PET NEURONAL TRACES KINETICS IN ISOLATED DISEASED HEARTS

描述：(改编自申请人的摘要)结构上 相关去甲肾上腺素类似物[C-11]偏羟基麻黄碱， [C-11]苯肾上腺素和[C-11]肾上腺素被开发为 心脏交感神经无创性成像研究中的放射性示踪剂 使用正电子发射断层扫描(PET)进行神经支配。令人震惊的变化 在这些神经元的动力学行为中，已经在PET中看到了 糖尿病自主神经病变和心力衰竭患者的研究。 示踪剂动力学改变与特定神经元异常有关 一直很困难，因为神经功能的几个假设性变化 可能会引起这样的变化。拟议研究的主要目标是 这些放射性示踪剂的动力学变化与特定神经元的相关性 糖尿病大鼠模型心脏交感神经元的变化 自主神经病变和心力衰竭。拟议的研究将建立在 在孤立的工作中进行的动力学研究的现有基础 老鼠心。糖尿病大鼠模型心脏的动力学研究 心力衰竭将被用来评估示踪剂的敏感性 心脏交感神经病理改变的动力学研究 人口。在示踪剂动力学研究之后，直接在体外 对心脏交感神经元几个关键成分的测量将 在相同的心脏中进行，以确定其程度和严重程度 病理引起的神经元改变。体外研究将包括 神经元性去甲肾上腺素转运体密度的测定 (Net)和囊泡单胺转运体(VMAT)以及组织 儿茶酚胺水平。通过确定动力学数据之间的相关性 以及体外发现，洞察到具体的潜在原因 可以获得示踪剂动力学中的扰动。此信息应为 帮助临床医生，他们正在研究心脏交感神经元 药物，以解释他们的临床发现。此外，这些研究 将提供有关这些疾病对 心脏交感神经种群。

DESCRIPTION: (Adapted from the applicant's abstract) The structurally related norepinephrine analogues [C-11]meta-hydroxyephedrine, [C-11]phenylephrine, and [C-11]epinephrine have been developed as radiotracers for non-invasive imaging studies of cardiac sympathetic innervation using positron emission tomography (PET). Striking alterations in the kinetic behavior of these neuronal tracers have been seen in PET studies of patients with diabetic autonomic neuropathy and heart failure. Associating the altered tracer kinetics with specific neuronal abnormalities has been difficult, as several hypothetical changes in neuronal function could cause such alterations. The major goal of the proposed studies is to correlate changes in the kinetics of these radiotracers to specific neuronal changes in cardiac sympathetic neurons using rat models of diabetic autonomic neuropathy and heart failure. The proposed studies will build on an existing foundation of kinetic studies performed in the isolated working rat heart. Kinetic studies in hearts isolated from rat models of diabetes and heart failure will be used to assess the sensitivity of the tracer kinetics to pathology-induced changes in cardiac sympathetic nerve populations. Following the tracer kinetic studies, direct in vitro measurements of several key components of cardiac sympathetic neurons will be performed in the same hearts to characterize the extent and severity of the pathology-induced neuronal changes. The in vitro studies will include determinations of the densities of neuronal norepinephrine transporters (NET) and vesicular monoamine transporters (VMAT), as well as tissue catecholamine levels. By identifying correlations between the kinetic data and the in vitro findings, insight into the specific underlying causes of perturbations in the tracer kinetics may be gained. This information should assist clinicians, who are studying cardiac sympathetic neurons with these agents, to interpret their clinical findings. In addition, these studies will provide new information concerning the affects of these diseases upon cardiac sympathetic nerve populations.