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

Journal Article · · Nuclear Medicine Communications
 [1];  [2];  [2];  [2];  [3];  [4];  [2]
  1. Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology; osti
  2. Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology
  3. Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology, and Dept. of Neurology, Neuroscience, Physical Therapy and Occupational Therapy
  4. Saint Louis Univ. School of Medicine, St. Louis, MO (United States). Dept. of Pharmacological and Physiological Science
+ Show Author Affiliations
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.
Research Organization:
Washington Univ., St. Louis, MO (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE
Grant/Contract Number:
SC0008432; SC0012737
OSTI ID:
1469801
Journal Information:
Nuclear Medicine Communications, Journal Name: Nuclear Medicine Communications Journal Issue: 5 Vol. 38; ISSN 0143-3636
Country of Publication:
United States
Language:
English

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Cited By (9)

[11C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers journal June 2019
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
Positron emission tomography imaging in evaluation of MS pathology in vivo journal August 2018
Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO journal January 2018
Molecular imaging of multiple sclerosis: from the clinical demand to novel radiotracers journal April 2019
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
PET Imaging of Microglial Activation—Beyond Targeting TSPO journal March 2018

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Related Subjects

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY
P2X7 receptor
PET radioligand
experimental autoimmune encephalomyelitis
neuroinflammation