In Vitro Evaluation of [3H]CPPC as a Tool Radioligand for CSF-1R

• DOI: 10.1021/acschemneuro.0c00802
• Publication Date: 2021-03-05T21:31:22Z
• Authors: Ashley C. Knight; Cassis Varlow; Tong Zi; Steven H. Liang; Lee Josephson; Karl Schmidt; Shil Patel; Neil Vasdev
• Keywords: Radioligand; Translocator protein; Ex vivo; Radioligand Assay

Microglia play a role in several central nervous system (CNS) diseases and are highly sought target for positron emission tomography (PET) imaging therapeutic intervention. 5-Cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([11C]CPPC) is radiopharmaceutical designed to selectively microglia via macrophage colony stimulating factor-1 receptor (CSF-1R) the CNS. Herein, we report first preclinical evaluation of [3H]CPPC using radioligand binding methods putative CSF-1R inhibitors rodent models neuroinflammation. The distribution by autoradiography did not align with 18 kDa translocator protein (TSPO) [3H]PBR28 IBA-1 staining microglia. In CNS, had considerable nonspecific binding, as indicated low displacement tritiated ligand unlabeled CPPC known CSF1R BLZ-945 PLX3397. Spleen was identified tissue that provided an adequate signal-to-noise ratio enable screening library 20 novel PLX3397 derivatives. However, lacked selectivity showed off-target substantial number kinase targets (204 out 403 tested) at concentration relevant vitro assays (10 μM). These findings suggest that, while may have utility tool peripheral inhibitors, it limited vivo CNS probe on basis current evaluation.