In Vivo Induction of P-Glycoprotein Function can be Measured with [(18)F]MC225 and PET

[Image: see text] P-Glycoprotein (P-gp) is an efflux pump located at the blood–brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [(18)F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K(1)) and volume of distribution (V(T)) were calculated, which reflect the in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K(1) and V(T) of [(18)F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K(1) was decreased by 34% (K(1)-high-dose = 0.20 ± 0.02 vs K(1)-control = 0.30 ± 0.02; p < 0.001) and in the low-dose group by 7% (K(1)-low-dose = 0.28 ± 0.02 vs K(1)-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain V(T) was decreased by 25% in the high-dose group (V(T)-high-dose = 5.92 ± 0.41 vs V(T)-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (V(T)-low-dose = 7.35 ± 0.38 vs V(T)-control = 7.82 ± 0.37; p = 0.38) compared to controls. k(2) values did not vary after treatment. The treatment did not affect the metabolism of [(18)F]MC225. Western blot studies using the whole-brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K(1) and V(T) values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [(18)F]MC225 and PET.