[18F]MC225 PET for the dose-response assessment of tariquidar inhibition of blood-brain barrier P-glycoprotein function in vivo

Lara Garcia Varela, Pascalle Mossel, Pablo Aguiar, Daniel Vazquez Matias, Aren van Waarde, Antoon Willemsen, Anna L. Bartels, Rudi Dierckx, Philip H. Elsinga, Gert Luurtsema

Research output: Contribution to journalMeeting AbstractAcademic

Abstract

Aim/Introduction: At the blood-brain barrier (BBB), P-glycoprotein (P-gp) is an efflux transporter that maintains homeostasis by protecting the brain from neurotoxic substances. BBB P-gp function may not be completely blocked but partially due to the effect of different Central-Nervous-System drugs or in patients with neurodegenerative diseases [1]. [18F]MC225 is a weak P-gp substrate tracer that may show higher sensitivity to detect small changes in the P-gp function than previously developed P-gp tracers [2,3].
This study aims to explore the sensitivity of [18F]MC225 to measure the effect of different doses of tariquidar (a P-gp inhibitor) and find the most appropriate fit to the doseresponse curve. Materials and Methods: Twenty-three rats were divided into seven groups (n=3-4) and injected with different doses of tariquidar (0 (control), 0.75, 1.5, 3, 6, 8, and 12mg/kg). Tariquidar was administered intravenously 30 min before the PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain the kinetic parameters K1 and VT, which allow the estimation of the P-gp function [2]. Dose-response curve was fitted to different models using GraphPad Prism v6. ANOVA and post-hoc analyses were performed to explore the differences in K1 and VT among groups. Results: The best fit was obtained using the four-parameters sigmoidal curve. The IC50 was 2.18±0.27 mg/kg, the minimum K1 value was 0.25 (0.15-0.36 95%CI) and the maximum K1 value was 0.99 (0.90-1.08 95%CI), which was reached with a dose of 6mg/kg. K1 values increased from 0.25±0.03 (control) to 0.39±0.14 in the 1.5mg/kg group, however, significant differences compared to controls were only found from a dose of 3 mg/kg on (K1=0.82±0.16; p=0.001). Similar results were obtained using the VT to estimate the P-gp function. Conclusion: The dose-response curve using either K1 or VT provided similar results. A tariquidar dose of 6mg/kg completely inhibited the P-gp function. A significant increase of K1 values was detected at 3mg/kg dose and a trend to increase was already seen after 1.5mg/kg. This study shows that [18F]MC225 seems an adequate tracer to measure small changes in the P-gp function in vivo and thus may be useful in Alzheimer and drug resistance studies where P-gp function can be partially altered. References: 1. Wanek T, et al. Mol Pharm. 2015;12:3214-252. Savolainen H, et al. J Cereb Blood Flow Metab. 2017;37:1286-983. Bauer M, et al. Clin Pharmacol Ther. 2019;105:1061-4
Original languageEnglish
Article numberOP-0273
Pages (from-to)S106
Number of pages1
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume48
Issue numberSuppl.1
Publication statusPublished - Sept-2021

Keywords

  • P-GLYCOPROTEIN
  • BLOOD-BRAIN BARRIER
  • POSITRON EMISSION TOMOGRAPHY
  • TARIQUIDAR
  • DOSE-RESPONSE CURVES
  • MC225

Cite this