PLX5622 hemifumarate is a highly selective, blood-brain barrier-permeable, and orally active CSF1R inhibitor with an IC50 of 0.016 μM and a Ki of 5.9 nM. It can be used to eliminate proliferating and specific microglia before and during disease progression and is applicable for inducing Alzheimer's disease models.

PLX5622 hemifumarate (1-20 μM; 3 days) effectively depletes microglia without affecting oligodendrocytes or astrocytes in cerebellar slices. At 4 μM for 3 days, it reduces NG2+ or PDGFRα+ cells by 30-40%, increasing to 90-95% at 20 μM. No reduction in NG2+ or PDGFRα+ OPCs is observed at 1 μM or 2 μM PLX5622 despite robust (~95%) depletion of microglial cells [3].

In preclinical studies, PLX5622 hemifumarate demonstrates significant microglial depletion in adult C57/Bl6 wild-type mice when administered at 1200 ppm in chow for durations of 3 days to 3 weeks, resulting in approximately 80% reduction after 3 days, and a 99% reduction after 3 weeks. Similar outcomes were observed in different brain regions including the cortex, striatum, cerebellum, and hippocampus when administered for 3 weeks. Intraperitoneal injections of 50 mg/kg in neonatal and adult rats for 14 days resulted in 80-90% microglia depletion within the first 3 days, surpassing 90% by day 7, and achieving more than 96% depletion by day 14, while astrocyte levels remained unchanged. Notably, neonates required only a single daily injection, while adults needed twice-daily injections for effective depletion. Furthermore, administration of PLX5622 in AIN-76A chow at 1200 mg/kg for 28 days significantly reduced microglia in the CNS of 14-month-old 5xfAD mice. The pharmacokinetic profile of PLX5622 across various species revealed differences in bioavailability, clearance, and half-life, notably demonstrating efficient absorption and clearance rates. For gavage dosing preparations, PLX5622 hemifumarate is dissolved in DMSO, mixed with a diluent consisting of hydroxypropyl methyl cellulose and Polysorbate 80, and sonicated to achieve a uniform suspension for administration.