Evaluation of new generation translocator protein ligand efficacy in a mouse model of Alzheimer`s disease.

2014 Fiscal Year Research-status Report

• Project/Area Number: 26830038
• Research Institution: National Institute of Radiological Sciences
• Principal Investigator: BARRON Anna 独立行政法人放射線医学総合研究所, 分子イメージング研究センター, 研究員 (40725694)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: Alzheimer`s disease / Neurosteroid / Cognition / Translocator protein

Outline of Annual Research Achievements

In order to identify novel TSPO ligands that exhibit desirable AD-biomarker outcomes, the steroidogenic efficacy and acute behavioral effects of three new generation TSPO ligands, CLINDE, PBR175, and PBR162, was evaluated in mice. CLINDE, which exhibited the most favorable behavioral and pharmacokinetic profile, was investigated further for its specificity and binding affinity in human brain. These findings indicate that the new generation TSPO imidazopyridine ligands, CLINDE, PBR-175 and PBR162 rapidly promote neurosteroidogenesis, thereby enhancing learning and memory function in vivo. These second generation TSPO ligands are promising therapeutic candidates with improved pharmacokinetic properties compared classic TSPO ligands.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Candidate TSPO ligands for evaluation that exhibit desirable AD-biomarker and pharmacokinetic outcomes have been identified, and assessment of efficacy in a mouse model of AD has begun.

Strategy for Future Research Activity

Candidate TSPO ligands identified in the first year of research are currently under evaluation for their ability to prevent the development of neuropathology in a mouse model of Alzheimer`s disease. The development of neuropathology is being longitudinally tracked in vivo using PET and MRI imaging. In vivo results will be corroborated with end-point biochemical analyses.

Causes of Carryover

For publication of results reviewers have requested we conduct additional analysis of neurosteroid levels on samples collected.

Expenditure Plan for Carryover Budget

For LC-MS/MS analysis of neurosteroid levels in samples collected in completed study.

Research Products

• [Presentation] In vivo evaluation of the therapeutic potential of novel translocator protein ligands (TSPO) for the treatment of Alzheimer`s disease (2015)
  • Author(s): Asih, P. R., Ji, B., Katsifis, A., Mattner, F., Caruso, D., Melcangi, R.C., Higuchi, M., Martins, R.N., Barron, A.M.
  • Organizer: Alzheimer`s Association International Conference
  • Place of Presentation: Washington, USA
  • Year and Date: 2015-07-18 – 2015-07-23
• [Presentation] Translocator protein as a therapeutic target for Alzheimer`s disease (2015)
  • Author(s): Barron, A.M., Asih, P. R., Ji, B., Katsifis, A., Pike, C.J., Martins, R.N., Higuchi, M.
  • Organizer: International Steroids and Nervous System
  • Place of Presentation: Torino, Italy
  • Year and Date: 2015-02-14 – 2015-02-18