1. Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism.
- Author
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Sokias R, Werry EL, Alison Cheng HW, Lloyd JH, Sohler G, Danon JJ, Montgomery AP, Du JJ, Gao Q, Hibbs DE, Ittner LM, Reekie TA, and Kassiou M
- Subjects
- HEK293 Cells, Heterocyclic Compounds chemistry, Humans, Ligands, Molecular Docking Simulation, Polymorphism, Single Nucleotide, Protein Binding, Pyrazoles chemistry, Pyrimidines chemistry, Radiopharmaceuticals chemistry, Receptors, GABA genetics, Heterocyclic Compounds metabolism, Pyrazoles metabolism, Pyrimidines metabolism, Radiopharmaceuticals metabolism, Receptors, GABA metabolism
- 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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