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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062399-04
Application #
6537559
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Balshaw, David M
Project Start
1999-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$368,650
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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