Abstract
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Objectives P-glycoprotein (P-gp) is one of the efflux transporter proteins expressed at the blood-brain barrier (BBB) responsible for clearing harmful compounds out of the brain. Altered P-gp function has been found in several neurological diseases.1 For reliable quantification in PET imaging, it is important that tracers used to image P-gp are selective and do not have affinity to other transporters, such as Breast Cancer Resistance Protein (BCRP). Purpose of this study was to evaluate the metabolism, brain kinetics and selectivity of [18F]MC225 in rats.
Methods [18F]MC225 was radiolabeled using a two-step alkylation method. Three groups of Sprague-Dawley rats were used: group 1 control, group 2 pretreated with 8 mg/kg of tariquidar to inhibit P-gp and group 3 pretreated with 8 mg/kg of tariquidar and 15 mg/kg of Ko143 to inhibit both P-gp and Bcrp.2 [18F]MC225 was injected i.v. and rats were scanned in the microPET for 1 h. Arterial blood samples were collected during the scan and analyzed on both UPLC and TLC. Whole blood and metabolite corrected plasma curves were used for kinetic modeling.
Results [18F]MC225 was synthesized with a radiochemical yield of 10 % in 80 min with a high specific activity (>200 GBq/µmol) and radiochemical purity (>97 %). After 1 h post injection, 20 % of the parent compound was intact in the plasma and 80 % in the brain. Best fitting in the kinetic modeling was obtained with a 1-tissue compartment model. Distribution volumes (VT) in the control group were 5-10, depending on the brain region. Highest uptake was found in the frontal cortex. After blocking P-gp with tariquidar (group 2), the VT values increased 2-4 fold. Group 3 had slightly higher VT values compared to group 2 in all the analyzed brain regions. However, this difference was not statistically significant.
Conclusions In rats, [18F]MC225 was found to be selective for P-gp over Bcrp and its metabolic stability is good. Therefore [18F]MC225 seems to be a suitable tracer for measuring P-gp function at the BBB.
Research Support Netherlands Technology Foundation STW (11741)