Abstract
BackgroundNon-invasive imaging of the activation status of microglia and the ability to identify a pro- or anti-inflammatory environment can provide valuable insights not only into pathogenesis of neuro-inflammatory and neurodegenerative diseases but also the monitoring of the efficacy of immunomodulatory therapies. P2X7R is highly expressed on pro-inflammatory microglia and [11C]SMW139, a specific P2X7R tracer for positron emission tomography imaging, showed good pharmacokinetics, stability, and brain permeability in vivo. Our objective was to evaluate the potential of [11C]SMW139 for PET imaging of neuroinflammation in vivo in the experimental autoimmune encephalomyelitis (EAE) model.MethodsWe induced EAE in Lewis rats by immunization with MBP 69-88 in complete Freund’s adjuvant (CFA). We determined the affinity of [11C]SMW139 to human and rat P2X7R using saturation binding assay. Using this tracer, PET imaging was performed at the peak of disease and in the recovery phase. In vivo blocking experiments were conducted to validate the specific brain uptake of the tracer. Immunohistochemistry staining and autoradiography were performed to evaluate the level of neuroinflammation and validate the specific binding of [11C]SMW139.Results[11C]SMW139 showed good affinity for the rat P2X7R with a Kd of 20.6 ± 1.7 nM. The uptake of [11C]SMW139 was significantly higher in EAE animals at the peak of disease compared to the recovery phase but not in CFA control animals. The amplitude of increase of [11C]SMW139 uptake showed significant positive correlation with clinical scores mainly in the spinal cord (Pearson = 0.75, Spearman = 0.76; p < 0.0001). Treating EAE animals with P2X7R antagonist JNJ-47965567 blocked the uptake of [11C]SMW139 in the spinal cord, cerebellum, and brain stem, demonstrating specific accumulation of the tracer. P-glycoprotein blocking with tariquidar (30 mg/kg) did not affect tracer penetration in the brain showing that [11C]SMW139 is not a Pgp substrate.ConclusionOur data shows that [11C]SMW139 is a promising PET tracer for imaging neuroinflammation and evaluating the dynamics of pro-inflammatory microglia in the brain. This can provide crucial insights into the role of microglia in disease progression and enables the development of novel treatment strategies aimed at modulating the immune response in order to promote neuroprotection.
Highlights
Neuroinflammation is a common feature across many neurodegenerative diseases like multiple sclerosis (MS) and Alzheimer’s and Parkinson’s disease and is believed to contribute to the detrimental factors that lead to neurodegeneration
We recently showed that P2X7 receptor (P2X7R) is highly expressed in brain tissue from Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model for MS, as well as in active and chronic active white matter lesions in post-mortem tissues of MS patients
We performed a saturation binding assay in order to determine if the binding affinity for rat P2X7R is in the acceptable range for a Positron emission tomography (PET) tracer
Summary
Neuroinflammation is a common feature across many neurodegenerative diseases like multiple sclerosis (MS) and Alzheimer’s and Parkinson’s disease and is believed to contribute to the detrimental factors that lead to neurodegeneration. We recently showed that P2X7R is highly expressed in brain tissue from Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model for MS, as well as in active and chronic active white matter lesions in post-mortem tissues of MS patients. Ory et al evaluated [11C]JNJ54173717 for targeting and binding to P2X7R in vitro and in vivo in rats as well as in NHP and demonstrated good brain permeability and target engagement in the brain [19]. Non-invasive imaging of the activation status of microglia and the ability to identify a pro- or antiinflammatory environment can provide valuable insights into pathogenesis of neuro-inflammatory and neurodegenerative diseases and the monitoring of the efficacy of immunomodulatory therapies. P2X7R is highly expressed on pro-inflammatory microglia and [11C]SMW139, a specific P2X7R tracer for positron emission tomography imaging, showed good pharmacokinetics, stability, and brain permeability in vivo. Our objective was to evaluate the potential of [11C]SMW139 for PET imaging of neuroinflammation in vivo in the experimental autoimmune encephalomyelitis (EAE) model
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