Discovery of a High-Affinity Fluoromethyl Analog of [C]5-Cyano--(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands.

[C] has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of with higher affinity to provide the potential for labeling with longer-lived fluorine-18 ( = 109.8 min) and for delivery of higher CSF1R-specific PET signal . Seven fluorine-containing analogs of were prepared and four were found to have high inhibitory potency (IC in low to sub-nM range) and selectivity at CSF1R comparable with itself. One of these, a 4-fluoromethyl analog (), was investigated more deeply by labeling with carbon-11 ( = 20.4 min) for PET studies in mouse and monkey. [C] showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [C] also failed to show specific binding at baseline. Moreover, both [C] and [C] showed brain efflux transporter substrate behavior in both species , although did not show liability toward human efflux transporters . Further development of [C] in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of with a view to possible application in human subjects.