Characterization of the novel PET Tracer PI-2620 for the assessment of Tau pathology in Alzheimer’s disease and other tauopathies

Objectives: Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The spreading of Tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron emission tomography has proved to be an important tool for the detection of amyloid-beta aggregates in the brain and is currently explored for detection of Tau in AD and other tauopathies. Several tracers targeting Tau have been discovered and tested in humans so far. However, limitations have been reported especially regarding their selectivity. Here we present data on the new tracer PI-2620 with improved characteristics specifically targeting Tau in AD and non-AD tauopathies. Methods: A series of compounds were synthesized and tested for affinity to aggregated Tau using human brain homogenates and isolated PHFs. Off-target binding was evaluated in competition assays using radiolabeled MAO A / B and beta-amyloid binders. Compounds with favorable properties were 18F-radiolabeled and tested for binding to AD and non-AD brain tissue using both, autoradiography (ARG) on human brain sections and competition experiments with brain homogenates. The specific binding was compared to the corresponding signals on brain tissues of non-demented control subjects. The pharmacokinetic profiles of the 18F-labeled test compounds were evaluated in mice. The PK of the lead candidate PI-2620 was further investigated in non-human primates. Results: The lead candidate displayed high affinity for Tau in AD brain homogenate competition-assays (IC50: 1.8 nM). Specific binding to Tau deposits was further demonstrated by ARG on AD brain sections (Braak I-VI), Pick's and PSP pathology, whereas no specific tracer binding was detected on brain slices from non-demented donors. In addition to its high affinity binding to Tau, the compound showed excellent off-target selectivity including beta-amyloid or MAO A/B. Good brain uptake and fast wash-out was observed in healthy mice and non-human primates. An automated radio-synthesis was established and validated. Conclusion: A promising new Tau PET imaging tracer with improved characteristics has been discovered with high affinity, good selectivity and excellent preclinical PK properties. The lead candidate is currently being evaluated in clinical studies.