Synthesis and Evaluation of a (18)F-Labeled Ligand for PET Imaging of Colony-Stimulating Factor 1 Receptor

Neuroinflammation involves activation of glial cells in the brain, and activated microglia play a particularly important role in neurodegenerative diseases such as Alzheimer’s disease (AD). In this study, we developed 5-cyano-N-(4-(4-(2-[(18)F]fluoroethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([(18)F]1) for PET imaging of colony-stimulating factor 1 receptor (CSF1R), an emerging target for neuroinflammation imaging. Non-radioactive ligand 1 exhibited binding affinity comparable to that of a known CSF1R inhibitor, 5-cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (CPPC). Therefore, we synthesized radioligand [(18)F]1 by radiofluorination of chlorine-substituted precursor 7 in 13–15% decay-corrected radiochemical yield. Dynamic PET/CT images showed higher uptake in the lipopolysaccharide (LPS)-treated mouse brain than in control mouse brain. Ex vivo biodistribution study conducted at 45 min after radioligand injection showed that the brain uptake in LPS mice increased by 78% compared to that of control mice and was inhibited by 22% in LPS mice pretreated with CPPC, indicating specificity of [(18)F]1 for CSF1R. A metabolism study demonstrated that the radioligand underwent little metabolism in the mouse brain. Taken together, these results suggest that [(18)F]1 may hold promise as a radioligand for CSF1R imaging.