α‐Synuclein Radiotracer Development and In Vivo Imaging: Recent Advancements and New Perspectives

Abstract

A BS TRACT: α-Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of α-synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of α-synucleinopathies. Although dopaminergic deficits detected with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish α-synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated α-synuclein (αSyn) could be a suitable imaging biomarker in α-synucleinopathies, because αSyn aggregation and therefore, Lewy pathology is evidently an early driver of α-synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated αSyn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated αSyn and Lewy pathology inclusion bodies cannot be assessed ante-mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated αSyn as an imaging biomarker in α-synucleinopathies, the current limitations with and lessons learned from αSyn radiotracer development, and finally to propose antibody-based ligands for imaging αSyn aggregates as a complementary tool rather than an alternative to small molecule ligands.

Single-domain antibody–based noninvasive in vivo imaging of α-synuclein or tau pathology

“…Currently, no specific α-syn imaging probes are approved for clinical use. Development of small molecules with such properties has been limited because of cross-reactivity with other β sheet peptides/proteins (15)(16)(17). We are not aware of other reports showing the diagnostic promise of sdAbs targeting α-syn.…”

“…However, since their general target is β sheet structures, they will always have some affinity for unrelated proteins and peptides, such as various amyloids that may deposit in the brain. The β sheet dyes that have been reported to detect α-syn aggregates bind strongly to Aβ and other β sheet structures and have not been deemed suitable for clinical use for α-syn imaging (15)(16)(17).…”

Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

“…Meanwhile, reliable biomarkers are still under exploration for subtyping PD and for monitoring disease progression and evaluating response to therapeutic interventions. Pathway‐specific biomarkers, such as the SNCA radiotracer 37 for SNCA ‐related PD and mitophagy pathway biomarkers for PARK2‐associated patients, might provide opportunities to monitor and evaluate the disease‐modifying effects of antisense therapeutics.…”

Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

“…Lastly, the structures of the fibrils vary between in vitro simulations and in animal models and measurements in the human brain. For detailed reviews about the development of PET tracers for α-synucleinopathies, see [ 192 , 193 ]. In the future, it remains to be seen whether a universal tracer can be developed that measures α-synuclein in vivo in humans.…”