PET Imaging Probes Targeting Cardiac Parasympathetic Innervation

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Cardiac autonomic dysfunction is well documented in many types of heart disease and is frequently associated with regional destruction of cardiac nerve populations. This can produce neural mechanisms that contribute to the genesis of cardiac arrhythmias, tachycardia and fibrillation, conditions which often lead to sudden death. This process involves not only the extrinsic sympathetic and parasympathetic nerves, but also afferent sensory nerves and a rich network of intrinsic cardiac nerves. Our lab at the University of Michigan has previously developed radiotracers for imaging sympathetic nerves, including [123I]metaiodobenzylguanidine ([123I]MIBG) for planar scintigraphy, [11C]meta-hydroxyephedrine ([11C]HED) for PET imaging, and recently 4-[18F]fluoro- meta-hydroxyphenethylguanidine ([18F]4F-MHPG) for quantifying regional sympathetic nerve density using tracer kinetic analysis. Clinical trials with [123I]MIBG and [11C]HED in heart failure have shown that higher levels of sympathetic denervation are associated with a greatly elevated risk of sudden death, thus neuronal imaging may improve risk stratification of patients being staged for implantable cardioverter defibrillators. Despite the successes in imaging sympathetic nerves, a current unmet need is a useful tracer for parasympathetic nerves. This has been an elusive goal for many reasons. Cholinergic parasympathetic nerves are primarily localized in atrial tissues, including the AV and SA nodes, small structures that are hard to image with PET due to the partial volume effect. Also, parasympathetic nerve density in the ventricles is much lower than the sympathetic nerves. Nevertheless, with the high spatial resolution of current PET/CT systems and advanced techniques such as cardiac and respiratory gating, it should be possible to image parasympathetic nerves if a tracer with high neuronal uptake and low non-specific binding can be found. In this study, we will evaluate two approaches to achieving this goal. First, we will test radiolabeled analogs of homocholine, a ‘false neurotransmitter’ that is transported into parasympathetic nerve terminals by the choline transporter (ChT), acetylated by choline acetyltranferase (ChAT) into acetylhomocholine, which is then stored in vesicles by the vesicular acetylcholine transporter (VAChT). An advantage of homocholine over other radiolabeled choline analogs for cardiac imaging is the resistance of acetylhomocholine to metabolism by acetylcholinesterase (AChE). The second approach will target AChE, which is expressed extraneuronally near cholinergic nerves. Specifically, 11C- and 18F-labeled analogs of a series of potent AChE inhibitors with sub-nanomolar binding affinities will be studied. Compared with many other AChE inhibitors (e.g., tacrine, donepezil), these N,N'-diphenethylsulfamides have much lower log P values, which should minimize non-specific binding in the heart. In vitro assays, digital autoradiography, and small animal PET studies in rats and non-human primates will be used to assess these two approaches. A PET tracer capable of imaging cardiac parasympathetic nerves would be a valuable clinical tool for assessing disease-induced damage to this important nerve population in patients with heart diseases.