Alpha-Synuclein PET tracer development-an overview about current efforts

Špela Korat, Natasha Shalina Rajani Bidesi, Federica Bonanno, Adriana di Nanni, Anh Nguyên Nhât Hoàng, Kristina Herfert, Andreas Maurer, Umberto Maria Battisti, Gregory David Bowden, David Thonon, Daniëlle Vugts, Albert Dirk Windhorst, Matthias Manfred Herth*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number847
JournalPharmaceuticals
Volume14
Issue number9
DOIs
Publication statusPublished - 1 Sep 2021

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