The intent of this research is to develop an imaging approach with positron emission tomography to quantitatively characterize the adrenergic innervation of the heart. Despite the physiological importance of norepinephrine (NE) as an adrenergic transmitter, no radiopharmaceutical exists that can quantitatively and non- invasively assess catecholamine accumulation and turnover in peripheral tissue. The work proposed for the next 5 years will focus on the radiosynthesis of true and false neurotransmitters and the use of these tracers to map cardiac neurophysiology in experimental and clinical studies. NE and a select number of false transmitters will be F-18-labeled and tested for their ability to serve as anatomical and functional neuronal mapping agents. False transmitters to be studied include: p-hydroxynorephedrine, octopamine, m-octopamine, and m-hydroxyamphetamine. Factors that will affect tracer choice are: 1) ease of synthesis; 2) specific activity requirements mandated by pharmacological potency; 3) metabolic fate; 4) informational content. The tracers will be validated first in animal experiments. In vivo tissue distribution, pretreatment studies with the uptake 1 blocker desmethylimipramine and chemical sympathectomy studies with 6-hydroxydopamine will determine the global accumulation in and selectivity for adrenergic nerves. Radio-HPLC analysis of blood and heart following i.v. tracer injection will be used to determine extent of metabolism and arterial input function. Correlation of tracer accumulation with tissue norepinephrine distribution in normal and regionally denervated heart will be performed in the dog. Based on first pass kinetics of myocardial uptake and turnover, a tracer kinetic model will be derived to quantitate regional sympathetic function. Applications will include determining the dependence of F-18-tracer depletion on time period and severity of ischemia, the time course of restoration of tracer following ischemic insult, and correlation of regional depletion of tracer with electrophysiological parameters such as conduction velocity and inducible arrhythmias. Clinical applications will include mapping the normal distribution of the heart adrenergic system, its reproducibility, and its relationship to age and cardiac work. The study of patients with cardiac transplants, diabetic neuropathy, acute infarction, unstable angina and congestive heart failure will be pursued.
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