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.
