The main focus of this project has been the development of radiotracers for the noninvasive assessment of cardiac sympathetic nerve function using scintigraphic imaging. Our laboratory has previously developed several successful tracers for cardiac sympathetic neurons, including [123I]meta-iodobenzylguanidine (MIBG) for SPECT imaging and [11C]meta-hydroxyephedrine (HED) and [11C]epinephrine (EPI) for PET imaging. All of these tracers are rapidly transported into cardiac sympathetic neurons as substrates of the norepinephrine transporter (NET), and then taken up into vesicles by the vesicular monoamine transporter (VMAT2). While the rapid neuronal uptake of these agents results in high quality heart images, their neuronal uptake rates are so fast that compartmental modeling of their kinetics fails. This also causes measures of tracer retention to be insensitive to nerve losses until those losses become severe. We believe this obstacle to accurate quantification can only be overcome with new kinetically superior, more information-rich tracers that possess optimal kinetics for tracer kinetic analyses. Such tracers would provide more accurate and sensitive measures of regional nerve density, allowing detection of denervation earlier in the course of diseases that cause nerve damage, such as diabetic autonomic neuropathy and heart failure. Early detection of denervation may be clinically important in terms of providing patients with effective therapies to halt or reverse denervation. In the last project period, we hypothesized that a radiolabeled NET substrate must possess two kinetic properties to be `ideal'for tracer kinetic analyses: (1) a slower neuronal uptake rate, and (2) a very long neuronal retention time, through efficient vesicular storage. We had further hypothesized that a tracer with these properties could be found among the many guanidines known to exert potent pharmacological effects on sympathetic neurons. Studies of 11C-phenethylguanidines yielded several compounds with the desired kinetic properties. N-[11C]guanyl-( )-meta-octopamine (GMO) emerged as the most promising 11C-labeled agent, while encouraging results with 4-fluoro- and 6-fluoro-meta-hydroxyphenethylguanidine (4F-MHPG, 6F-MHPG) support the development of these compounds into 18F-labeled tracers. In the current proposal, a major goal is to perform imaging studies of GMO in monkeys with microPET to assess its suitability for quantitative PET studies in humans. A second major goal is to prepare and evaluate 18F-labeled 4F-MHPG and 6F-MHPG. Also, work on radiolabeled guanidines will extend to two new series based on 2-(2-pyrindinyl)ethylguanidine and guanoxan. These new series include structures with ring fluorine substitutions as part of ongoing efforts to develop an optimal 18F-labeled tracer. Tracer bioevaluation methods will include kinetic studies in isolated rat heart, biodistribution and metabolism studies in rats, assays of NET and VMAT2 transport kinetics in cells, and metabolism and microPET studies in monkeys. This systematic study of 11C- and 18F-guanidines should result in the development of a tracer with optimal kinetics for quantifying cardiac sympathetic nerve density with PET.

Public Health Relevance

Many diseases, including diabetes, heart failure, heart attacks (infarction) and Parkinson's disease are known to cause severe damage to the nerves of the heart, which may contribute to sudden cardiac death. The main goal of this project is to develop nuclear medicine imaging studies that can be used by doctors to take pictures of the damage to the nerves of the heart in patients with these diseases. These imaging studies will help doctors understand how the nerves of the heart are damaged in diseases, and also can be used to study if the nerve damage can be stopped or reversed with new drug therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079540-27
Application #
7810736
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Danthi, Narasimhan
Project Start
1981-08-01
Project End
2012-05-30
Budget Start
2010-05-31
Budget End
2011-05-30
Support Year
27
Fiscal Year
2010
Total Cost
$382,492
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Jang, Keun Sam; Jung, Yong-Woon; Gu, Guie et al. (2013) 4-[18F]Fluoro-m-hydroxyphenethylguanidine: a radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography. J Med Chem 56:7312-23
Raffel, David M; Chen, Wei; Jung, Yong-Woon et al. (2013) Radiotracers for cardiac sympathetic innervation: transport kinetics and binding affinities for the human norepinephrine transporter. Nucl Med Biol 40:331-7
Jang, Keun Sam; Jung, Yong-Woon; Sherman, Phillip S et al. (2013) Synthesis and bioevaluation of [(18)F]4-fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG): a novel radiotracer for quantitative PET studies of cardiac sympathetic innervation. Bioorg Med Chem Lett 23:1612-6
Raffel, David M; Koeppe, Robert A; Jung, Yong-Woon et al. (2013) Quantification of cardiac sympathetic nerve density with N-11C-guanyl-meta-octopamine and tracer kinetic analysis. J Nucl Med 54:1645-52
Swaminathan, Shanker; Shen, Li; Risacher, Shannon L et al. (2012) Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Brain Imaging Behav 6:1-15
Wong, Ka Kit; Raffel, David M; Koeppe, Robert A et al. (2012) Pattern of cardiac sympathetic denervation in idiopathic Parkinson disease studied with 11C hydroxyephedrine PET. Radiology 265:240-7
Chou, Kelvin L; Koeppe, Robert A; Bohnen, Nicolaas I (2011) Rhinorrhea: a common nondopaminergic feature of Parkinson's disease. Mov Disord 26:320-3
Gilman, S; Koeppe, R A; Nan, B et al. (2010) Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes. Neurology 74:1416-23
Bohnen, N I; Müller, M L T M; Koeppe, R A et al. (2009) History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73:1670-6
Raffel, David M; Jung, Yong-Woon; Gildersleeve, David L et al. (2007) Radiolabeled phenethylguanidines: novel imaging agents for cardiac sympathetic neurons and adrenergic tumors. J Med Chem 50:2078-88

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