Evaluation of [18F]JNJ-CSF1R-1 as a Positron Emission Tomography Ligand Targeting Colony-Stimulating Factor 1 Receptor.

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-([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.

PROCEDURES: 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.

RESULTS

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.

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.