The proposed research is directed at developing small-molecule probes that readily enter the brain and specifically bind to myelin membranes. Abnormality and changes associated with myelin are seen in many neurodegenerative disorders. Thus, direct assessment of the myelin content in vivo in the central nervous system has been an important goal in protection and repair of axonal damage. Although magnetic resonance imaging (MRI) is conventionally used for detection of brain lesions with high sensitivity, MRI does not directly monitor myelin content. It does not differentiate between lesions caused by demyelination and inflammation. For in vivo MR studies on myelin, molecular probes are required as contrast agents that are specific for myelin membranes. We propose to develop molecular probes suitable for magnetic resonance imaging studies of myelin. Development of myelin-imaging probes would also allow other MR imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) to better studies myelin changes in the brain. We hypothesize that small-molecule probes can be developed as myelin-imaging agents that selectively accumulate in the myelinated brain regions with suitable in vitro and in vivo properties for MR studies. To test this hypothesis, we have identified a lead compound, termed BMB, which readily enters the brain and selectively binds to myelin. We plan to further evaluate this lead myelin-imaging agent to address the following specific aims: 1) Further evaluate the lead myelin-binding compound through in vitro binding assays and tissue staining to quantitatively determine the binding affinity and specificity; 2) Characterize the in vitro MR properties of BMB following binding to isolated brain myelin fractions and incubation in brain tissue sections; 3) Characterize the in vivo MR properties of the probes in normal control mice and mouse models of demyelination and remyelination. It is anticipated that completion of the project will prove the concept that molecular probes can be developed for in vivo MR studies of myelin, and serve as a basis for further development and application in human subjects. This research has following impacts on public health: 1) effective detection of demyelination at early stages to aid in definitive diagnosis; 2) correlation of the demyelinated lesion burden with the severity of symptoms, and 3) facilitation of efficacy evaluation of remyelination therapies currently under development. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS054109-01A1
Application #
7146860
Study Section
Special Emphasis Panel (ZRG1-BDCN-F (11))
Program Officer
Utz, Ursula
Project Start
2006-09-26
Project End
2008-06-30
Budget Start
2006-09-26
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$173,813
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
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