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First published online September 14, 2007, 10.2967/jnumed.107.040279
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Journal of Nuclear Medicine Vol. 48 No. 10 1724-1732
© 2007 by Society of Nuclear Medicine
doi: 10.2967/jnumed.107.040279

Basic Science Investigation

PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (–)-Cocaine

Joanna S. Fowler1–3,, Carsten Kroll4, Richard Ferrieri1, David Alexoff1, Jean Logan1, Stephen L. Dewey1, Wynne Schiffer1, David Schlyer1, Pauline Carter1, Payton King1, Colleen Shea1, Youwen Xu1, Lisa Muench5, Helene Benveniste1,6, Paul Vaska1 and Nora D. Volkow5,7

1 Brookhaven National Laboratory, Upton, New York; 2 Mount Sinai School of Medicine, New York, New York; 3 Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York; 4 University of Mainz, Mainz, Germany; 5 National Institute on Alcoholism and Alcohol Abuse, Rockville, Maryland; 6 Department of Anesthesiology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York; and 7 National Institute on Drug Abuse, Rockville, Maryland

Correspondence: For correspondence or reprints contact: Joanna S. Fowler, PhD, Medical Department, Bldg. 555, Brookhaven National Laboratory, P.O. Box 5000, Upton, NY 11973. E-mail: fowler{at}bnl.gov

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (–)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods: d- and l-methamphetamine and (–)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2–3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(–)-cocaine in both brain and peripheral organs in the same animal. Results: 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(–)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(–)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for 11C-d-methamphetamine. Conclusion: Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for the more intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of 11C-d-methamphetamine and 11C-(–)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (–)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolites may account for the reported renal toxicity of d-methamphetamine in humans.

Key Words: PET • methamphetamine • 11C • brain • peripheral organs

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.


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