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

Abstract

Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as 123 Imetaiodobenzylguanidine ( 123 I-MIBG) and 11 C-(-)-meta-hydroxyephedrine ( 11 C-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-11 C-guanyl-(-)-meta-octopamine ( 11 C-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 11 C-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 11 C-GMO kinetics yielded estimates of the rate constants K 1 (mL/min/g), k 2 (min 21 ), and k 3 (min 21 ). These values were used to calculate a net uptake rate con-. In addition, Patlak graphical analyses of 11 C-GMO kinetics yielded Patlak slopes K p (mL/min/g), which represent alternative measurements of the net uptake rate constant K i . 11 C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. Results: In isolated rat hearts, the neuronal uptake rate of 11 C-GMO was 8 times slower than 11 C-HED and 12 times slower than 11 C-MIBG. 11 C-GMO also had a long neuronal retention time (.200 h). Compartmental modeling of 11 C-GMO kinetics in the monkey heart proved stable under all conditions. Calculated net uptake rate constants K i tracked desipramine-induced reductions of available NET in a dose-dependent manner, with a half maximal inhibitory concentration (IC 50 ) of 0.087 6 0.012 mg of desipramine per kilogram. Patlak analysis provided highly linear Patlak plots, and the Patlak slopes K p also declined in a dose-dependent manner (IC 50 5 0.068 6 0.010 mg of desipramine per kilogram). Conclusion: Compartmental modeling and Patlak analysis of 11 C-GMO kinetics each provided quantitative parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with 11 C-GMO can provide robust and sensitive quantitative measures of regional cardiac sympathetic nerve densities in human hearts. It has been more than 30 y since radioiodinated metaiodobenzylguanidine (MIBG) was first introduced for scintigraphic imaging of cardiac sympathetic innervation (1). Since then, several other radiotracers, including 11 C-(-)-meta-hydroxyephedrine ( 11 C-HED) and 11 C-(-)-epinephrine ( 11 C-EPI), have been developed to assess cardiac sympathetic nerve integrity with PET (2). Clinical studies with these tracers have made significant contributions to our understanding of cardiac sympathetic dysfunction in many diseases (3). In addition, recent...

[18F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

“…This was better heart-to-blood contrast than the ratio measured for [ 18 F] 1 , which was H/B = 3.0 ± 0.5. 17, 18 Final heart-to-liver (H/L) ratios for [ 18 F] 2 were 2.2 ± 0.8. Due to faster clearance of activity from the liver, contrast between heart and liver was a little better for [ 18 F] 1 , with final H/L = 2.5 ± 0.3.…”

“…The slower neuronal uptake rate makes the rate constant associated with this process more identifiable from the cardiac PET kinetics, and the rapid uptake and long retention in storage vesicles eliminates one rate constant from the kinetic model, leading to more reliable and consistent parameter estimates. 17 …”

“…PET studies with [ 11 C]GMO in non-human primates showed that the myocardial kinetics of this tracer could be successfully analyzed using compartmental modeling methods or Patlak graphical analysis to obtain an estimates of the ‘net uptake rate constant’ K i (mL/min/g) as a measure of regional sympathetic nerve density. 17 In control studies and pharmacological blocking studies with the NET inhibitor desipramine (DMI) in rhesus macaque monkeys, the K i values from compartmental modeling analysis were found to decrease with increasing DMI doses along a sigmoidal dose-response curve, with an IC 50 of 0.087 mg/kg and a Hill slope n H = –0.70. Similar results were obtained using the Patlak slopes K p (mL/min/g) from Patlak graphical analysis of [ 11 C]GMO kinetics, as an alternative estimate of the K i values (IC 50 = 0.068 mg/kg, n H = –0.54).…”

Advanced Tracers in PET Imaging of Cardiovascular Disease

“…However, PET imaging with [ 11 C]HED cannot accurately quantify regional nerve densities due to the rapid neuronal uptake rates. Raffel et al [ 116 ] recently synthesized N- 11 C-guanyl-(-)-meta-octopamine ([ 11 C]GMO), which has a much slower NET transport rate and is trapped in storage vesicles. Initial results have shown that [ 11 C]GMO provides robust and sensitive quantitative measurements of regional cardiac sympathetic nerve density and might be able to detect mild-to-moderate sympathetic nerve loss at the early stages of cardiac denervation.…”

Imaging of the Cardiac Sympathetic Nervous System Has Potential Value in the Evaluation of Patients with Heart Failure with Preserved Ejection Fraction

“…Therefore, an important limitation to this study is the use of the semiquantitative RI. Along these lines, it has been debated that the 11 C-HED RI may not be sensitive enough to detect mild-to-moderate nerve loss (29). Recently, a fully quantitative kinetic model has been established for 11 C-HED (30) and confirmed that the quantitative parameter, volume of distribution, is nonlinearly related to SUV and RI, especially in the setting of lower radiotracer uptake.…”