Molecular imaging of cardiac sympathetic innervation by 11C-mHED and PET: from man to mouse?
Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using PET in humans. Small-animal PET should enable noninvasive quantitation of the sympathetic nervous system in mouse models of human disease. For mice, however, the radioactivity needed to give acceptable image quality may be associated with a mass of unlabeled compound sufficient to block the binding of radioligand to its target. The present study assesses the feasibility of using [N-methyl-(11)C]meta-hydroxyephedrine ((11)C-mHED) to measure norepinephrine reuptake in humans, to determine cardiac innervation in mice.


METHODS
Anesthetized mice were placed in a small-animal PET scanner. (11)C-mHED (containing 18% precursor metaraminol) was injected via a tail vein into each animal simultaneously. Fifteen minutes later, animals were injected with saline or metaraminol which competes with mHED for norepinephrine reuptake. (18)F-FDG was injected at 60 min to identify heart regions. After reconstruction of the list-mode data, radioactivity in myocardial regions was computed using in-house software, and time-activity curves were plotted.


RESULTS
Hearts were clearly visualized after injection of (11)C-mHED. Injection of metaraminol at doses less than 50 nmol x kg(-1) had no effect, whereas doses greater than 100 nmol x kg(-1) caused a dose-dependent loss of specifically bound radioactivity.


CONCLUSIONS
(11)C-mHED was successfully used to visualize and assess myocardial innervation in mice. Uptake of (11)C-mHED is displaceable by the false transmitter metaraminol. The total molar dose of metaraminol and (11)C-mHED must be considered in the analysis of PET data.
Law
Marilyn P
MP
Department of Nuclear Medicine, University Hospital, University of Münster, Münster, Germany. mplaw@uni-muenster.de
Schäfers
Klaus
K
Kopka
Klaus
K
Wagner
Stefan
S
Schober
Otmar
O
Schäfers
Michael
M
D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging* / Q000294:innervation*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008680:Metaraminol / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013045:Species Specificity; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging*
D000316:Adrenergic alpha-Agonists; D019275:Radiopharmaceuticals; C065363:3-hydroxyephedrine; D008680:Metaraminol; D004809:Ephedrine