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

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26830038
• Research Institution: National Institute of Radiological Sciences
• Principal Investigator: Barron Anna 国立研究開発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: translocator protein / nootropic / Alzheimer`s disease / neuroactive steroid

Outline of Annual Research Achievements

Neuroactive steroid levels were measured by liquid chromatography tandem mass spectrometry in the brains of samples collected in the previous year to confirm the ability of the novel TSPO ligands, CLINDE, PBR-175 and PBR-162, to alter neurosteroidogenesis in vivo.
The specificity and pharmacokinetic properties, including biodistribution and receptor occupancy, of the novel TSPO ligands was assessed by competitive PET imaging using the highly specific TSPO ligand [11C]PK-11195. While all three novel ligands rapidly penetrated the brain, CLINDE was the most stable. Since affinity for TSPO of many second generation TSPO ligands is greatly reduced by a common polymorphism, we evaluated the affinity of our novel ligands in human brain homogenates from high-affinity binder (HAB) and low-affinity binder (LAB) subjects. Since CLINDE exhibited the most favorable behavioral and pharmacokinetic profile, its specificity was confirmed in TSPO knockout mice, with no effect on learning and memory observed in these mice. 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.

Research Products

• [Journal Article] Neurosteroidogenesis today: Novel targets for neurosteroid synthesis and action and their relevance for translational research (2015)
  • Author(s): Patrizia Porcu, Anna M Barron, Cheryl Frye, S-Y Yang, Roberto Cosimo Melcangi, GianCarlo Panzica
  • Journal Title: Journal of Neuroendocrinology Volume: 28(2) Pages: 1-19
  • DOI: 10.1111/jne.12351
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Impact of Luteinizing hormone and Testosterone on beta amyloid (Aβ) accumulation: animal and human clinical studies (2015)
  • Author(s): [2]Verdile, G.V., Asih, P. Barron, A.M., Whajoepramono, E.J., Ittner, L.M., Martins, R.N.
  • Journal Title: Hormones and Behavior Volume: 76 Pages: 81-90
  • DOI: 10.1016/j.yhbeh.2015.05.020
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] In vivo evaluation of the therapeutic potential of novel translocator protein (TSPO) ligands for the treatment of Alzheimer's disease (2015)
  • Author(s): Asih, P.R., Bin, J., 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 DC
  • Year and Date: 2015-07-17 – 2015-07-23
  • Int'l Joint Research