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

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 9; p. 847
• Main Authors: Korat, Špela, Bidesi, Natasha Shalina Rajani, Bonanno, Federica, Di Nanni, Adriana, Hoàng, Anh Nguyên Nhât, Herfert, Kristina, Maurer, Andreas, Battisti, Umberto Maria, Bowden, Gregory David, Thonon, David, Vugts, Daniëlle, Windhorst, Albert Dirk, Herth, Matthias Manfred
• Format: Journal Article Web Resource
• Language: English
• Published: Basel MDPI AG 26.08.2021; MDPI
• Subjects: alpha-synuclein; Brain research; Chemistry; Chimie; Clinical trials; DNA repair; Drug Discovery; imaging; Molecular Medicine; Nervous system; Neurodegeneration; Parkinson's disease; Patients; Pharmaceutical Science; Phosphorylation; Physical, chemical, mathematical & earth Sciences; Physique, chimie, mathématiques & sciences de la terre; positron emission tomography; Proteins; Review; synucleinopathies; United States > US
• DOI: 10.3390/ph14090847
• ISSN: 1424-8247

Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-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 α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-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 α-syn pathology. The lack of a defined crystal structure of α-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 α-syn PET tracers.