The intent of this proposal is to develop positron-emitting tracers to characterize both the sympathetic and parasympathetic innervation of the heart. The false adrenergic neurotransmitter [11C]meta-hydroxyephedrine (MHED), developed during the present grant period, has been successfully used to map the sympathetic nerve density of the human heart. This proposal will focus initially on developing analogs of MHED and biogenic catecholamines that: 1) are more resistant to metabolism; 2) can be readily labeled with [18F]fluoride; and 3) enhance the application of tracer kinetic modeling. A major new initiative will seek to develop presynaptic cholinergic markers based on the potent acetylcholine storage blocking drug benzovesamicol (BVM). Structural modifications of [11C]- and [18F]BVM will be made to decrease tracer uptake in non-target tissues such as blood and lung. A minor study will be aimed at testing the feasibility of mapping myocardial postsynaptic beta-adrenoceptor density with [11C]esmolol, a cardioselective, intravenous beta-blocker with an ultra- short action that is kinetically compatible with the 20 minute half-life of 11C. The heart affinity and mechanism of localization of tracers developed in this proposal will be determined by in vivo experiments in animals. Tissue distribution studies, drug blocking protocols, and global and regional denervated heart models will be used to asses neuronal sensitivity. Radio- HPLC analysis of blood and heart following i.v. tracer injection will be used to determine extent of metabolism and arterial input function. Based on first-pass kinetics of myocardial uptake and turnover, tracer kinetic models will be derived to quantitate regional neuronal function.
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