The long term objective of this project is the development of new PET radiotracers for the study of abnormalities of the myocardium and its innervation in patients at risk for sudden cardiac death. Recognition of these abnormalities using the animal models of Project 2 will provide an important means of validation for new compounds, and will help to identity neuronal and biochemical markers of heart function which undergo disease-related changes detectable with PET. The discovery of tracers that can be of value in identifying early stage disease and assessment of effectiveness of therapeutic strategies, and their transfer into use in clinical imaging protocols, are the ultimate goals of this project. One specific goal is the design of novel radioligands for ATP-gated potassium channels (K/ATP), as possible markers of cardiac excitability and energy status. New 18F and 11C-analogs of benzopyran based K/ATP channel openers (KCO's), as well as K/ATP channel blockers (KCB's) will be synthesized and their cardiac binding properties in normal hearts and animal models of disease will be explored in conjunction with other projects in this SCOR application. We will test the hypothesis that disease-related perturbations of heart K/ATP activity can be visualized by radiotracer methods. This is the first effort to examine the important K/ATP regulatory component of excitable tissue in vivo with PET. A new quaternary muscarinic antagonist radioligand called N-[11C]methyl- (+)-2a-tropanyl benzilate (MTRB), which has previously been evaluated in normal rodents and dogs side by side with N-[11C]methyl-quinuclidinyl benzilate (MQNB), and found to have slower and tighter heart binding kinetics than MQNB in the open chest dog, will now be examined in disease models. Its sensitivity to detecting disease-related changes in changes in heart binding will be compared with that of the established muscarinic tracer MQNB, studies in Project 4. Second generation """"""""clinical"""""""" 18F-labeled muscarinic receptor ligands and 18F-catecholamine analogs will be developed which are more efficient to prepare that 11C-analogs, and can provide multiple patient tracer doses from a single sythesis. The precursor and labeling chemistry will be carried out, candidate ligands will be examined in animals, and validated compounds will be developed for eventual human use in a clinical setting.
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