Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [ 18 F]MC225 and PET

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

*Corresponding author for this work

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The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [18F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [18F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar. Twenty-three rats were intravenously injected with different doses of tariquidar ranging from 0.75 to 12 mg/kg, 30-min before the dynamic [18F]MC225-PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain influx constant K1 and distribution volume VT, which allow the estimation of P-gp function. ANOVA and post-hoc analyses of K1 values showed significant differences between controls and groups with tariquidar doses >3 mg/kg; while applying VT the analyses showed significant differences between controls and groups with tariquidar doses >6 mg/kg. Dose-response curves were fitted using different models. The four-parameter logistic sigmoidal curve provided the best fit for K1 and VT data. Half-maximal inhibitory doses (ID50) were 2.23 mg/kg (95%CI: 1.669-2.783) and 2.93 mg/kg (95%CI: 1.135-3.651), calculated with K1 or VT values respectively. According to the dose-response fit, differences in [18F]MC225-K1 values could be detected at tariquidar doses ranging from 1.37 to 3.25 mg/kg. Our findings showed that small changes in the P-gp function, caused by low doses of tariquidar, could be detected by [18F]MC225-K1 values, which confirms the high sensitivity of the radiotracer. The results suggest that [18F]MC225 may allow the quantification of moderate P-gp impairments, which may allow the detection of P-gp dysfunctions at the early stages of a disease and potential transporter-mediated drug-drug interactions.
Original languageEnglish
Pages (from-to)500-507
Number of pages7
JournalJournal of Controlled Release
Early online date20-May-2022
Publication statusPublished - 1-Jul-2022


  • Dosing; Drug action; Efflux transporters; P-glycoprotein; Pharmacokinetics; Radiotracer sensitivity.

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