Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with 11 C-Metoclopramide PET

J Nucl Med. 2020 Jul;61(7):1050-1057. doi: 10.2967/jnumed.119.237198. Epub 2019 Dec 5.

Abstract

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (k E,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in k E,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between k E,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in k E,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11C-metoclopramide in all animal groups. Conclusion: 11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.

Keywords: 11C-metoclopramide; APP/PS1-21 mice; Alzheimer disease; P-glycoprotein induction; β-amyloid clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Acyltransferases*
  • Amyloidosis / diagnostic imaging*
  • Amyloidosis / metabolism*
  • Animals
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / metabolism*
  • Carbon Radioisotopes*
  • Disease Models, Animal
  • Female
  • Metoclopramide*
  • Mice

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carbon Radioisotopes
  • Carbon-11
  • Acyltransferases
  • phosphatidylethanolamine - dolichol acyltransferase
  • Metoclopramide