PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models.

Abstract

Parkinson's disease is one of the fastest-growing neurodegenerative disorders, with no effective treatments to modify its progression. Microglial-driven neuroinflammation, mediated by NLRP3 inflammasome activation, plays a key role in disease onset and progression. The NLRP3 inflammasome is upregulated in microglia from Parkinson's disease patients and activated by oxidative stress and a-synuclein aggregates, triggering the release of pro-inflammatory mediators that contribute to neuroinflammation and neuronal death. MCC950, the first described specific NLRP3 inhibitor, has shown promise in Parkinson's disease models but is limited by suboptimal pharmacokinetics and safety, hindering its clinical development. Here, we developed a novel NLRP3 inflammasome inhibitor, MCC7840 (also known as Inzomelid or Emlenoflast), and utilised clinically relevant PET-MRI imaging biomarkers to assess its therapeutic efficacy in preclinical models of Parkinson's disease. MCC7840 inhibited NLRP3 in human and mouse microglia with nanomolar potency, while demonstrating improved systemic exposure, half-life, brain permeability, and bioavailability compared to MCC950. In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome, MCC7840 effectively inhibited mortality and demonstrated superior potency compared to MCC950. Chronic oral administration of MCC7840 protected against neuroinflammation, motor deficits, and dopamine loss in both 6-hydroxydopamine and preformed α-synuclein fibril mouse models of Parkinson's disease. Radiotracer imaging of multiple PET markers in the same mouse revealed that MCC7840 attenuated neuroinflammation ([18F]DPA-714), preserved dopamine uptake ([18F]FDOPA), mitigated dopamine transporter loss ([18F]FBCTT), and reduced blood-brain barrier leakage (gadolinium contrast MRI). Notably, MCC7840 was effective in a slowly progressing 12-month α-synuclein model, even when administered after symptom onset, 4 months post-α-synuclein injection. These findings highlight the utility of PET/MRI as a non-invasive tool to evaluate drug efficacy and support MCC7840, and other brain-penetrant NLRP3 inhibitors, as promising disease-modifying therapies for Parkinson's disease, warranting future clinical investigation.