实现的目标，原因有很多。胆碱能副交感神经主要位于 心房组织，包括房室结和SA结，由于 部分体积效应此外，心室中的副交感神经密度比交感神经密度低得多。 神经尽管如此，随着当前PET/CT系统的高空间分辨率和先进技术的发展， 例如心脏和呼吸门控，如果使用 在本研究中，我们将评估两种方法， 实现这一目标。首先，我们将测试高胆碱的放射性标记类似物，一种“假神经递质”， 通过胆碱转运蛋白（ChT）转运到副交感神经末梢，被胆碱乙酰化 乙酰转移酶（ChAT）转化为乙酰高胆碱，然后由囊泡乙酰胆碱储存在囊泡中。 转运蛋白（VAChT）。高胆碱优于其他放射性标记的胆碱类似物用于心脏的优点 成像是乙酰高胆碱对乙酰胆碱酯酶（AChE）代谢的抗性。第二 该方法将靶向乙酰胆碱酯酶，其在胆碱能神经附近的神经元上表达。具体来说，11 C-和 将研究一系列具有亚纳摩尔结合亲和力的有效AChE抑制剂的18F标记类似物。 与许多其他AChE抑制剂（例如，他克林、多奈哌齐），这些N，N’-二苯基乙基磺酰胺具有 低得多的log P值，这应该使心脏中的非特异性结合最小化。体外试验，数字 放射自显影和大鼠和非人灵长类动物的小动物PET研究将用于评估这些 两种方法。PET示踪剂能够成像心脏副交感神经将是一个有价值的临床 评估心脏病患者对这一重要神经群体的疾病引起的损伤的工具。