QUANTIFICATION OF HEART BETA ADRENERGIC RECEPTORS

心脏 β 肾上腺素能受体的定量

• 批准号: 6390304
• 负责人: RAYMOND F MUZIC
• 金额: $ 31.52万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390304
• 关键词: amphetamines; beta adrenergic receptor; beta antiadrenergic agent; biological models; computer simulation; denervation; heart; heart pharmacology; mathematical model; membrane transport proteins; model design /development; norepinephrine; pharmacokinetics; positron emission tomography; protein structure function; receptor binding; receptor expression; swine

DESCRIPTION: (Adapted from applicant's abstract): Health Relevance: Beta-adrenergic receptors (beta-ARs) play a fundamental role in the regulation of heart function. Changes in the amount and binding properties of beta-ARs are implicated in coronary heart disease, congestive and ischemic heart failure, cardiomyopathy, sudden death, arrhythmia, and mitral valve disease. Drugs that interact with the beta-ARs, beta-blockers, are widely prescribed to treat heart disease. Since the in vitro behavior of receptors often differs from their in vivo behavior, a method to assess beta-ARs in vivo is essential for improving our understanding and treatment of heart diseases. Moreover, a relatively noninvasive test could be used to assess patients individually. Proposed Work: a significant component of the tissue uptake of (S)-[18F]fluorocarazolol as measured by positron emission tomography (PET) reflects specific binding to beta-ARs. However, it also reflects nonspecific uptake, radioactive metabolites in the myocardium, and possibly uptake related to the norepinephrine transporter. Therefore, quantitative assessment of beta-AR specific binding and of beta-AR concentration requires a mathematical model of fluorocarazolol pharmacokinetics. To formulate this model, details of fluorocarazolol pharmacokinetics will be clarified via in vitro and in vivo experiments (Aims 1 to 2) and via computer simulation to compare compartmental and distributed pharmacokinetic models (Aim 3). A mathematical model of fluorocarazolol pharmacokinetics will be formulated in accordance with the results of Aims 1 to 3. This model will then be used to analyze PET data collected from pigs with normal and elevated concentrations of beta-AR. The validity of the model and its utility to assess beta-AR concentration and binding properties in vivo will be evaluated based on comparison to results obtained via in vitro assay of myocardial samples (Aim 4). Significance: Although [11C]CGP 12177 has been used to estimate myocardial beta-AR concentration in vivo, there are numerous advantages for using [18F]fluorocarazolol. Perhaps the most significant is that fluorocarazolol reaches internalized receptors whereas CGP 12177 does not. Completion of the proposed work could lead to a method for estimating the fraction of receptors that are internalized. It would entail two PET experiments using [18F]fluorocarazolol; one at baseline and one following administration of unlabeled 9commercially available) CGP 12177 to block surface receptors.

描述：（改编自申请人摘要）：健康相关性： β-肾上腺素能受体（β-AR）在调节 心脏功能。β-AR的数量和结合特性的变化是 与冠心病，充血性和缺血性心力衰竭， 心肌病、猝死、心律失常和二尖瓣疾病。的药物 与β受体相互作用，β受体阻滞剂，被广泛用于治疗心脏病 疾病由于受体在体外的行为通常与它们在体内的行为不同， 体内行为，体内评估β-AR的方法对于改善 我们对心脏病的理解和治疗。此外，相对 非侵入性测试可用于对患者进行个体评估。 拟议工作：组织摄取的重要组成部分 通过正电子发射断层扫描（PET）测量的（S）-[18 F]氟卡拉唑醇 反映了与β-AR的特异性结合。然而，它也反映了非特异性 摄取，心肌中的放射性代谢物，以及可能的摄取相关 去甲肾上腺素转运蛋白因此，定量评估 β-AR特异性结合和β-AR浓度的确定需要一个数学模型。 氟卡拉唑醇药代动力学模型。为了制定这一模型， 氟卡拉唑醇的药代动力学将通过体外和体内研究来阐明。 实验（目标1至2），并通过计算机模拟比较房室模型 和分布式药代动力学模型（目标3）。 氟卡拉唑醇药代动力学的数学模型将在 与目标1至3的结果一致。该模型将用于 分析从正常和升高浓度的猪中收集的PET数据， β-AR模型的有效性及其评估β-AR的效用 将基于以下因素评价体内浓度和结合特性： 与通过心肌样品的体外测定获得的结果的比较（目的 4）。 意义：虽然[11 C]CGP 12177已用于估计心肌 在体内的β-AR浓度，有许多优点，使用 [18F]氟卡拉唑醇。也许最重要的是氟卡拉唑醇 而CGP 12177不能。完成 拟议的工作可能导致一种方法，估计受体的分数， 这些都是内在的。这将需要两个PET实验， [18F]氟卡拉唑醇;基线时一次， 未标记的9个市售）CGP 12177来阻断表面受体。