Objective: The aim of our project is to develop small molecular weight compounds (Morphomers™) which bind selectively to alpha-synuclein (aSyn) aggregates, in order to generate diagnostic PET imaging agents for Parkinson’s disease (PD).

Background: The accumulation of aggregated aSyn within selectively vulnerable neuronal populations is a key event in the pathogenesis of PD and other neurodegenerative synucleinopathies. There is a strong association, supported by the Braak staging scheme, between the formation of aSyn inclusions -the Lewy bodies and Lewy neurites- and PD progression. Therefore, a PET tracer targeting aSyn will address an unmet clinical need; it would facilitate monitoring of disease progression and at the same time it would enable early disease diagnosis thereby allowing early therapeutic intervention and corresponding better patient outcomes. A required feature of such PET agent is to have high selectivity for aSyn over Aβ and tau in order to differentiate PD from other proteinopathies that share common clinical and pathological features.

Methods: Morphomer™ compounds that are designed to interact with β-sheet-rich structures are evaluated by their intrinsic fluorescence properties for their ability to bind to aSyn aggregates over Tau tangles and Aβ plaques directly on human brain sections of PD and AD donors. These results are confirmed by radioactive binding assays and autoradiography experiments with human brain-derived material. Finally, the binding affinities of selected compounds to total homogenates from diseased tissues are assessed by Back-Scattering Interferometry technology.

Results: Several Morphomers™ were identified to have high affinity for aSyn pathological structures that are found in human PD brain samples of late Braak stages and exhibit clear target engagement as demonstrated by the ability to stain aSyn on tissue sections. Importantly, the compounds show selectivity for aSyn aggregates over other targets.

Conclusions: A PET imaging program is under development to detect aSyn pathology in PD patients which would enable diagnosis and clinical management of PD. Applications of such PET imaging agents have the potential to radically change how treatment of PD and other synucleinopathies is approached. Several candidate compounds have been identified with desirable characteristics in terms of selectivity for aSyn as well as pharmacokinetic profile with fast brain-uptake and wash out properties.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-pet-tracers-of-alpha-synuclein-for-the-diagnosis-of-parkinsons-disease/