Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism.
Basic Information
ID: ALA4706576
Journal: Eur J Med Chem
Title: Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism.
Authors: 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,Kassiou M
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.
CiteXplore: 32920427
DOI: 10.1016/j.ejmech.2020.112725
Patent ID: ┄