Work

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

Year: 2025

Type: article

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 Ki 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 (KD’s = 1–1.5 nM) and Pick’s disease tissue (KD = 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c02988