Alpha-synuclein

Alpha-synuclein is a small presynaptic protein whose misfolded, aggregated forms define the synucleinopathies: Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Unlike amyloid and tau, which both have approved PET agents, no small molecule targeting misfolded alpha-synuclein has been approved by the FDA as a PET radiopharmaceutical, and the inability to quantify these aggregates in vivo limits accurate clinical diagnosis across the whole group.

The target is hard for physical reasons. The aggregates are intracellular and, in Parkinson's disease, present at far lower density than cortical amyloid plaques, and the protein has several conformational strains. The most advanced tracer, [18F]ACI-12589 from AC Immune, demonstrated this precisely in a 42-participant study published in Nature Communications in 2023: binding statistically separated multiple system atrophy patients from healthy controls and from other neurodegenerative disorders, with clear signal in cerebellar white matter and middle cerebellar peduncles, but showed limited binding in Parkinson's disease despite binding post-mortem Parkinson's tissue.

The competing measurement has already succeeded. Seed amplification assays on cerebrospinal fluid are reported at 87.7% sensitivity and 96.3% specificity for Parkinson's disease in the PPMI cohort, with a pooled meta-analysis across biomatrices at 0.86 and 0.92. What those assays cannot do is localise or quantify pathology, or measure whether a drug reduced it, and they are markedly less reliable in multiple system atrophy. That residual is where an imaging agent would have to earn its place.