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Issue 1, 2017
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Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination

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Abstract

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 N-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 5–6-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.

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

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Publication details

The article was received on 15 Sep 2016, accepted on 11 Nov 2016 and first published on 15 Nov 2016


Article type: Research Article
DOI: 10.1039/C6MD00523C
Med. Chem. Commun., 2017,8, 202-210
  • Open access: Creative Commons BY-NC license
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    Determination and reduction of translocator protein (TSPO) ligand rs6971 discrimination

    R. Sokias, E. L. Werry, S. W. Chua, T. A. Reekie, L. Munoz, E. C. N. Wong, L. M. Ittner and M. Kassiou, Med. Chem. Commun., 2017, 8, 202
    DOI: 10.1039/C6MD00523C

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