Kolb H, Arteaga J, Cashion D, Chen G, Gangadharmath U, Gomez F, Kasi D, Liang Q, Szardenings K, Siemens JW.
Discovery of Novel [18F]-PET Agents for Imaging Neurofibrillary Tangles (NFTs).
Human Amyloid Imaging Abstract. 2012 Jan 1;
Background: There are two main neuropathologic hallmarks in AD, senile neuritic plaques around an amyloid beta core and neurofibrillar protein aggregates containing tau protein. In AD patients tau is abnormally phosphorylated and loses its normal function.
Methods: In order to screen many compounds as potential tau binders, we developed a competitive autoradiography screening method utilizing human AD brain sections. Selectivity of tau binding compounds was determined by competition experiments in tau rich or Aβ rich brain sections. Grey and white matter binding was measured for each candidate. Brain uptake of [F18]-labeled tracers was measured in rodents and non-human primates. Metabolism and pharmacokinetic studies were performed in mice.
Results: We have discovered several novel, small molecule tau binding compounds that show high selectivity for native tau aggregates in human AD brain sections over β-amyloid. Several of these candidates were further optimized and shown to have a high brain uptake/fast clearance in mice, rats, and primates. White matter distribution in non-human primates is very low. Metabolism studies of our lead candidates show very good stability in plasma and no metabolite presence in mouse brains.
Conclusions: We have identified several novel small heterocyclic compounds that bind to human PHF-tau. Our in vitro and in vivo studies confirm that our lead candidates [F18]-T807 and T808 bind to PHF-tau selectively over β-amyloid, shows good PK and metabolic properties, and exhibits excellent brain uptake/washout kinetics in rodent and non-human brains.