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Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue

[Image: see text] Radioligands targeting microglia cells have been developed to identify and determine neuroinflammation in the living brain. One recently discovered ligand is JNJ-64413739 that binds selectively to the purinergic receptor P2X7R. The expression of P2X7R is increased under inflammatio...

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Autores principales: Mikkelsen, Jens D., Aripaka, Sanjay S., Kaad, Sif, Pazarlar, Burcu A., Pinborg, Lars, Finsen, Bente, Varrone, Andrea, Bang-Andersen, Benny, Bastlund, Jesper F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9817075/
https://www.ncbi.nlm.nih.gov/pubmed/36535632
http://dx.doi.org/10.1021/acschemneuro.2c00561
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author Mikkelsen, Jens D.
Aripaka, Sanjay S.
Kaad, Sif
Pazarlar, Burcu A.
Pinborg, Lars
Finsen, Bente
Varrone, Andrea
Bang-Andersen, Benny
Bastlund, Jesper F.
author_facet Mikkelsen, Jens D.
Aripaka, Sanjay S.
Kaad, Sif
Pazarlar, Burcu A.
Pinborg, Lars
Finsen, Bente
Varrone, Andrea
Bang-Andersen, Benny
Bastlund, Jesper F.
author_sort Mikkelsen, Jens D.
collection PubMed
description [Image: see text] Radioligands targeting microglia cells have been developed to identify and determine neuroinflammation in the living brain. One recently discovered ligand is JNJ-64413739 that binds selectively to the purinergic receptor P2X7R. The expression of P2X7R is increased under inflammation; hence, the ligand is considered useful in the detection of neuroinflammation in the brain. [(18)F]JNJ-64413739 has been evaluated in healthy subjects with positron emission tomography; however, the in vitro binding properties of the ligand in human brain tissue have not been investigated. Therefore, the purpose of this study was to measure B(max) and K(d) of [(3)H]JNJ-64413739 using autoradiography on human cortical tissue sections resected from a total of 48 patients with treatment-resistant epilepsy. Correlations between the specific binding of [(3)H]JNJ-64413739 with age, sex, and duration of disease were explored. Finally, to examine the relationship between P2X7R and TSPO availability, specific binding of [(3)H]JNJ-64413739 and [(123)I]CLINDE was examined in the same tissue. The binding was measured in both cortical gray and subcortical white matter. Saturation revealed a K(d) (5 nM) value similar between gray and white matter but a larger B(max) in the white than in the gray matter. The binding was completely displaced by the cold ligand and structurally different P2X7R ligands. The variability in saturable binding among the samples was found to be 38% in gray and white matter but was not correlated to either age, sex, or the duration of the disease. Interestingly, there was no significant correlation between [(3)H]JNJ-64413739 and [(123)I]CLINDE binding. These data demonstrate that [(3)H]JNJ-64413739 is a suitable radioligand for evaluating the distribution and expression of the P2X7R in the human brain.
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spelling pubmed-98170752023-01-07 Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue Mikkelsen, Jens D. Aripaka, Sanjay S. Kaad, Sif Pazarlar, Burcu A. Pinborg, Lars Finsen, Bente Varrone, Andrea Bang-Andersen, Benny Bastlund, Jesper F. ACS Chem Neurosci [Image: see text] Radioligands targeting microglia cells have been developed to identify and determine neuroinflammation in the living brain. One recently discovered ligand is JNJ-64413739 that binds selectively to the purinergic receptor P2X7R. The expression of P2X7R is increased under inflammation; hence, the ligand is considered useful in the detection of neuroinflammation in the brain. [(18)F]JNJ-64413739 has been evaluated in healthy subjects with positron emission tomography; however, the in vitro binding properties of the ligand in human brain tissue have not been investigated. Therefore, the purpose of this study was to measure B(max) and K(d) of [(3)H]JNJ-64413739 using autoradiography on human cortical tissue sections resected from a total of 48 patients with treatment-resistant epilepsy. Correlations between the specific binding of [(3)H]JNJ-64413739 with age, sex, and duration of disease were explored. Finally, to examine the relationship between P2X7R and TSPO availability, specific binding of [(3)H]JNJ-64413739 and [(123)I]CLINDE was examined in the same tissue. The binding was measured in both cortical gray and subcortical white matter. Saturation revealed a K(d) (5 nM) value similar between gray and white matter but a larger B(max) in the white than in the gray matter. The binding was completely displaced by the cold ligand and structurally different P2X7R ligands. The variability in saturable binding among the samples was found to be 38% in gray and white matter but was not correlated to either age, sex, or the duration of the disease. Interestingly, there was no significant correlation between [(3)H]JNJ-64413739 and [(123)I]CLINDE binding. These data demonstrate that [(3)H]JNJ-64413739 is a suitable radioligand for evaluating the distribution and expression of the P2X7R in the human brain. American Chemical Society 2022-12-19 /pmc/articles/PMC9817075/ /pubmed/36535632 http://dx.doi.org/10.1021/acschemneuro.2c00561 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Mikkelsen, Jens D.
Aripaka, Sanjay S.
Kaad, Sif
Pazarlar, Burcu A.
Pinborg, Lars
Finsen, Bente
Varrone, Andrea
Bang-Andersen, Benny
Bastlund, Jesper F.
Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title_full Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title_fullStr Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title_full_unstemmed Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title_short Characterization of the Novel P2X7 Receptor Radioligand [(3)H]JNJ-64413739 in Human Brain Tissue
title_sort characterization of the novel p2x7 receptor radioligand [(3)h]jnj-64413739 in human brain tissue
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9817075/
https://www.ncbi.nlm.nih.gov/pubmed/36535632
http://dx.doi.org/10.1021/acschemneuro.2c00561
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