Reversing binding sensitivity to A147T translocator protein,RSC Medicinal Chemistry

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Reversing binding sensitivity to A147T translocator protein
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-03-12 , DOI: 10.1039/c9md00580c
Sophie V Vo ₁ , Samuel D Banister _{2,

3} , Isaac Freelander ₃ , Eryn L Werry ₃ , Tristan A Reekie ₄ , Lars M Ittner ₅ , Michael Kassiou ₃

Affiliation

The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [¹¹C]DPA-713, has been hampered by the presence of a common polymorphism (A147T TSPO), at which all second-generation TSPO ligands lose affinity. Little is known about what drives binding at A147T compared to WT TSPO. This study aimed to identify moieties in DPA-713, and related derivatives, that influence binding at A147T compared to WT TSPO. We found changes to the nitrogen position and number in the heterocyclic core influences affinity to WT and A147T to a similar degree. Hydrogen bonding groups in molecules with an indole core improve binding at A147T compared to WT, a strategy that generated compounds that possess up to ten-times greater affinity for A147T. These results should inform the future design of compounds that bind both A147T and WT TSPO for use in neuroinflammation imaging.

中文翻译：

逆转对 A147T 易位蛋白的结合敏感性

易位蛋白（TSPO）是神经炎症显像剂开发的靶标。TSPO PET 配体（例如 [ ¹¹ C]DPA-713）的临床转化因常见多态性（A147T TSPO）的存在而受到阻碍，所有第二代 TSPO 配体都失去亲和力。与 WT TSPO 相比，对于驱动 A147T 结合的因素知之甚少。本研究旨在鉴定 DPA-713 及相关衍生物中与 WT TSPO 相比影响 A147T 结合的部分。我们发现杂环核心中氮位置和数量的变化对 WT 和 A147T 的亲和力影响程度相似。与 WT 相比，具有吲哚核心的分子中的氢键基团可改善 A147T 的结合，这种策略生成的化合物对 A147T 的亲和力高出十倍。这些结果将为未来设计结合 A147T 和 WT TSPO 的化合物用于神经炎症成像提供信息。

更新日期：2020-03-12

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