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  3. PET imaging assist investigation of HDAC6 expression change in MDD and evaluating antidepressant efficacy of a newly developed HDAC6 inhibitor

PET imaging assist investigation of HDAC6 expression change in MDD and evaluating antidepressant efficacy of a newly developed HDAC6 inhibitor

  • Eur J Med Chem. 2024 Sep 26:280:116908. doi: 10.1016/j.ejmech.2024.116908.
Xiao Zhong 1,  Xiaoai Wu 2,  Yanting Zhou 3,  Rui Wu 3,  Jingyi Yang 4,  Honghai Yin 2,  Hui Meng 3,  Weiyao Xie 3,  Gang Liu 3,  Changning Wang 5,  Ping Bai 6,  Wei Zhang 7
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 3 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4 Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 5 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, United States.
  • 6 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: pingbai@scu.edu.cn.
  • 7 West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
PMID: 39366254 DOI: 10.1016/j.ejmech.2024.116908
Abstract

The histone deacetylase 6 (HDAC6) is closely related to the pathogenesis of depression in epigenetic regulation. However, it remains unclear how HDAC6 expression changes in depression pathophysiology and whether it is a target for antidepressant treatment. Herein, we investigate the expression change of HDAC6 in major depressive disorder (MDD) and evaluate the efficacy of a novel HDAC6 Inhibitor, PB200, using positron emission tomography (PET) imaging. PET imaging studies with an HDAC6 PET probe [18F]Bavarostat allied with in vitro experiments demonstrated significantly increased HDAC6 expression in the brains of MDD mice. To investigate if pharmacological inhibition of HDAC6 can exert antidepressant effects, a series of naphthyridine-based HDAC6 inhibitors were designed and synthesized, among which PB200 demonstrated high selectivity and inhibitory activity against HDAC6, favorable metabolic stability, and excellent brain uptake. Moreover, PB200 exhibited significant antidepressant effects by restoring abnormal HDAC6 expression level and alleviating neuroinflammation. These results imply that targeting HDAC6 shows promise as a therapeutic strategy for depression, and PB200 is a potential therapeutic option for treating MDD.

Keywords

Antidepressant; HDAC6 expression; Inhibitors; Major depressive disorder; PET imaging.

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