Xiang J, Tao Y, Xia Y, Luo S, Zhao Q, Li B, Zhang X, Sun Y, Xia W, Zhang M, Kang SS, Ahn EH, Liu X, Xie F, Guan Y, Yang JJ, Bu L, Wu S, Wang X, Cao X, Liu C, Zhang Z, Li D, Ye K. Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies. Cell. 2023 Aug 3;186(16):3350-3367.e19. Epub 2023 Jul 7 PubMed.

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  1. The Michael J. Fox Foundation has supported α-synuclein PET tracer development for over a decade and has funded more than $30 million in research. It is likely that a tracer will need to be highly selective with minimal binding to other targets including other pathological proteins (Aβbeta, tau, TDP43) and bind to α-synuclein with very high affinity, likely low or subnanomolar. F0502B has many promising properties but it needs further optimization before it is ready for human testing. The affinity may need to be improved and it is unclear about potential binding to other targets. Also, it seems that the brain penetrance will need to be improved (see time-activity curves in Figure 7).

    Along with the report in 2022 by AC Immune that its α-synuclein tracer, ACI-12589, shows evidence of binding to α-synuclein in the cerebellum in MSA patients, the field has finally shown progress in the development of α-synuclein PET tracers for use in research and trials. In fact, AC Immune showed data at AAIC for a newly developed tracer that shows promise for use in Parkinson’s disease studies.

    In addition to the tracers mentioned above, MJFF is currently funding four projects that will test α-synuclein tracers in human subjects later this year or in early 2024.  Each of these tracers bind to α-synuclein with low nM or picomolar affinity. I am aware of several other tracers that are also close to human testing. In my opinion, we are on the cusp of having a selective α-synuclein PET tracer that performs well in Parkinson’s disease.

    View all comments by Jamie Eberling

  2. Building on the strength of CSF seed amplification assays for α-synuclein, there are now several efforts underway to biologically define and stage Lewy body disease, including PD, PD dementia, and dementia with Lewy bodies (DLB). These efforts represent a step forward in enabling clinical trials for disease-modifying therapies for people with Lewy pathology, potentially even preventive trials, given the recent BioFINDER and PPMI data showing that synuclein is detectible years in advance of clinical diagnosis. Furthermore, the proposed addition of synuclein to the NIA-AA criteria as non-AD pathology highlights the importance of biomarkers in differential diagnosis. Both of these dynamics will be informed and strengthened by PET tracers, which will ideally provide additional data regarding the spatial distribution of Lewy pathology in the brain during life, and enable prospective studies of the evolution of Lewy pathology, both in the natural course of disease and in response to therapeutics.

    View all comments by Keith Fargo

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