The intent of this research is to develop a myocardial imaging agent that localizes selectively in the adrenergic nerves of the heart. Despite the physiological importance of norepinephrine (NE) as an adrenergic transmitter, no radiopharmaceutical exists that can assess catecholamine accumulation and turnover in peripheral tissue. This proposal focuses on radioiodinated derivatives of aminobenzylguanidine and F-18-analogs of 3,4-dihydroxybenzylguanidine. These radiotracers are designed not to be substrates for monoamine oxidase or catechol-O-methyltransferase. Optimally they will redistribute in the heart over time to reflect true adrenergic nerve density rather than an adrenergic nerve pattern determined by initial myocardial blood flow, as is apparently the case with exogenous NE. The following methods will be used: 1. Synthesis of 22 aminobenzylguanidines, hydroxybenzylguanidines, catecholguanidines or catecholguanidine cogeners radiolabeled with either H-3, F-18 or I-125. 2. Performance of a structure-tissue distribution-relationship study with these radiotracers in dogs that screens for selective concentration in the heart and other adrenergic-rich tissue. 3. Determination of the neuronal selectivity of promising radiotracers in the heart by means of 6-hydroxydopamine sympathectomy studies. 4. Assessment of the regional heart distribution and its correlation with the endogenous NE concentration pattern. 5. Performance of cellular and metabolism studies which help determine the mechanism(s) and kinetics of heart localization.
Showing the most recent 10 out of 33 publications
