Measurement of cyclosporin induced changes in P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

• Published in: European journal of nuclear medicine and molecular imaging
• Main Authors: Mossel, Pascalle, Salvi de Souza, Giordana, Willemsen, Antoon T. M., Stormezand, Gilles N., Colabufo, Nicola A., Toyohara, Jun, Boersma, Hendrikus H., Dierckx, Rudi A. J. O., Lammertsma, Adriaan A., Bartels, Anna L., Luurtsema, Gert
• Format: Journal Article
• Language: English
• Published: Germany 08.05.2025
• Subjects: CsA; Pharmacology; BBB; P-gp; Positron emission tomography
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-025-07320-0

P-glycoprotein (P-gp) or multidrug-resistance protein is one of the most extensively studied efflux transporters at the blood-brain barrier (BBB). Changes in P-gp function are associated with several neurodegenerative and psychiatric diseases, including Alzheimer's disease, Parkinson's disease and schizophrenia and with the bioavailability of several pharmaceuticals in the brain, causing multi-drug resistance or side effects. PET imaging can be used to measure the P-gp function in vivo. This study aims to validate [ F]MC225 as specific P-gp PET tracer with the use of cyclosporin as selective P-gp inhibitor. Fourteen healthy volunteers (age 67 ± 5y) were included. Subjects underwent twice a 60 min dynamic [ F]MC225 (200MBq) PET scan with continuous arterial blood sampling and a cerebral T1-weighted MRI as anatomical reference. During the second scan, in five subjects, cyclosporin was administered in a dose of 2.5 mg/kg/hour, starting 30 min prior to the scan, to inhibit the BBB P-gp function. Tissue time-activity curves of preselected brain regions (Hammer's atlas) were fitted to a reversible two-tissue compartment model (2T4k) using the metabolite corrected plasma and uncorrected whole blood curves as input functions. No significant difference was found in plasma kinetics, plasma curves, plasma-to-whole blood ratio, and the parent fraction of the baseline scans and scans after administration of cyclosporin. Volume of distribution values in whole brain grey matter showed a significant increase (6.18 ± 1.29 to 9.00 ± 1.29 mL·cm p = 0.03) after the administration of cyclosporin. The outcomes of the current study reflect the potential ability of [ F]MC225 to measure cyclosporin induced changes in P-gp function at the human BBB in vivo. EudraCT 2020-001564-28.