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

El Biali, Myriam
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
Geneva Univ Hosp, Div Clin Pharmacol & Toxicol, Geneva, Switzerland Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Breuil, Louise
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Univ Paris Saclay, CNRS, Inserm, CEA,Serv Hosp Freder Joliot,Lab Imagerie Biomedica, Orsay, France Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Jackwerth, Matthias
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Mairinger, Severin
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Weber, Maria
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Woelfl-Duchek, Michael
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

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Rausch, Ivo
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Med Univ Vienna, Ctr Med Phys & Biomed Engn, QIMP Team, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Nics, Lukas
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Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Hacker, Marcus
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Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Rodrigo, Sebastian
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Univ Paris Saclay, CNRS, Inserm, CEA,Serv Hosp Freder Joliot,Lab Imagerie Biomedica, Orsay, France Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Bouilleret, Viviane
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Univ Paris Saclay, CNRS, Inserm, CEA,Serv Hosp Freder Joliot,Lab Imagerie Biomedica, Orsay, France
Univ Paris Saclay, AP HP, Neurophysiol & Epileptol, Kremlin Bicetre, Paris, France Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

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Pataraia, Ekaterina
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Med Univ Vienna, Dept Neurol, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Tournier, Nicolas
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Univ Paris Saclay, CNRS, Inserm, CEA,Serv Hosp Freder Joliot,Lab Imagerie Biomedica, Orsay, France Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Bauer, Martin
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

Langer, Oliver
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Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Div Nucl Med, Vienna, Austria Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria
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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