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Parkinson’s disease (PD) is characterized by alpha-synuclein (α-syn) aggregation, dopaminergic (DA) neuron loss, and neuroinflammation. Synucleinopathy, the α-syn-related pathology, is the central to the pathogenetic processes observed in the brains of patients with PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). We are seeking an animal model with synucleinopathy that can comprehensively replicate these pathologies and adhere to suitable timeframes for preclinical research for positron emission tomography (PET) imaging studies. Adeno-associated virus (AAV) carrying the mutated human α-syn gene and S87N α-syn preformed fibrils (PFF) were co-injected into the left substantia nigra (SN) of mouse brains. Immunohistochemistry (IHC) and PET/CT imaging were performed at different time points to detect the key pathologies in the brain. This model resulted in accelerated α-syn pathology, detectable as early as two weeks post-injection, alongside DA neuron loss, microglial activation, reduced synaptic density, and impaired mitochondrial function within five weeks. Pathology remained spatially localized. In summary, this AAV/PFF hybrid model offers a rapid, region-specific platform for studying synucleinopathies such as PD, as well as for evaluating PET ligands for disease diagnosis and monitoring.

Purpose Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([ 18 F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 18 F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation. Procedures A cell-based MSD assay was used to measure the IC 50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [ 18 F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and App SAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [ 18 F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study. Results JNJ-CSF1R-1 is a 12 nM (IC 50 ) inhibitor of CSF1R. ​[ 18 F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the App SAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[ 18 F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[ 18 F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics. Conclusion ​[ 18 F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([18F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([18F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.PURPOSEColony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([18F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([18F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.A cell-based MSD assay was used to measure the IC50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [18F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and AppSAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [18F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.PROCEDURESA cell-based MSD assay was used to measure the IC50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [18F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and AppSAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [18F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.JNJ-CSF1R-1 is a 12 nM (IC50) inhibitor of CSF1R. ​[18F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the AppSAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[18F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[18F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.RESULTSJNJ-CSF1R-1 is a 12 nM (IC50) inhibitor of CSF1R. ​[18F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the AppSAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[18F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[18F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.​[18F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.CONCLUSION​[18F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.