title: Evaluation of [18F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats: Kinetics, metabolism, and selectivity.
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 [18F]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 ( VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VTvalues, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.
authors.affiliation: 1 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Heli
authors.initials: H
authors.lastname: Savolainen
authors.affiliation: 2 Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam, Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: 1 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: 3 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, Bari, Italy.|4 Biofordrug slr, Bari, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.affiliation: 3 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, Bari, Italy.|4 Biofordrug slr, Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: 1 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Antoon Tm
authors.initials: AT
authors.lastname: Willemsen
authors.affiliation: 1 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Luurtsema
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005462:Fluorine Radioisotopes; D007546:Isoquinolines; C000621385:MC225 compound; D019275:Radiopharmaceuticals; D013764:Tetrahydronaphthalenes
keywords: Blood–brain barrier; brain imaging; breast cancer resistance protein; kinetic modeling; positron emission tomography