Our project aims to develop a brain imaging agent for alpha-synuclein, a key protein involved in Parkinson’s disease (PD) pathology. Such an agent will help (i) diagnose PD earlier, (ii) track pathology over time and (iii) monitor the efficacy of therapeutics reducing alpha-synuclein aggregates. The AC Immune team identified promising compounds that will be refined to target such an agent. The final deliverable is a compound with suitable characteristics for use as an alpha-synuclein PET (Positron Emission Tomography) imaging agent for use in human diagnosis, clinical trials and, eventually, routine treatment of PD.
The aim is to develop novel compounds as human PET tracers for alpha-synuclein, satisfying key criteria of high affinity for alpha-synuclein aggregates, high selectivity for alpha-synuclein over other aggregated human proteins (tau, amyloid-beta), binding to early forms of aggregated proteins, and high brain penetration and rapid clearance from brain.
We identified compounds with activity at alpha-synuclein and promising properties as PET ligands. In this project we will: (i) produce new compounds based on existing lead structures, (ii) screen on human PD brain sections to identify fluorescent compounds able to stain alpha-synuclein aggregates selectively, (iii) determine the affinity of compounds using binding assays, (iv) assess compound selectivity using both binding and staining of human brain sections, (v) assess the interactions of interesting compounds with Lewy bodies (aggregates of alpha-synuclein and a pathological hallmark of PD), and (vi) characterize the brain levels and kinetics of compounds as potential PET ligands.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Identification of an alpha-synuclein PET tracer would improve the accuracy and early diagnosis of PD, Lewy body disorders and other synucleopathies, as well as play a major biomarker role in clinical trials of disease progression.
Next Steps for Development:
If successful, this study will allow identification of lead alpha-synuclein imaging compounds that could rapidly enter into clinic. Next steps towards clinical use would involve fluorination of compounds to evaluate brain penetration, stability, metabolism in different species, followed by standard toxicity assessment before first-in-human studies.
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity as a lead supporter providing funding for this project.