Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism

Renee Sokias, Eryn L. Werry, Hei Wun Alison Cheng, James H. Lloyd, Greta Sohler, Jonathan J. Danon, Andrew P. Montgomery, Jonathan J. Du, Quanqing Gao, David E. Hibbs, Lars M. Ittner, Tristan A. Reekie, Michael Kassiou*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Given the complex nature of TSPO binding, and the lack of non-discriminating high-affinity ligands at both wild type and A147T forms of TSPO, a series of novel TSPO ligands containing various heterocyclic scaffolds was developed to explore the pharmacophoric drivers of affinity loss at TSPO A147T. In general, N-benzyl-N-methyl-substituted amide ligands showed increased affinity at TSPO A147T, and a pyrazolopyrimidine acetamide containing this motif displayed low nanomolar binding affinities to both TSPO forms.

Original languageEnglish
Article number112725
Pages (from-to)1-12
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume207
Early online date15 Aug 2020
DOIs
Publication statusE-pub ahead of print - 15 Aug 2020

Keywords

  • Docking
  • Microglia
  • Non-discriminating
  • Polymorphism
  • Structure-activity relationships
  • TSPO

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    Sokias, R., Werry, E. L., Alison Cheng, H. W., Lloyd, J. H., Sohler, G., Danon, J. J., ... Kassiou, M. (2020). Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism. European Journal of Medicinal Chemistry, 207, 1-12. [112725]. https://doi.org/10.1016/j.ejmech.2020.112725