QUANTIFICATION OF HEART BETA ADRENERGIC RECEPTORS

心脏 β 肾上腺素能受体的定量

• 批准号: 6184642
• 负责人: RAYMOND F MUZIC
• 金额: $ 30.82万
• 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/6184642
• 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：(改编自申请者摘要)：健康相关性： β-肾上腺素能受体(β-AR)在这一过程中起着重要的调节作用。 心脏功能的变化。β-AR的数量和结合性质的变化是 与冠心病、充血性和缺血性心力衰竭有关， 心肌病、猝死、心律失常和二尖瓣病变。毒品，即 与β-受体相互作用，β-受体阻滞剂被广泛用于治疗心脏 疾病。因为受体的体外行为往往与其体内的不同 活体行为，一种评估体内β-受体的方法对于改善 我们对心脏病的认识和治疗。而且，相对来说，一个 无创检测可用于对患者进行个体化评估。 拟议工作：组织摄取的一个重要组成部分 正电子发射体层摄影法测定(S)-[18F]氟卡唑 反映与β-AR的特异性结合。然而，它也反映了非特定的 心肌中放射性代谢物的摄取，以及可能与摄取相关的 去甲肾上腺素转运体。因此，量化评估是一项重要的工作 β-AR的特异性结合和β-AR浓度需要数学上的 氟卡唑的药代动力学模型。为了制定这一模型，详细说明 氟卡唑的体外和体内药代动力学研究 实验(目标1至2)和通过计算机模拟来比较隔室 和分布式药代动力学模型(目标3)。 氟卡唑药代动力学的数学模型将在#年建立。 与目标1至3的结果一致。然后，该模型将用于 分析从浓度正常和升高的猪身上收集的PET数据 β-AR。模型的有效性及其在评估β-AR中的应用 体内的浓度和结合特性将基于以下各项进行评估 与心肌样品体外检测结果的比较(AIM 4)。 意义：虽然[11C]cgp 12177已被用于估计心肌梗死面积 在体内的β-AR浓度，有很多优点使用 [18F]氟卡唑醇。也许最重要的是氟卡唑醇 可到达内化受体，而CGp 12177不能。已完成的 拟议的工作可能会导致一种估计受体比例的方法 这些都是内化的。这将需要两次PET实验，使用 [18F]氟卡唑醇；一次在基线，一次在给药后 未标记的9市售)Cgp 12177以阻断表面受体。