Evaluation of in vivo and in vitro binding property of a novel candidate PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers

Background

Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for neuroinflammation and tumor-associated macrophages. However, existing positron emission tomography (PET) tracers for CSF1R imaging often suffer from limited specificity or sensitivity.

Results

We have performed ¹¹C-labeled radiosynthesis of compound FJRD (3-((2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)ethynyl)-N-(4-methoxyphenyl)-4-methylbenzamide), which exhibits excellent affinity for CSF1R, and evaluated its in vivo and in vitro binding properties. PET images of [¹¹C]FJRD show low brain uptake and specific binding in the living organs, except the kidneys in both normal mice and rats. In vitro autoradiographs demonstrate high levels of specific binding in all investigated organs, including the brain, spleen, liver, kidneys and lungs, when self-blocking was used. The addition of CPPC partially blocked in vitro [¹¹C]FJRD binding in these organs, with blocking effects ranging from 9 to 67%. In contrast, the other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effects, suggesting unignorable off-target binding in these organs. Furthermore, specific binding of [¹¹C]CPPC and [¹¹C]GW2580 was faint in the mouse organs, with [¹¹C]CPPC demonstrating detectable binding only in the spleen.

Conclusions

These results suggest that [¹¹C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [¹¹C]CPPC and [¹¹C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging.