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OtherBASIC SCIENCE INVESTIGATIONS

P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using 11C-N-Desmethyl-Loperamide in Monkeys

Jeih-San Liow, William Kreisl, Sami S. Zoghbi, Neva Lazarova, Nicholas Seneca, Robert L. Gladding, Andrew Taku, Peter Herscovitch, Victor W. Pike and Robert B. Innis
Journal of Nuclear Medicine January 2009, 50 (1) 108-115; DOI: https://doi.org/10.2967/jnumed.108.056226
Jeih-San Liow
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William Kreisl
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Sami S. Zoghbi
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Neva Lazarova
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Nicholas Seneca
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Robert L. Gladding
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Andrew Taku
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Peter Herscovitch
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Victor W. Pike
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Robert B. Innis
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Abstract

11C-Loperamide is an avid substrate for P-glycoprotein (P-gp), but it is rapidly metabolized to 11C-N-desmethyl-loperamide (11C-dLop), which is also a substrate for P-gp and thereby contaminates the radioactive signal in the brain. Should further demethylation of 11C-dLop occur, radiometabolites with low entry into the brain are generated. Therefore, we evaluated the ability of 11C-dLop to quantify the function of P-gp at the blood–brain barrier in monkeys. Methods: Six monkeys underwent 12 PET scans of the brain, 5 at baseline and 7 after pharmacologic blockade of P-gp. A subset of monkeys also underwent PET scans with 15O-water to measure cerebral blood flow. To determine whether P-gp blockade affected peripheral distribution of 11C-dLop, we measured whole-body biodistribution in 4 monkeys at baseline and after P-gp blockade. Results: The concentration of 11C-dLop in the brain was low under baseline conditions and increased 5-fold after P-gp blockade. This increase was primarily caused by an increased rate of entry into the brain rather than a decreased rate of removal from the brain. With P-gp blockade, uptake of radioactivity among brain regions correlated linearly with blood flow, suggesting a high single-pass extraction. After correction for cerebral blood flow, the uptake of 11C-dLop was fairly uniform among brain regions, suggesting that the function of P-gp is fairly uniformly distributed in the brain. On whole-body imaging, P-gp blockade significantly affected distribution of radioactivity only to the brain and not to other visually identified source organs. The effective dose estimated for humans was approximately 9 μSv/MBq. Conclusion: PET with 11C-dLop can quantify P-gp function at the blood–brain barrier in monkeys. The single-pass extraction of 11C-dLop is high and requires correction for blood flow to accurately measure the function of this efflux transporter. The low uptake at baseline and markedly increased uptake after P-gp blockade suggest that 11C-dLop will be useful to measure a wide range of P-gp functions at the blood–brain barrier in humans.

  • molecular imaging
  • radiotracer tissue kinetics
  • P-glycoprotein
  • loperamide
  • PET

Footnotes

  • COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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Journal of Nuclear Medicine: 50 (1)
Journal of Nuclear Medicine
Vol. 50, Issue 1
January 2009
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P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using 11C-N-Desmethyl-Loperamide in Monkeys
Jeih-San Liow, William Kreisl, Sami S. Zoghbi, Neva Lazarova, Nicholas Seneca, Robert L. Gladding, Andrew Taku, Peter Herscovitch, Victor W. Pike, Robert B. Innis
Journal of Nuclear Medicine Jan 2009, 50 (1) 108-115; DOI: 10.2967/jnumed.108.056226

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P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using 11C-N-Desmethyl-Loperamide in Monkeys
Jeih-San Liow, William Kreisl, Sami S. Zoghbi, Neva Lazarova, Nicholas Seneca, Robert L. Gladding, Andrew Taku, Peter Herscovitch, Victor W. Pike, Robert B. Innis
Journal of Nuclear Medicine Jan 2009, 50 (1) 108-115; DOI: 10.2967/jnumed.108.056226
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