Quantification of Cardiac Sympathetic Nerve Density with N-11C-Guanyl-meta-Octopamine and Tracer Kinetic Analysis

Journal of Nuclear Medicine

Keun Sam Jang¹  Guie Gu¹  Phillip S. Sherman¹  David M. Raffel¹  Carole A. Quesada¹  Robert A. Koeppe¹  Yong-Woon Jung¹ 

[1] Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan

关键词: norepinephrine transporter;    hydroxyephedrine;    metaiodobenzylguanidine;    positron emission tomography;   

DOI  :  10.2967/jnumed.113.120659

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as 123I-metaiodobenzylguanidine (123I-MIBG) and 11C-(–)-meta-hydroxyephedrine (11C-HED) are flow-limited tracers because of their rapid NET transport rates. This prevents successful application of kinetic analysis techniques and causes semiquantitative measures of tracer retention to be insensitive to mild-to-moderate nerve losses. N-11C-guanyl-(–)-meta-octopamine (11C-GMO) has a much slower NET transport rate and is trapped in storage vesicles. The goal of this study was to determine whether analyses of 11C-GMO kinetics could provide robust and sensitive measures of regional cardiac sympathetic nerve densities. Methods: PET studies were performed in a rhesus macaque monkey under control conditions or after intravenous infusion of the NET inhibitor desipramine (DMI). Five desipramine dose levels were used to establish a range of available cardiac NET levels. Compartmental modeling of 11C-GMO kinetics yielded estimates of the rate constants K1 (mL/min/g), k2 (min−1), and k3 (min−1). These values were used to calculate a net uptake rate constant Ki (mL/min/g) = (K1k3)/(k2 + k3). In addition, Patlak graphical analyses of 11C-GMO kinetics yielded Patlak slopes Kp (mL/min/g), which represent alternative measurements of the net uptake rate constant Ki. 11C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. Results: In isolated rat hearts, the neuronal uptake rate of 11C-GMO was 8 times slower than 11C-HED and 12 times slower than 11C-MIBG. 11C-GMO also had a long neuronal retention time (>200 h). Compartmental modeling of 11C-GMO kinetics in the monkey heart proved stable under all conditions. Calculated net uptake rate constants Ki tracked desipramine-induced reductions of available NET in a dose-dependent manner, with a half maximal inhibitory concentration (IC50) of 0.087 ± 0.012 mg of desipramine per kilogram. Patlak analysis provided highly linear Patlak plots, and the Patlak slopes Kp also declined in a dose-dependent manner (IC50 = 0.068 ± 0.010 mg of desipramine per kilogram). Conclusion: Compartmental modeling and Patlak analysis of 11C-GMO kinetics each provided quantitative parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with 11C-GMO can provide robust and sensitive quantitative measures of regional cardiac sympathetic nerve densities in human hearts.

【 授权许可】

Unknown