title: 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)I-metaiodobenzylguanidine ((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 K1 (mL/min/g), k2 (min(-1)), and k3 (min(-1)). These values were used to calculate a net uptake rate constant K(i) (mL/min/g) = (K1k3)/(k2 + k3). 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 (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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, USA. raffel@umich.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Raffel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: Yong-Woon
authors.initials: YW
authors.lastname: Jung
authors.forename: Guie
authors.initials: G
authors.lastname: Gu
authors.forename: Keun Sam
authors.initials: KS
authors.lastname: Jang
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Sherman
authors.forename: Carole A
authors.initials: CA
authors.lastname: Quesada
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging* / Q000294:innervation*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009655:Octopamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging* / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; C520642:N-guanyl-m-octopamine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D009655:Octopamine; D006147:Guanine
keywords: hydroxyephedrine; metaiodobenzylguanidine; norepinephrine transporter; positron emission tomography