Structure–Activity Relationships and Evaluation of 2-(Heteroaryl-cycloalkyl)-1H-indoles as Tauopathy Positron Emission Tomography Radiotracers

Abstract

Structure–activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had K_i values in the range of 5–14 nM in Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) post-mortem brain tissues. One of the more promising new compounds ([³H]75) bound with high affinity in AD, PSP, and CBD tissues (K_D’s = 1–1.5 nM) and Pick’s disease tissue (K_D = 3.8 nM). Autoradiography studies with [³H]75 demonstrated specific binding in AD, PSP, and CBD post-mortem tissues. Nonhuman primate brain PET imaging with [¹⁸F]75 demonstrated a peak standardized uptake value (SUV) of ∼5 in the cerebellum, ∼4.5 in the cortex, and ∼4 in whole brain with SUV 2-to-90 min ratios of 3.9 in whole brain, 4.9 in cortex, and 4.5 in cerebellum. Compound [¹⁸F]75 is a promising candidate for translation to human brain PET imaging studies.