PLX5622 hemifumarate is a highly selective, brain-penetrant, and orally active CSF1R inhibitor with an IC50 of 0.016 μM and Ki of 5.9 nM. It allows for extended and specific microglial elimination preceding and during pathology development and demonstrates desirable PK properties in various animals [1] [2].

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.