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. ? ? ? ?
| 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 |
| 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 |
| 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, Yanming; Wu, Chunying; Caprariello, Andrew V et al. (2009) In vivo quantification of myelin changes in the vertebrate nervous system. J Neurosci 29:14663-9 |
| Wu, Chunying; Wei, Jinjun; Tian, Donghua et al. (2008) Molecular probes for imaging myelinated white matter in CNS. J Med Chem 51:6682-8 |
| Wu, Chunying; Tian, Donghua; Feng, Yue et al. (2006) A novel fluorescent probe that is brain permeable and selectively binds to myelin. J Histochem Cytochem 54:997-1004 |
