Reversing binding sensitivity to A147T translocator protein

Sophie V. Vo; Samuel D. Banister; Isaac Freelander; Eryn L. Werry; Tristan A. Reekie; Lars M. Ittner; Michael Kassiou

doi:10.1039/C9MD00580C

Reversing binding sensitivity to A147T translocator protein†

Sophie V. Vo,‡^a Samuel D. Banister,‡^bc Isaac Freelander,^c Eryn L. Werry,^c Tristan A. Reekie,

^d Lars M. Ittner^e and Michael Kassiou

*^c

Author affiliations

* Corresponding authors

^a Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, Australia

^b The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia

^c School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
E-mail: michael.kassiou@sydney.edu.au

^d Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory 2600, Australia

^e Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, 2 Technology Place, North Ryde, New South Wales 2109, Australia

Abstract

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.

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DOI: https://doi.org/10.1039/C9MD00580C
Article type: Research Article
Submitted: 16 Dec 2019
Accepted: 22 Feb 2020
First published: 12 Mar 2020

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RSC Med. Chem., 2020,11, 511-517

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Reversing binding sensitivity to A147T translocator protein

S. V. Vo, S. D. Banister, I. Freelander, E. L. Werry, T. A. Reekie, L. M. Ittner and M. Kassiou, RSC Med. Chem., 2020, 11, 511 DOI: 10.1039/C9MD00580C

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RSC Medicinal Chemistry

Reversing binding sensitivity to A147T translocator protein†

Abstract

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Reversing binding sensitivity to A147T translocator protein

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