Evaluation of [F-18]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity

Heli Savolainen, Albert D. Windhorst, Philip H. Elsinga, Mariangela Cantore, Nicola A. Colabufo, Antoon T. M. Willemsen, Gert Luurtsema*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [F-18]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes (V-T) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [F-18]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral V-T values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [F-18]MC225 was moderate (at 1h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [F-18]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.

Original languageEnglish
Pages (from-to)1286-1298
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number4
Early online date1-Jan-2016
DOIs
Publication statusPublished - 1-Apr-2017

Keywords

  • Blood-brain barrier
  • brain imaging
  • breast cancer resistance protein
  • kinetic modeling
  • positron emission tomography
  • CANCER RESISTANCE PROTEIN
  • ALZHEIMERS-DISEASE
  • ABC TRANSPORTERS
  • IN-VITRO
  • HUMANS
  • RADIOPHARMACEUTICALS
  • PENETRATION
  • COOPERATION
  • INHIBITION
  • EXPRESSION

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