PBT434 is a novel, brain-penetrant, small molecule inhibitor of α-synuclein aggregation. In transgenic animal models of Parkinson disease (A53T) and MSA (PLP-α-Syn), PBT434 reduced α-synuclein aggregation, preserved neurons and improved motor function. Glial cell inclusions were also reduced in a murine MSA model. PBT434 is thought to act by redistributing reactive iron across membranes, thereby blocking intracellular protein aggregation and oxidative stress. The affinity of PBT434 for iron is greater than that of α-synuclein but lower than that of iron trafficking proteins, e.g., ferritin.

PBT434 methanesulfonate is an orally active, potent α-synuclein aggregation inhibitor with the ability to cross the blood-brain barrier. Acting as an iron chelator, it modulates transcellular iron trafficking, inhibits iron-mediated redox activity, and prevents iron-mediated aggregation of α-synuclein. PBT434 methanesulfonate also safeguards against the loss of substantia nigra pars compacta neurons (SNpc), showing promise for Parkinson’s disease (PD) research.