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

Structure-activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had <i>K</i>_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]<b>75</b>) bound with high affinity in AD, PSP, and CBD tissues (<i>K</i>_D's = 1-1.5 nM) and Pick's disease tissue (<i>K</i>_D = 3.8 nM). Autoradiography studies with [³H]<b>75</b> demonstrated specific binding in AD, PSP, and CBD post-mortem tissues. Nonhuman primate brain PET imaging with [¹⁸F]<b>75</b> 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]<b>75</b> is a promising candidate for translation to human brain PET imaging studies.