Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion
bodies of alpha-synuclein (-syn) also called -synucleinopathies. Detection of these inclusions is
thus far only possible by histological examination of postmortem brain tissue. The possibility of
non-invasively detecting -syn will therefore provide valuable insights into the disease progression
of -synucleinopathies. In particular, -syn imaging can quantify changes in monomeric, oligomeric,
and fibrillic -syn over time and improve early diagnosis of various -synucleinopathies or monitor
treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique
that can quantify target expression and drug occupancies when a suitable tracer exists. As such,
novel -syn PET tracers are highly sought after. The development of an -syn PET tracer faces
several challenges. For example, the low abundance of -syn within the brain necessitates the
development of a high-affinity ligand. Moreover, -syn depositions are, in contrast to amyloid
proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another
challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau,
which are often co-localized with -syn pathology. The lack of a defined crystal structure of -syn
has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a
comprehensive overview of current efforts in the development of selective -syn PET tracers.