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（β-AR）在调节中发挥重要作用 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有关， 心肌病、猝死、心律失常和二尖瓣疾病。药物 与 β-AR 相互作用，β-受体阻滞剂被广泛用于治疗心脏病 疾病。由于受体的体外行为通常与其体内行为不同 体内行为，一种体内评估 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 无创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 通过正电子发射断层扫描 (PET) 测量的 (S)-[18F]氟咔唑 反映了与 β-AR 的特异性结合。但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 浓度需要数学计算 氟卡拉唑尔药代动力学模型。为了制定这个模型，详细信息 氟咔唑洛尔药代动力学将通过体外和体内阐明 实验（目标 1 至 2）并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）。 氟卡拉唑尔药代动力学的数学模型将在 与目标 1 至 3 的结果一致。然后该模型将用于 分析从正常和升高浓度的猪身上收集的 PET 数据 β-AR。该模型的有效性及其评估 beta-AR 的实用性 体内浓度和结合特性将根据 与通过心肌样本体外测定获得的结果进行比较（目标 4). 意义：虽然 [11C]CGP 12177 已被用于估计心肌 体内β-AR浓度，使用有许多优点 [18F]氟咔唑醇。也许最重要的是氟咔唑 到达内化受体，而 CGP 12177 则不能。完成 拟议的工作可能会产生一种估计受体比例的方法 是内化的。这需要使用两次 PET 实验 [18F]氟咔唑醇；一项在基线时，一项在给药后 未标记的 9 市售）CGP 12177 可阻断表面受体。