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Title: Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response

Abstract

OBJECTIVE: The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [11C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis. METHODS: [11C]GSK1482160 was synthesized with high specific activity and high radiochemical purity. Radioligand saturation and competition binding assays were performed for [11C]GSK1482160 using HEK293-hP2X7R living cells. Micro-PET studies were carried out in nonhuman primates. In vitro autoradiography and immunohistochemistry studies were then carried out to evaluate tracer uptake and P2X7 expression in experimental autoimmune encephalomyelitis (EAE) rat lumbar spinal cord at EAE-peak and EAE-remitting stages compared with sham rats. RESULTS: [11C]GSK1482160 binds to HEK293-hP2X7R living cells with high binding affinity (Kd=5.09±0.98 nmol/l, Ki=2.63±0.6 nmol/l). Micro-PET studies showed high tracer retention and a homogeneous distribution in the brain of nonhuman primates. In the EAE rat model, tracer uptake of [11C]GSK1482160 in rat lumbar spinal cord was the highest at the EAE-peak stage (277.74±79.74more » PSL/mm), followed by the EAE-remitting stage(149.00±54.14 PSL/mm2) and sham (66.37±1.4 PSL/mm2). The tracer uptake correlated strongly with P2X7-positive cell counts, activated microglia numbers, and disease severity. CONCLUSION: We conclude that [11C]GSK1482160 has the potential for application in monitoring neuroinflammation.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [1]
  1. Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology
  2. Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology, and Dept. of Neurology, Neuroscience, Physical Therapy and Occupational Therapy
  3. Saint Louis Univ. School of Medicine, St. Louis, MO (United States). Dept. of Pharmacological and Physiological Science
Publication Date:
Research Org.:
Washington Univ., St. Louis, MO (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1469801
Grant/Contract Number:  
SC0008432; SC0012737; NS058714; NS41509
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nuclear Medicine Communications
Additional Journal Information:
Journal Volume: 38; Journal Issue: 5; Journal ID: ISSN 0143-3636
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; experimental autoimmune encephalomyelitis; neuroinflammation; P2X7 receptor; PET radioligand

Citation Formats

Han, Junbin, Liu, Hui, Liu, Chunling, Jin, Hongjun, Perlmutter, Joel S., Egan, Terrance M., and Tu, Zhude. Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response. United States: N. p., 2017. Web. doi:10.1097/MNM.0000000000000660.
Han, Junbin, Liu, Hui, Liu, Chunling, Jin, Hongjun, Perlmutter, Joel S., Egan, Terrance M., & Tu, Zhude. Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response. United States. https://doi.org/10.1097/MNM.0000000000000660
Han, Junbin, Liu, Hui, Liu, Chunling, Jin, Hongjun, Perlmutter, Joel S., Egan, Terrance M., and Tu, Zhude. 2017. "Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response". United States. https://doi.org/10.1097/MNM.0000000000000660. https://www.osti.gov/servlets/purl/1469801.
@article{osti_1469801,
title = {Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response},
author = {Han, Junbin and Liu, Hui and Liu, Chunling and Jin, Hongjun and Perlmutter, Joel S. and Egan, Terrance M. and Tu, Zhude},
abstractNote = {OBJECTIVE: The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [11C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis. METHODS: [11C]GSK1482160 was synthesized with high specific activity and high radiochemical purity. Radioligand saturation and competition binding assays were performed for [11C]GSK1482160 using HEK293-hP2X7R living cells. Micro-PET studies were carried out in nonhuman primates. In vitro autoradiography and immunohistochemistry studies were then carried out to evaluate tracer uptake and P2X7 expression in experimental autoimmune encephalomyelitis (EAE) rat lumbar spinal cord at EAE-peak and EAE-remitting stages compared with sham rats. RESULTS: [11C]GSK1482160 binds to HEK293-hP2X7R living cells with high binding affinity (Kd=5.09±0.98 nmol/l, Ki=2.63±0.6 nmol/l). Micro-PET studies showed high tracer retention and a homogeneous distribution in the brain of nonhuman primates. In the EAE rat model, tracer uptake of [11C]GSK1482160 in rat lumbar spinal cord was the highest at the EAE-peak stage (277.74±79.74 PSL/mm), followed by the EAE-remitting stage(149.00±54.14 PSL/mm2) and sham (66.37±1.4 PSL/mm2). The tracer uptake correlated strongly with P2X7-positive cell counts, activated microglia numbers, and disease severity. CONCLUSION: We conclude that [11C]GSK1482160 has the potential for application in monitoring neuroinflammation.},
doi = {10.1097/MNM.0000000000000660},
url = {https://www.osti.gov/biblio/1469801}, journal = {Nuclear Medicine Communications},
issn = {0143-3636},
number = 5,
volume = 38,
place = {United States},
year = {Mon May 01 00:00:00 EDT 2017},
month = {Mon May 01 00:00:00 EDT 2017}
}

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Works referencing / citing this record:

Evaluation of Microglial Activation in Multiple Sclerosis Patients Using Positron Emission Tomography
journal, March 2018


In vivo Imaging of Glial Activation in Alzheimer's Disease
journal, August 2018


Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO
journal, January 2018


PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation
journal, January 2019


Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation
journal, April 2018


Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers
journal, April 2019


PET Imaging of Microglial Activation—Beyond Targeting TSPO
journal, March 2018


Positron emission tomography imaging in evaluation of MS pathology in vivo
journal, August 2018