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Parametric Imaging of P-Glycoprotein Function at the Blood–Brain Barrier Using kE,brain-maps Generated from [11C]Metoclopramide PET Data in Rats, Nonhuman Primates and Humans

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Abstract

Purpose

PET imaging using [11C]metoclopramide revealed the importance of P-glycoprotein (P-gp, ABCB1) in mediating the brain-to-blood efflux of substrates across the blood–brain barrier (BBB). In this work, the elimination rate constant from the brain (kE,brain), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [11C]metoclopramide PET data.

Procedures

kE,brain parameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). kE,brain values (h−1) obtained under baseline conditions were compared with values obtained after complete P-gp inhibition using tariquidar in rats (n = 4) and baboons (n = 4) or after partial inhibition using cyclosporine A in humans (n = 10). In baboons, the sensitivity of kE,brain to measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, kE,brain-maps were generated in each species using PMOD software.

Results

The linear part of the log-transformed brain TACs occurred from 10 to 30 min after radiotracer injection in rats, from 15 to 60 min in baboons, and from 20 to 60 min in humans. P-gp inhibition significantly decreased kE,brain values by 39 ± 12% in rats (p < 0.01), by 32 ± 6% in baboons (p < 0.001), and by 37 ± 22% in humans (p < 0.001). In baboons, P-gp inhibition consistently decreased the brain-to-plasma efflux rate constant k2 (36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (VT, 101 ± 12%, p < 0.001). In all studied species, brain kE,brain-maps displayed decreased P-gp-mediated efflux across the BBB.

Conclusions

kE,brain of [11C]metoclopramide provides a simple outcome parameter to describe P-gp function in the living brain when arterial input function data are unavailable, although less sensitive than VT. kE,brain-maps represent easy to compute parametric images reflecting the effect of P-gp on [11C]metoclopramide elimination from the brain.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

Funding by ANR19-CE17-0027 (EPIFLUX). LB AND DV received a joined grant from CEA/AP-HP.

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Authors and Affiliations

  1. Inserm, CNRS, CEA, BioMaps, Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, Université Paris-Saclay, CEA/SHFJ, 4 Place du Général Leclerc 91400, Orsay, France

    Louise Breuil, Dominique Vodovar, Solène Marie, Sylvain Auvity, Sébastien Goutal, Sebastian Rodrigo & Nicolas Tournier

  2. Inserm UMR-S1144, University of Paris Cité, 75006, Paris, France

    Louise Breuil, Dominique Vodovar & Sylvain Auvity

  3. Department of Clinical Pharmacology, Medical University of Vienna, 1090, Vienna, Austria

    Myriam El Biali, Martin Bauer & Oliver Langer

  4. Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090, Vienna, Austria

    Oliver Langer

Authors
  1. Louise Breuil
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  2. Myriam El Biali
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  4. Solène Marie
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  5. Sylvain Auvity
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  7. Sébastien Goutal
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  8. Sebastian Rodrigo
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  9. Oliver Langer
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  10. Nicolas Tournier
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Contributions

NT, LB, MB, and OL designed the study. LB, ME, DV, SM, SA, MB, SG, and SR analyzed the data. LB and NT wrote the first draft of the manuscript. All authors provided critical review and approved the final manuscript.

Corresponding author

Correspondence to Nicolas Tournier.

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Breuil, L., El Biali, M., Vodovar, D. et al. Parametric Imaging of P-Glycoprotein Function at the Blood–Brain Barrier Using kE,brain-maps Generated from [11C]Metoclopramide PET Data in Rats, Nonhuman Primates and Humans. Mol Imaging Biol 25, 1135–1141 (2023). https://doi.org/10.1007/s11307-023-01864-z

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  • DOI: https://doi.org/10.1007/s11307-023-01864-z

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