S4‐03‐02: Discovery of novel [18F]‐PET agents for imaging neurofibrillary tangles (NFTs)

Abstract

There are two main neuropathologic hallmarks in AD, senile neuritic plaques (SP) around an amyloid beta core and neurofibrillar protein aggregates containing tau protein. In AD patients tau is abnormally phosphorylated and loses its normal function. Unlike ß-amyloid plaque deposition, human post-mortem studies indicate that neurofibrillary tangle density correlates with neurodegeneration and cognitive impairment. Furthermore, abundant neurofibrillary tangles are not observed in cognitively unimpaired individuals, in contrast to ß-amyloid plaques that can be present also in cognitively normal people. Therefore, a tau PET tracer might be a good diagnostic tool for Alzheimer's disease that can be correlated with the progression of clinical symptoms. In order to screen many compounds as potential tau binders, we developed a competitive autoradiography screening method utilizing human AD brain sections. Brain sections from over 40 human AD brains were immunostained for tau and Aß and quantified by area measurements. Selectivity of tau binding compounds was determined by competition experiments in tau rich or Aß rich brain sections. Grey and white matter binding was measured for each candidate. Double staining of fluorescent analogs confirms binding of these compounds to tau tangles in AD brains. Brain uptake of [F18]-labeled tracers was measured in rodents and monkeys. Metabolism and pharmacokinetic studies were performed in mice. We have discovered several novel, small molecule tau binding compounds that show high selectivity for native tau aggregates in human AD brain sections over ß-amyloid. Several of these candidates were further optimized to show a high brain uptake/fast clearance in mice, rats, and monkeys. White matter distribution in monkeys is very low. Metabolism studies of our lead candidates show very good stability in plasma and no metabolite presence in mouse brains. We have identified several novel small heterocyclic tau binders. Our in vitro and in vivo studies confirm that our lead candidate [F18]-T808 binds to tau selectively over ß-amyloid, shows good PK and metabolic properties, and exhibits excellent brain uptake/washout kinetics in rodent and monkey brains.