Background: P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [¹¹ C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [¹¹ C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.

Methods: Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [¹¹ C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K₁ ) and from brain to plasma (k₂ ), and the total volume of distribution (V_T = K₁ /k₂ ).

Results: DRE patients but not DSE patients showed significantly higher k₂ values and a trend towards lower V_T values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k₂ : hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).

Conclusions: [¹¹ C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k₂ seems to be the most sensitive parameter to measure increased P-gp function with [¹¹ C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [¹¹ C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.

Trial registration: EudraCT 2019-003137-42. Registered 28 February 2020.