Vincent Darmency, Switzerland
AC Immune ResearchAuthor Of 1 Presentation
DISCOVERY OF PET TRACERS FOR TDP-43 PROTEINOPATHIES
Abstract
Aims
Intracellular aggregation of TDP-43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) as well as patients with limbic-predominant age-related TDP-43 encephalopathy (LATE). Having better tools to aid in more accurate and earlier diagnosis would substantially improve patient care. Thus, our aim is to provide the first tracer for the detection of TDP-43 aggregates by positron emission tomography (PET) to enhance diagnosis, staging, longitudinal measurement of disease progression and assessment of therapeutic efficacy in clinical trials.
Methods
Various methods including radiobinding and autoradiography were established to screen small molecules from our proprietary MorphomerTM library. Both recombinant and TDP-43 aggregates obtained from brain tissue of patients with TDP-43 proteinopathies were used. For selected compounds, the physico-chemical properties, ADME and pharmacokinetic profiles were evaluated.
Results
Screening of the MorphomerTM library led to identifying compounds binding to recombinant TDP-43 aggregates with Ki < 20 nM and confirmed on pathological TDP-43 derived from FTLD-TDP samples. Selectivity over other aggregation-prone proteins (amyloid beta, alpha-synuclein and Tau) was established. Target engagement on FTLD-TDP brain sections was demonstrated for selected compounds by autoradiography. Compounds with favorable CNS properties were profiled in pharmacokinetic studies.
Conclusions
Medicinal chemistry compound optimization and iterative design allowed the identification of compounds that bind to pathological TDP-43 with low nanomolar affinity. Compounds displaying suitable CNS pharmacokinetic profiles of a quick uptake with a fast and complete washout are being investigated to select a PET tracer for further development.