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

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

  • J Med Chem. 2025 Mar 27;68(6):6462-6492. doi: 10.1021/acs.jmedchem.4c02988.
Jeffrey S Stehouwer 1,  Guofeng Huang 1,  Dinahlee Saturnino Guarino 2,  Manik L Debnath 3,  Ashok Polu 1,  Steven J Geib 4,  Brian Lopresti 1,  Milos D Ikonomovic 3 5,  Neale Mason 1,  Robert H Mach 2,  Chester A Mathis 1
Affiliations

Affiliations

  • 1 Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.
  • 2 Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
  • 3 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.
  • 4 X-ray Crystallography Laboratory, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.
  • 5 Geriatric Research and Clinical Education, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, United States.
PMID: 40068019 DOI: 10.1021/acs.jmedchem.4c02988
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.

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