In vivo imaging agents targeting Tau aggregates

Summary

Principal Investigator: HANK KUNG
Affiliation: University of Pennsylvania
Country: USA
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease of the brain, symptoms include dementia, cognitive impairment and memory loss. The disease has a very significant medical importance because it is affecting millions of older population with increasing incidence. Formation and accumulation of aggregates of ¿-amyloid aggregates (A¿ plaques) and tau (tangles) in the brain are distinctive hallmarks of this insidious disease. Both are protein aggregates that contain parallel ¿-sheet structures. The aggregates are likely to be linked to the patho-physiology of neurodegeneration of brain cells. Currently, early appraisal of clinical symptoms for diagnosis of AD is often difficult and unreliable. Therefore, there is an urgent need for in vivo imaging agents, which can specifically demonstrate the location and density of tangles and plaques in the brain. The objective of this project is to develop potential F-18 and I-123 labeled diagnostic imaging agents, which specifically detect tangles (tau aggregates) in the brain using positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively. Imaging tau (tangles), a biomarker for AD, may lead to improve understanding of disease progression and it may potentially be useful for monitoring drug treatment targeting the formation of hyperphosphorylated tau in the brain cells. Based on recent success from our laboratory on developing A¿ plaque-targeting imaging agents, we believe that it is feasible to expand into the area of developing new selective probes for tangles. It is generally accepted that brain samples of corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) patients contain predominately tangles (consisting mainly tau aggregates). Using postmortem brain tissue samples of CBD and PSP for homogenate binding assay and tissue section labeling, we hope to selectively detect tau binding. Three specific aims are proposed: I). In vitro binding assay for specific binding of tau aggregates. II). Synthesis of new compounds. III). In vitro autoradiography of brain sections. IV). Selected compounds will be labeled and evaluated further by in vivo biodistribution study using normal mice. The proposed specific aims are innovative and carefully crafted to meet the stringent requirements for selecting tau-specific imaging agents. We believe that tau-selective imaging agents can be successfully developed and they will serve an unmet need as diagnostic tools for early detection of AD. Alzheimer's disease and other Tauopathies are neurodegenerative diseases of the brain. They are becoming increasingly significant medical problems in our aging society. In order to address the enormous future healthcare burdens that they pose, we need to find effective diagnostic tools and therapeutics for neurodegenerative diseases now. The most significant anatomical hallmarks of these diseases are the presence of ¿-amyloid (A¿) plaques, and neurofibrillary tangles, which contain highly phosphorylated Tau proteins. The objective of this project is to develop F and I labeled molecular imaging agents that can selectively detect 18 123 Tau aggregates in the living human brain. In conjunction with PET (positron emission tomography) or SPECT (single photon computed tomography) these agents will be critically important tools that will be able to visualize and quantify the accumulation of Tau aggregates in the brain of patients with neurodegenerative diseases. The critical objective of this project is to find a F or I compound with a high binding affinity to Tau 18 123 aggregates which can deliver sufficient signal correlated with Tau aggregates in the living human brain. The potential benefits of developing these imaging agents include: a) More precise diagnosis and monitoring of the progression of AD or Tauopathies in symptomatic patients; b) Improved risk stratification of asymptomatic elderly patients prior to AD or other Tauopathy related disorders; c) Better understanding the role of Tau aggregate accumulation in progression of MCI and AD patients; d) Catalyzation of the development of anti-Tau therapies.
Funding Period: 2007-08-01 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Synthesis of biphenyltrienes as probes for beta-amyloid plaques
    Zhi-Ping Zhuang
    Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Med Chem 49:2841-4. 2006
  2. ncbi Fluoro-pegylated (FPEG) imaging agents targeting Abeta aggregates
    Karin A Stephenson
    Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, Pennsylvania 19104, USA
    Bioconjug Chem 18:238-46. 2007
  3. ncbi Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for beta-amyloid plaques
    Wenchao Qu
    Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104, USA
    Bioorg Med Chem Lett 18:4823-7. 2008

Scientific Experts

  • HANK KUNG
  • Mei-Ping Kung
  • Zhi-Ping Zhuang
  • Wenchao Qu
  • Mei Ping Kung
  • Shunichi Oya
  • Catherine Hou
  • Karin A Stephenson
  • Daniel M Skovronsky
  • Rajesh Manchandra
  • Seok Rye Choi
  • Seok-Rye Choi
  • Wei Zhang
  • Zhiping Zhuang
  • Zhi Ping Zhuang
  • Rajesh Chandra

Detail Information

Publications4

  1. ncbi Synthesis of biphenyltrienes as probes for beta-amyloid plaques
    Zhi-Ping Zhuang
    Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Med Chem 49:2841-4. 2006
    ..When labeled with suitable radionuclides, they are useful as in vivo imaging agents for detecting Abeta plaques in the brains of Alzheimer's patients...
  2. ncbi Fluoro-pegylated (FPEG) imaging agents targeting Abeta aggregates
    Karin A Stephenson
    Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, Pennsylvania 19104, USA
    Bioconjug Chem 18:238-46. 2007
    ..This approach appears to be effective in some core structures, but it cannot be uniformly applied to all structures...
  3. ncbi Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for beta-amyloid plaques
    Wenchao Qu
    Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104, USA
    Bioorg Med Chem Lett 18:4823-7. 2008
    ..These preliminary results identified that indolylphenylacetylene, 14, may be a good lead for further structural modification to develop a useful Abeta plaque imaging agent...