18F-Labeled 7-Azaindole-Based Radioligands for Imaging Colony-Stimulating Factor 1 Receptor in Glioblastoma

Abstract A series of 7-azaindole-based compounds were designed and synthesized as novel colony-stimulating factor 1 receptor (CSF1R) ligands. Four potent ligands (IC50 < 40 nM) were radiolabeled with fluorine-18 via the 5-fluoroethoxy substituent on the 7-azaindole ring and evaluated comprehensively in rodents and U87MG glioma models. Among them, [18F]PLX6 (IC50 = 12.3 nM) showed modest brain uptake and rapid clearance in rats. Micro-PET/CT imaging resulted in clear visualization of both subcutaneous and intracranial orthotopic U87MG gliomas. Treatment with PLX3397 or PLX5622 significantly reduced tumor uptake, indicating specific binding of [18F]PLX6 to CSF1R. Ex vivo autoradiography at 30 min postinjection (p.i.) confirmed high tumor-to-brain ratio (10.14 ± 1.52) and specific binding of [18F]PLX6 to CSF1R. Metabolic analysis showed that intact [18F]PLX6 was the predominant radioactive species in tumors at 30 min p.i. These results support further evaluation of [18F]PLX6 as a promising PET imaging agent for noninvasive visualization of CSF1R expression in glioblastoma.