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

被引:1
作者
El Biali, Myriam [1 ,2 ]
Breuil, Louise [3 ]
Jackwerth, Matthias [1 ]
Mairinger, Severin [1 ,4 ]
Weber, Maria [1 ]
Woelfl-Duchek, Michael [1 ,4 ]
Bamminger, Karsten [4 ]
Rausch, Ivo [5 ]
Nics, Lukas [4 ]
Hacker, Marcus [4 ]
Rodrigo, Sebastian [3 ]
Bouilleret, Viviane [3 ,6 ]
Zeitlinger, Markus [1 ]
Pataraia, Ekaterina [7 ]
Tournier, Nicolas [3 ]
Bauer, Martin [1 ]
Langer, Oliver [1 ,4 ]
机构
[1] Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
[2] Geneva Univ Hosp, Div Clin Pharmacol & Toxicol, Geneva, Switzerland
[3] Univ Paris Saclay, CNRS, Inserm, CEA,Serv Hosp Freder Joliot,Lab Imagerie Biomedica, Orsay, France
[4] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria
[5] Med Univ Vienna, Ctr Med Phys & Biomed Engn, QIMP Team, Vienna, Austria
[6] Univ Paris Saclay, AP HP, Neurophysiol & Epileptol, Kremlin Bicetre, Paris, France
[7] Med Univ Vienna, Dept Neurol, Vienna, Austria
来源
FLUIDS AND BARRIERS OF THE CNS | 2024年 / 21卷 / 01期
基金
奥地利科学基金会;
关键词
Blood-brain barrier; P-glycoprotein; Drug-resistant epilepsy; C-11]Metoclopramide; PET; BLOOD-BRAIN-BARRIER; EXPRESSION; RESISTANCE; C-11-METOCLOPRAMIDE; DEFICIENCY; METABOLISM; INCREASES; SUBSTRATE; KINETICS; IMPACT;
D O I
10.1186/s12987-024-00588-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 [C-11]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [C-11]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 [C-11]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[C-11]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 [C-11]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. [C-11]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.
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页数:12
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