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¹¹C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

Correspondence: For correspondence or reprints contact: Sami S. Zoghbi, PhD, National Institute of Mental Health/National Institutes of Health, Molecular Imaging Branch, 31 Center Dr., Room B2-B37, MSC 2035, Bethesda, MD 20892-0135. E-mail: sami.zoghbi{at}nih.gov

Loperamide, an opiate receptor agonist, does not cross the blood–brain barrier because it is a substrate for the permeability-glycoprotein (P-gp) efflux pump. We evaluated ¹¹C-loperamide as a PET radiotracer to measure P-gp function in vivo. Methods: Monkeys were injected with ¹¹C-loperamide, and PET brain images were acquired for 120 min. The baseline scans were followed by scans acquired after administration of either of 2 P-gp inhibitors, (2R)-anti-5-{3-[4-(10,11-dichloromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (DCPQ) or tariquidar. Both the PET scans and ex vivo measurements were obtained in P-gp knockout and wild-type mice. Results: Pharmacologic inhibition of P-gp in monkeys dose-dependently increased brain activity, with a 3.7-fold effect at the highest DCPQ dose (8 mg/kg intravenously). This increase of brain activity was not caused peripherally, because DCPQ insignificantly changed the plasma concentration and plasma protein binding of radiotracer. Furthermore, the structurally dissimilar inhibitor, tariquidar, also increased brain uptake with potency equal to that of DCPQ. P-gp knockout mice had 3-fold higher brain activity on PET than did wild-type animals. Four radiometabolites were detected in the plasma and brains of ex vivo mice. The most lipophilic radiometabolite was found to be comobile with reference dLop on high-performance liquid chromatography. The brain concentrations of ¹¹C-loperamide and the putative ¹¹C-dLop were about 16-fold greater in P-gp knockout mice than in wild-type mice. Conclusion: Both ¹¹C-loperamide and its putative radiometabolite ¹¹C-dLop are avid P-gp substrates. ¹¹C-dLop may be superior to ¹¹C-loperamide in measuring P-gp function at the blood–brain barrier, because further demethylation of ¹¹C-dLop will generate radiometabolites that have little entry into the brain.

Key Words: ¹¹C-loperamide • P-gp • brain efflux pump • PET • blood–brain barrier

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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