TY - JOUR T1 - Quantification of Cardiac Sympathetic Nerve Density with <em>N</em>-<sup>11</sup>C-Guanyl-<em>meta</em>-Octopamine and Tracer Kinetic Analysis JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.113.120659 SP - jnumed.113.120659 AU - David M. Raffel AU - Robert A. Koeppe AU - Yong-Woon Jung AU - Guie Gu AU - Keun Sam Jang AU - Phillip S. Sherman AU - Carole A. Quesada Y1 - 2013/09/01 UR - http://jnm.snmjournals.org/content/early/2013/07/23/jnumed.113.120659.abstract N2 - 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 (&gt;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. ER -