BLZ945 derivatives for PET imaging of colony stimulating factor-1 receptors in the brain

Background: The kinase colony stimulating factor-1 receptor (CSF-1R) has recently been identified as a novel therapeutic target for decreasing tumor associated macrophages and microglia load in cancer treatment. In glioblastoma multiforme (GBM), a high-grade cancer in the brain with extremely poor prognosis, macrophages and microglia can make up to 50% of the total tumor mass. Currently, no non-invasivemethods are available formeasuring CSF-1R expression in vivo. The aim of this work is to develop a PET tracer for imaging of CSF-1R receptor expression in the brain for future GBM patient selection and treatment monitoring. Methods: BLZ945 and a derivative that potentially allows for fluorine-18 labelingwere synthesized and evaluated in vitro to determine their affinity towards CSF-1R. BLZ945was radiolabeledwith carbon-11 by N-methylation of des-methyl-BLZ945 using [C-11]CH3I. Following administration to healthy mice, metabolic stability of [C-11]BLZ945 in blood and brain and activity distributionwere determined ex vivo. PET scanningwas performed at baseline, efflux transporter blocking, and CSF-1R blocking conditions. Finally, [C-11]BLZ945 binding was evaluated in vitro by autoradiography on mouse brain sections. Results: BLZ945 was the most potent compound in our series with an IC50 value of 6.9 +/- 1.4 nM. BLZ945 was radiolabeled with carbon-11 in 20.7 +/- 1.1% decay corrected radiochemical yield in a 60min synthesis procedure with a radiochemical purity of >95% and a molar activity of 153 +/- 34 GBq.mu mol(-1). Ex vivo biodistribution showed moderate brain uptake and slow wash-out, in addition to slow blood clearance. The stability of BLZ945 in blood plasma and brain was >99% at 60 min post injection. PET scanning demonstrated BLZ945 to be a substrate for efflux transporters. High brain uptake was observed, whichwas shown to bemostly non-specific. In accordance, in vitro autoradiography on brain sections revealed high non-specific binding. Conclusions: [C-11]BLZ945, a CSF-1R PET tracer, was synthesized in high yield and purity. The tracer has high potency for the target, however, future studies are warranted to address non-specific binding and tracer efflux before BLZ945 or derivatives could be translated into humans for brain imaging. (C) 2021 Published by Elsevier Inc.

Automated summary

The study aims to develop a PET tracer for imaging CSF-1R receptor expression in the brain to aid in future GBM patient selection and treatment monitoring.