HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raffel, D. M. Articles by Wieland, D. M. Search for Related Content PubMed PubMed Citation Articles by Raffel, D. M. Articles by Wieland, D. M.

Sensitivity of [¹¹C] Phenylephrine Kinetics to Monoamine Oxidase Activity in Normal Human Heart

Cyclotron/PET Facility, Division of Nuclear Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence: For correspondence or reprints contact: David M. Raffel, PhD, Cyclotron/PET Facility, 3480 Kresge III Building, University of Michigan, Ann Arbor, MI 48109-0552.

ABSTRACT

Phenylephrine labeled with ¹¹C was developed as a radiotracer for imaging studies of cardiac sympathetic nerves with PET. A structural analog of norepinephrine, (–)-[¹¹C] phenylephrine (PHEN) is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and stored invesicles. PHEN is also a substrate for monoamine oxidase (MAO). The goal of this study was to assess the importance of neuronal MAO activity on the kinetics of PHEN in the normal human heart. MAO metabolism of PHEN was inhibited at the tracer level by substituting deuterium atoms for the two hydrogen atoms at the -carbon side chain position to yield the MAO-resistant analog D2-PHEN. Methods: Paired PET studies of PHEN and D2-PHEN were performed in six normal volunteers. Hemodynamic and electrocardiographic responses were monitored. Blood levels of intact radiotracer and radiolabeled metabolites were measured in venous samples taken during the 60 min dynamic PET study. Myocardial retention of the tracers was regionally quantified as a retention index. Tracer efflux between 6 and 50 min after tracer injection was fit to a single exponential process to obtain a washout half-time for all left ventricular regions. Results: Although initial heart uptake of the two tracers was similar, D2-PHEN cleared from the heart 2.6 times more slowly than PHEN (mean half-time 155 ± 52 versus 55 ± 10 min, respectively; P < 0.01). Correspondingly, heart retention of D2-PHEN at 40–60 min after tracer injection was higher than PHEN (mean retention indices 0.086 ± 0.018 versus 0.066 ± 0.011 mL blood/min/mL tissue, respectively; P < 0.003). Conclusion: Efflux of radioactivity from normal human heart after uptake of PHEN is primarily due to metabolism of the tracer by neuronal MAO. Related mechanistic studies in the isolated rat heart indicate that vesicular storage of PHEN protects the tracer from rapid metabolism by neuronal MAO, suggesting that MAO metabolism of PHEN leaking from storage vesicles leads to the gradual loss of PHEN from the neurons. Thus, although MAO metabolism influences the rate of clearance of PHEN from the neurons, MAO metabolism is not the rate-determining step in the observed efflux rate under normal conditions. Rather, the rate at which PHEN leaks from storage vesicles is likely to be the rate-limiting step in the observed efflux rate.

Key Words: ¹¹C-phenylephrine • monoamine oxidase • norepinephrine transporter • sympathetic nervous system • PET

This article has been cited by other articles:

				D. N. Tipre, J. J. Fox, D. P. Holt, G. Green, J. Yu, M. Pomper, R. F. Dannals, and F. M. Bengel In Vivo PET Imaging of Cardiac Presynaptic Sympathoneuronal Mechanisms in the Rat J. Nucl. Med., July 1, 2008; 49(7): 1189 - 1195. [Abstract] [Full Text] [PDF]

				J. S. Fowler, J. Logan, G.-J. Wang, N. D. Volkow, W. Zhu, D. Franceschi, N. Pappas, R. Ferrieri, C. Shea, V. Garza, et al. PET Imaging of Monoamine Oxidase B in Peripheral Organs in Humans J. Nucl. Med., October 1, 2002; 43(10): 1331 - 1338. [Abstract] [Full Text] [PDF]