Evaluation of a Novel P-glycoprotein Inducer Using [18F]MC225 and PET

Lara Garcia Varela, David Vállez García, Manuel Rodriguez-Pérez, Rodrigo Moraga Amaro, Nicola Antonio Colabufo, Pablo Aguiar, Tomás Sobrino, Rudi Dierckx, Aren van Waarde, Philip H. Elsinga, Gert Luurtsema

Research output: Contribution to journalMeeting AbstractAcademic


Aim/Introduction: P-glycoprotein (P-gp) is an efflux pump located at the blood-brain barrier (BBB). Its main function is the protection of the central nervous system via the efflux of neurotoxic compounds from the brain (1). A decline
in P-gp function has been related to the pathogenesis of neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease (2). Drugs called P-gp inducers have the potential to restore the P-gp function and are considered as
possible candidates for the treatment of neurodegenerative diseases. MC111, (4’-((4-cyclohexylpiperazin-1-yl)methyl)-[1,1’-biphenyl-4-ol)), was selected as a promising P-gp inducer due to its ability to increase P-gp expression and
function in colo-320 cells (3). Our study aims to evaluate the P-gp inducing effect of MC111 in vivo using the P-gp tracer [18F]MC225 (4) and Positron Emission Tomography (PET). Materials and Methods: Eighteen healthy male Wistar rats were treated with either vehicle solution, 4.5mg/kg of MC111 (low-dose group) or 6mg/kg of MC111 (high-dose group) (n=6 per group). Animals underwent a 60-minutes dynamic-PET scan with arterial-blood sampling, 24 hours after the treatment with the inducer. Data were analysed using a 1-Tissue-Compartment-Model fit, fixing the volume of blood to 5% and using metabolite-corrected plasma as input function. K1 and VT were used to measure the P-gp function (4). Results: The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole-brain and all the selected brain regions. In the high-dose group, whole-brain K1 decreased by 34% (K1-high-dose=0.2±0.02
vs K1-control=0.3±0.02; p≤0.001) and in the low-dose group by 7% (K1-low-dose=0.28±0.02 vs K1-control=0.3±0.02; p=0.411) compared to controls. Whole-brain VT decreased by 25% in the high-dose group (VT-high-dose=5.8±0.37 vs VT-control=7.8±0.37; p≤0.001) and by 6% in the low-dose
group (VT-low-dose=7.35±0.37 vs VT-control=7.8±0.37; p=0.371) compared to controls. k2 values did not vary after treatment. Moreover, the treatment did not affect the metabolism of [18F]MC225. Conclusion: The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Therefore, the results verify that MC111 has an induction effect in vivo. These data also confirm the ability of [18F]
MC225 to measure increases in the P-gp function at the BBB in rats.
Original languageEnglish
Pages (from-to)S113
Number of pages1
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue numberSuppl.1
Publication statusPublished - 2020


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