Discovery and optimization of the first‐in‐class TDP‐43 PET tracer

Background Intracellular aggregation of TDP‐43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) and 30‐50% of patients with clinical diagnosis of Alzheimer’s disease. Sensitive fluid or imaging biomarkers of TDP‐43 pathology are currently not available. Direct detection of TDP‐43 aggregates by positron emission tomography (PET) holds promise for a more accurate diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials. Methods Using ACI’s Morphomer® small molecule library focused on brain penetrant and beta sheet binding compounds, initial hits were identified, and iterative medicinal chemistry applied to discover compounds with optimized properties. Radiobinding and autoradiography experiments on FTLD‐TDP brain samples were used to evaluate affinity and target engagement. These techniques were also used to assess selectivity over other aggregation‐prone proteins using brain material from Alzheimer’s (AD) and Parkinson’s disease (PD) cases. Brain pharmacokinetic (PK) profile was obtained in mice, followed by assessment of brain uptake, distribution and washout for selected 18F radiolabeled compounds in non‐human primates (NHP). Results Several chemical series showing nanomolar binding affinity to aggregated TDP‐43 from patient brain samples were identified. The specificity of binding was further confirmed by high resolution autoradiography enabling visualization of target engagement on TDP‐43 inclusions in FTLD‐TDP brain sections. In addition, the most advanced compounds differentiated FTLD‐TDP from control by classical autoradiography on patient brain sections. Selectivity over amyloid beta, alpha‐synuclein and Tau was observed. The compounds with the most favorable brain penetrantion properties demonstrated fast and substantial brain uptake and fast and complete washout in NHPs. Conclusions First‐in‐class TDP‐43 PET ligands have been discovered with the potential to identify FTLD‐TDP pathology by PET. These tools may finally allow the ability to detect and follow the progression of TDP‐43 pathology in the brains of living patients with certain TDP‐43 proteinopathies.