Journal article Open Access

Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination

Sokias, Renee; Werry, Eryn L; Chua, Sook W; Reekie, Tristan A; Munoz, Lenka; Wong, Erik CN; Ittner, Lars M; Kassiou, Michael


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{
  "DOI": "10.1039/C6MD00523C", 
  "container_title": "Med. Chem. Commun.", 
  "title": "Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination", 
  "issued": {
    "date-parts": [
      [
        2016, 
        11, 
        15
      ]
    ]
  }, 
  "abstract": "<p>The 18 kDa translocator protein (TSPO) is a target for development of diagnostic imaging agents for glioblastoma and neuroinflammation. Clinical translation of TSPO imaging agents 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). Disclosed brain-permeant second-generation TSPO ligands bind TSPO A147T with reduced affinity compared to the wild type protein (TSPO WT). Efforts to develop a TSPO ligand that binds TSPO WT and TSPO A147T with similarly high affinity have been hampered by a lack of knowledge about how ligand structure differentially influences interaction with the two forms of TSPO. To gain insight, we have established human embryonic kidney cell lines stably over-expressing human TSPO WT and TSPO A147T, and tested how modifications of a novel <em>N</em>-alkylated carbazole scaffold influence affinity to both TSPO isoforms. Most of the new analogues developed in this study showed high affinity to TSPO WT and a 5\u20136-fold lower affinity to TSPO A147T. Addition of electron-withdrawing substituents yielded analogues with highest affinity for TSPO A147T without decreasing affinity for TSPO WT. This knowledge can be used to inform further development of non-discriminating TSPO ligands for use as diagnostic markers for glioblastoma and neuroinflammation irrespective of rs6971.</p>", 
  "author": [
    {
      "family": "Sokias, Renee"
    }, 
    {
      "family": "Werry, Eryn L"
    }, 
    {
      "family": "Chua, Sook W"
    }, 
    {
      "family": "Reekie, Tristan A"
    }, 
    {
      "family": "Munoz, Lenka"
    }, 
    {
      "family": "Wong, Erik CN"
    }, 
    {
      "family": "Ittner, Lars M"
    }, 
    {
      "family": "Kassiou, Michael"
    }
  ], 
  "page": "202-210", 
  "volume": "8", 
  "type": "article-journal", 
  "id": "291817"
}
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