RADIOLIGAND BINDING ASSAYS FOR COMPARISON OF TAU PET PROBES, PBB3 AND T807, IN DETECTION OF TAU PATHOLOGIES IN ALZHEIMER'S DISEASE AND PSP BRAINS, AND NEUROTOXIC TAU SPECIES IN A TRANSGENIC MOUSE MODEL

Abstract

Tau PET enables in vivo detection of tau deposits, core lesions in diverse neurodegenerative disorders including Alzheimer's disease (AD) and progressive superanuclear palsy (PSP). Whether different tau tracers detect disease-specific tau deposits of various isoforms, species and reflect tau-induced neurotoxicity remains unclear. We investigated binding properties of tau tracers, [11C]PBB3 and [18F]T807 in AD and PSP postmortem brains, and examine the association of in vitro and in vivo [11C]PBB3 binding with neuronal loss in tau transgenic mouse models. Homologous and heterologous competitions of [11C]PBB3 and [18F]T807 binding with unlabeled PBB3 and T807 were assayed with homogenates of the brains of AD (3R+4R tauopathy), PSP (4R tauopathy), control subjects and 4R mutant tau transgenic mice (rTg4510 and PS19 strains). [11C]PBB3-PET and MRI were carried out in rTg4510 (n = 5) and wild-type (n = 7) mice aged 7-10 months, followed by in vitro binding and fluorescence analyses. [11C]PBB3 bound to high- and low-affinity components in the temporal and frontal cortices of an AD patient, and 40% of specific [11C]PBB3 binding was blocked by T807 with low-affinity. In contrast, PBB3 displaced 80% of [18F]T807 binding in AD brain with high-affinity, indicating the presence of multiple binding components with distinct reactivity with these two probes on AD tau fibrils. [11C]PBB3 bound to a single high-affinity site in the motor cortex and basal ganglia of a PSP case, which was not displaceable by T807. Less [18F]T807 binding to PSP tissues was observed, and was nearly fully blocked by PBB3 with considerably high-affinity. [11C]PBB3 also bound to the forebrain of rTg4510 mice and brainstem of PS 19 mice with affinity similar to values in human AD and PSP brains. Image analyses indicated robust correlation among in vitro and in vivo [11C]PBB3 binding and regional atrophy in the forebrain of rTg4510 mice, in agreement with histochemical and immunohistochemical distributions of tau deposits captured by PBB3 and phospho-tau antibodies. Our results indicate distinct mode of binding of PBB3 and T807 to multiple sites on tau fibrils, which may be variable among AD, PSP and other tauopathies. The intimate correlation between [11C]PBB3 binding and regional atrophy in rTg4510 mice supports the ability of [11C]PBB3 to detect neurotoxic tau species in both in vitro and in vivo assays.