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

TL;DR

Researchers tested a new PET tracer for imaging CSF1R, finding it more sensitive than existing tracers but with off-target binding issues.

Contribution

A novel PET tracer, [11C]FJRD, was developed and compared to existing CSF1R tracers with improved sensitivity but lower specificity.

Findings

[11C]FJRD showed low brain uptake and specific binding in most organs except kidneys in normal mice and rats.

Cold CPPC partially blocked [11C]FJRD binding in various organs, while GW2580 and BLZ945 had minimal blocking effects.

[11C]CPPC and [11C]GW2580 showed faint specific binding in mouse organs, with [11C]CPPC detectable in the spleen.

Abstract

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

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) with 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 kidneys in the normal mice and rats. In-vitro autoradiographs show high-level specific binding in all investigated organs including brain, spleen, liver, kidneys and lungs when used self-blocking. Addition of cold CPPC partially blocked in-vitro [11C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Meanwhile specific bindings of [11C]CPPC and [11C]GW2580 were faint in the mouse organs except [11C]CPPC specific binding detectable in the spleen.

These results suggest [11C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [11C]CPPC and [11C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging.

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