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

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