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FIRST-IN-HUMAN PET STUDIES WITH THE NEXT GENERATION TAU AGENT 18-F PI-2620 IN ALZHEIMER’S DISEASE, PROGRESSIVE SUPRANUCLEAR PALSY, AND CONTROLS

      Background

      Intracellular tau deposition is a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Recently, positron emission tomography tau probes have been developed for in vivo detection of brain tau load, although quantification is challenging due to high off-target binding and slow kinetics. Further, different tau radiotracers have different affinities for tau species. PI-2620 is a novel tracer with an IC50 of 1.8 nM for tau in AD brain homogenate competition-assays and binds specifically to tau deposits in AD brain sections (Braak I-VI), Pick’s, and progressive supranuclear palsy (PSP) pathologies. This first-in-human study assesses 18-F-labelled PI-2620 in AD, PSP, and healthy volunteers.

      Methods

      In an ongoing clinical imaging study, participants diagnosed with mild Alzheimer’s (AD), non-AD tauopathies (e.g. PSP), and healthy volunteers (HV) undergo dynamic PET imaging for over 3 h following 370 MBq bolus injection of 18F-PI-2620. Venous blood is obtained to characterize the kinetics of parent compound and metabolites.

      Results

      Initial imaging data shows robust brain uptake and fast wash-out in non-target regions with peak SUV = 4-4.5. There was no increased uptake seen in choroid plexus, striatum, amygdala, or other regions noted in first generation tau agents. In AD, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and cingulate. SUVr time curves demonstrate a plateau at 90-100 min post injection with resultant SUVrs of 2.5-2.8.in abnormal regions, whilst HV demonstrated shorter time to secular equilibrium (60-70 min) and lower SUVrs (1.0-1.2) in comparable brain regions. Finally, PSP subjects demonstrated focal and symmetric increased uptake in the globus (SUVr=1.99-2.11) and midbrain (SUVr=2.41-2.58). Blood data confirmed fast kinetics with 20% of parent compound present at 60 min and the presence of polar metabolites.

      Conclusions

      Initial PI-2620 PET first-in-human studies demonstrate excellent brain penetrance, favorable kinetics, and high target specificity with low nonspecific binding and high signal in regions of expected tau pathology.