[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients

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 t...

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Published in:	Fluids and barriers of the CNS Vol. 21; no. 1; pp. 87 - 12
Main Authors:	Biali, Myriam El, Breuil, Louise, Jackwerth, Matthias, Mairinger, Severin, Weber, Maria, Wölfl-Duchek, Michael, Bamminger, Karsten, Rausch, Ivo, Nics, Lukas, Hacker, Marcus, Rodrigo, Sebastian, Bouilleret, Viviane, Zeitlinger, Markus, Pataraia, Ekaterina, Tournier, Nicolas, Bauer, Martin, Langer, Oliver
Format:	Journal Article
Language:	English
Published:	London BioMed Central 28.10.2024 BioMed Central Ltd Springer Nature B.V BMC
Subjects:	[11C]Metoclopramide Adult Anticonvulsants ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism Biomedical and Life Sciences Biomedicine Blood Blood-Brain Barrier Blood-Brain Barrier - diagnostic imaging Blood-Brain Barrier - metabolism Brain Brain - diagnostic imaging Brain - metabolism Brain diseases Carbon Radioisotopes Carbon Radioisotopes - pharmacokinetics Central nervous system Central nervous system depressants Choroid plexus Convulsions & seizures Disease resistance Drug dosages Drug resistance Drug Resistant Epilepsy Drug Resistant Epilepsy - diagnostic imaging Drug Resistant Epilepsy - metabolism Epilepsy Epilepsy, Temporal Lobe Epilepsy, Temporal Lobe - diagnostic imaging Epilepsy, Temporal Lobe - metabolism Female Glycoproteins Hematology Hippocampus Human health and pathology Humans Life Sciences Magnetic Resonance Imaging Magnetic Resonance Imaging - methods Male Medical examination Medical research Medicine, Experimental Metabolites Metoclopramide Middle Aged Neurobiology Neuroimaging Neurosciences P-Glycoprotein Pathophysiology Patients PET PET imaging Pharmaceutical sciences Pharmacology Plasma Positron emission tomography Positron-Emission Tomography - methods Seizures Seizures (Medicine) Seizures - diagnostic imaging Seizures - metabolism Superior temporal gyrus Temporal gyrus Temporal lobe Tomography Up-Regulation Up-Regulation - physiology Young Adult Connecticut Germany P-glycoprotein Drug-resistant epilepsy [ Blood-brain barrier C]Metoclopramide PET [11C]Metoclopramide
ISSN:	2045-8118, 2045-8118
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Summary:	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 ( K 1 ) and from brain to plasma ( k 2 ), and the total volume of distribution ( V T = K 1 / k 2 ). Results DRE patients but not DSE patients showed significantly higher k 2 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 ( k 2 : 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 k 2 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 PMCID: PMC11514750
ISSN:	2045-8118 2045-8118
DOI:	10.1186/s12987-024-00588-8