PET Imaging Probes Targeting Cardiac Parasympathetic Innervation

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文献记载，并经常与 心脏神经种群的局部破坏。这可以产生神经机制，有助于 心律失常、心动过速和纤颤的发生，这些情况通常会导致猝死。 这一过程不仅涉及外源性交感神经和副交感神经，而且还涉及传入感觉。 神经和丰富的心脏内脏神经网络。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[123I]间苯基胍([123I]MIBG) 对于平面闪烁成像，用于PET成像的[11C]间羟基麻黄碱([11C]HED)，以及最近的4-[18F]氟- 间羟基苯乙基胍([18F]4F-MHPG)定量局部交感神经密度 示踪剂动力学分析。[123I]MIBG和[11C]HED治疗心力衰竭的临床试验表明，较高的水平 交感神经丧失与猝死的风险大大增加有关，因此神经元成像 可能会改善植入心脏复律除颤器分期的患者的风险分层。尽管 在交感神经成像方面的成功，目前尚未得到满足的需求是副交感神经的有用示踪剂。 出于许多原因，这一直是一个难以实现的目标。胆碱能副交感神经主要定位于 心房组织，包括房室和窦房结，这些小结构很难用PET成像，因为 部分体积效应。脑室内的副交感神经密度也远低于交感神经。 太紧张了。然而，由于目前PET/CT系统的高空间分辨率和先进的技术 例如心脏和呼吸系统的门控，如果示踪剂有 神经元摄取较高，非特异性结合较低。在这项研究中，我们将评估两种方法 为实现这一目标。首先，我们将测试高胆碱的放射性标记类似物，这是一种“虚假的神经递质” 由胆碱转运体(CHT)转运到副交感神经末梢，由胆碱乙酰化 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 运输船(游艇)。高胆碱与其他放射性标记胆碱类似物相比在心脏治疗中的优势 成像是乙酰胆碱酯酶(AChE)对乙酰高胆碱代谢的抵抗。第二 Approach将以AChE为靶点，AChE在神经外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有效AChE抑制剂的18F标记类似物。 与许多其他AChE抑制剂(如他克林、多奈哌齐)相比，这些N，N‘-二苯乙基磺胺具有 更低的对数P值，这应该会将心脏中的非特异性结合降至最低。数字体外分析 在大鼠和非人类灵长类动物中的放射自显影和小动物PET研究将被用来评估这些 有两种方法。一种能够成像心脏副交感神经的PET示踪剂将是有价值的临床应用 评估疾病对心脏病患者这一重要神经群体的损害的工具。

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.