QUANTIFICATION OF HEART BETA ADRENERGIC RECEPTORS

心脏 β 肾上腺素能受体的定量

• 批准号: 2831257
• 负责人: RAYMOND F MUZIC
• 金额: $ 34.69万
• 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/2831257
• 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：（改编自申请人的摘要）：健康相关性： β-肾上腺素能受体（Beta-ARS）在调节中起着基本作用 心脏功能。 Beta-AR的数量和结合特性的变化是 与冠心病有关，充血和缺血性心力衰竭， 心肌病，猝死，心律不齐和二尖瓣疾病。吸毒 与Beta-ARS相互作用，Beta-Blockers被广泛规定以治疗心脏 疾病。由于受体的体外行为通常与他们的体外不同 体内行为，一种评估体内β-ARS的方法对于改进 我们对心脏病的理解和治疗。而且，相对 非侵入性测试可用于单独评估患者。 拟议的工作：组织吸收的重要组成部分 （S） - [18F]通过正电子发射断层扫描（PET）测量的氟卡唑醇 反映了特定的与β-ARS的结合。但是，它也反映了非特异性的 摄取心肌中的放射性代谢物，并可能与摄取有关 到去甲肾上腺素转运蛋白。因此，定量评估 beta-ar特定的结合和β-ar浓度需要数学 氟卡唑药代动力学的模型。为了制定此模型， 将通过体外和体内阐明氟卡唑药物动力学 实验（目标1到2）和通过计算机模拟比较隔室 和分布式药代动力学模型（AIM 3）。 氟瓜唑酚药代动力学的数学模型将在 根据目标1到3的结果。然后，此模型将用于 分析从正常和浓度升高的猪收集的PET数据 beta-ar。该模型的有效性及其评估Beta-AR的实用性 将根据体内的浓度和结合特性根据 与通过心肌样品的体外测定获得的结果进行比较（AI​​M 4）。 意义：尽管[11C] CGP 12177已用于估计心肌 Beta-Ar浓度在体内，使用许多优点 [18F]氟瓜唑酚。也许最重要的是氟卡唑醇 到达内部化受体，而CGP 12177则没有。完成 拟议的工作可能导致一种估计受体分数的方法 被内在化。它需要使用两个宠物实验 [18F]氟瓜唑酚；一个在基线，一个以下管理 未标记的9售货）CGP 12177可阻止表面受体。