Research and development of therapeutics for neurodegenerative diseases are hampered by lack of tools for accurate early diagnosis and monitoring of disease progression. For amyotrophic lateral sclerosis (ALS) and frontotemporal dementia(FTD), nuclear depletion and aggregation of TAR DNA-binding protein-43 (TDP-43) was identified a decade ago as the major hallmark in the majority of ALS cases and in 45% of FTD cases also defined as FTLD-TDP (frontotemporal lobar degeneration). Positron emission tomography (PET) is a sensitive and non-invasive technique which is already used for the detection of amyloid-beta aggregates in the brain for Alzheimer’s disease (AD) and has result in clinical candidates for Tau aggregates detection in the brain for AD and tauopathies. Therefore, detection of TDP-43 aggregates with PET imaging agents holds promise for disease diagnosis and staging.<br/>AC Immune proprietary library of small molecules was screened using human FTLD-TDP brain sections. The screening led to the identification of a number of hits. The confirmed hits were evaluated by direct staining on distinct human brain sections with the three main pathological FTLD-TDP subtypes A, B and C. Close analogues from the library and newly synthesized compounds were then tested on FTLD-TDP human brain sections which resulted in the identification of several compounds binding to TDP-43 pathological inclusions. Based on physicochemical properties, structural diversity, and ADME properties, selected compounds were then profiled in <i>in vivo</i> pharmacokinetic studies. This work resulted in the identification of the first compounds interacting with pathological TDP-43 aggregates with favourable properties for CNS penetration.

Toward the discovery of PET radiotracer for imaging TDP-43 aggregates in FTD and ALS patients

255th National Meeting (2018)

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