The proposed research is aimed at developing radiopharmaceuticals that readily enter the brain and selectively localize in the white matter via direct binding to myelin membranes. Abnormality and changes associated with myelin membranes in the central nervous system play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. Thus, direct assessment of myelin content in vivo has been an important goal in protection and repair of axonal damage. However, the lack of molecular probes has limited the progress of myelin imaging and hindered efficacy evaluation of novel myelin repair therapies currently under development. To meet this need, we plan to develop myelin-imaging agents uniquely suited for use in clinical imaging modalities such as positron emission tomography (PET). We hypothesize that small-molecule PET probes can be developed, which will freely enter the brain, directly and selectively bind to myelin membranes. To test this hypothesis, we have identified some lead compounds with promising binding properties for in vivo studies, which allows us to address the following specific aims: 1) Rationally design and synthesize a selected series of myelin-imaging agents and quantitatively evaluate their binding properties in vitro for structure-activity relationship studies;2) Radiolabel selected agents with positron-emitting 11C or 18F and assess the in vivo binding properties in animal models of demyelination to determine the rates of brain entry, clearance, and specific retention in the brain;3) Evaluate the pharmacokinetic profiles and metabolism of selected myelin-imaging agents through PET studies in non-human primates for potential application in human subjects. It is anticipated that completion of the project will lead to the development of imaging markers that are suitable for application in human subjects.

Public Health Relevance

This research project has following important impacts on public health: 1) facilitation of efficacy evaluation of therapies currently under development that are aimed at prevention of axonal damage and myelin repair;2) direct correlation of myelin changes with clinical outcomes;3) aid in early and accurate diagnosis and subtyping of MS and related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061837-04
Application #
8113314
Study Section
Special Emphasis Panel (ZRG1-NT-B (01))
Program Officer
Utz, Ursula
Project Start
2008-09-30
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$336,569
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Frullano, Luca; Zhu, Junqing; Miller, Robert H et al. (2013) Synthesis and characterization of a novel gadolinium-based contrast agent for magnetic resonance imaging of myelination. J Med Chem 56:1629-40
Wu, Chunying; Zhu, Junqing; Baeslack, Jonathan et al. (2013) Longitudinal positron emission tomography imaging for monitoring myelin repair in the spinal cord. Ann Neurol 74:688-98
Shi, Hong; Sheng, Baiyang; Zhang, Feng et al. (2013) Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function. Am J Physiol Heart Circ Physiol 304:H796-805
Frullano, Luca; Zhu, Junqing; Wang, Changning et al. (2012) Myelin imaging compound (MIC) enhanced magnetic resonance imaging of myelination. J Med Chem 55:94-105
Condie, Allison G; Gerson, Stanton L; Miller, Robert H et al. (2012) Two-photon fluorescent imaging of myelination in the spinal cord. ChemMedChem 7:2194-203
Wang, Changning; Wu, Chunying; Popescu, Daniela C et al. (2011) Longitudinal near-infrared imaging of myelination. J Neurosci 31:2382-90
Frullano, Luca; Wang, Changning; Miller, Robert H et al. (2011) A myelin-specific contrast agent for magnetic resonance imaging of myelination. J Am Chem Soc 133:1611-3
Wang, Changning; Wu, Chunying; Zhu, Junqing et al. (2011) Design, synthesis, and evaluation of coumarin-based molecular probes for imaging of myelination. J Med Chem 54:2331-40
Wang, Changning; Popescu, Daniela C; Wu, Chunying et al. (2010) In situ fluorescence imaging of myelination. J Histochem Cytochem 58:611-21
Wu, Chunying; Wang, Changning; Popescu, Daniela C et al. (2010) A novel PET marker for in vivo quantification of myelination. Bioorg Med Chem 18:8592-9

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