In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

ABSTRACT: A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [³H]1 provided K_D (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [¹⁸F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Bindin

SUBMITTER: Graham TJA 

PROVIDER: S-EPMC10424182 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature