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The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain

BACKGROUND: Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [(18)F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinet...

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Autores principales: Goutal, Sébastien, Guillermier, Martine, Becker, Guillaume, Gaudin, Mylène, Bramoullé, Yann, Luxen, André, Lemaire, Christian, Plenevaux, Alain, Salmon, Eric, Hantraye, Philippe, Barret, Olivier, Van Camp, Nadja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026785/
https://www.ncbi.nlm.nih.gov/pubmed/33826008
http://dx.doi.org/10.1186/s13550-021-00777-8
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author Goutal, Sébastien
Guillermier, Martine
Becker, Guillaume
Gaudin, Mylène
Bramoullé, Yann
Luxen, André
Lemaire, Christian
Plenevaux, Alain
Salmon, Eric
Hantraye, Philippe
Barret, Olivier
Van Camp, Nadja
author_facet Goutal, Sébastien
Guillermier, Martine
Becker, Guillaume
Gaudin, Mylène
Bramoullé, Yann
Luxen, André
Lemaire, Christian
Plenevaux, Alain
Salmon, Eric
Hantraye, Philippe
Barret, Olivier
Van Camp, Nadja
author_sort Goutal, Sébastien
collection PubMed
description BACKGROUND: Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [(18)F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [(18)F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (V(ND)) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. RESULTS: [(18)F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (V(T)) or large uncertainty of the estimate). 2TCM with coupled fit K(1)/k(2) across brain regions stabilized the quantification, and confirmed a lower specific signal of [(18)F]UCB-H compared to the newest SV2A-ligands. However, the measures of V(ND) and the influx parameter (K(1)) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [(19)F]UCB-H, demonstrating only 50% displacement of the total [(18)F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of V(T) with only a small bias compared to 2TCM. CONCLUSIONS: Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-021-00777-8.
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spelling pubmed-80267852021-04-27 The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain Goutal, Sébastien Guillermier, Martine Becker, Guillaume Gaudin, Mylène Bramoullé, Yann Luxen, André Lemaire, Christian Plenevaux, Alain Salmon, Eric Hantraye, Philippe Barret, Olivier Van Camp, Nadja EJNMMI Res Original Research BACKGROUND: Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [(18)F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [(18)F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (V(ND)) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. RESULTS: [(18)F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (V(T)) or large uncertainty of the estimate). 2TCM with coupled fit K(1)/k(2) across brain regions stabilized the quantification, and confirmed a lower specific signal of [(18)F]UCB-H compared to the newest SV2A-ligands. However, the measures of V(ND) and the influx parameter (K(1)) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [(19)F]UCB-H, demonstrating only 50% displacement of the total [(18)F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of V(T) with only a small bias compared to 2TCM. CONCLUSIONS: Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-021-00777-8. Springer Berlin Heidelberg 2021-04-07 /pmc/articles/PMC8026785/ /pubmed/33826008 http://dx.doi.org/10.1186/s13550-021-00777-8 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Research
Goutal, Sébastien
Guillermier, Martine
Becker, Guillaume
Gaudin, Mylène
Bramoullé, Yann
Luxen, André
Lemaire, Christian
Plenevaux, Alain
Salmon, Eric
Hantraye, Philippe
Barret, Olivier
Van Camp, Nadja
The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title_full The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title_fullStr The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title_full_unstemmed The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title_short The pharmacokinetics of [(18)F]UCB-H revisited in the healthy non-human primate brain
title_sort pharmacokinetics of [(18)f]ucb-h revisited in the healthy non-human primate brain
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026785/
https://www.ncbi.nlm.nih.gov/pubmed/33826008
http://dx.doi.org/10.1186/s13550-021-00777-8
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