Molecular Imaging of Neurons in the Brain

James Olson, M.D., Ph.D.

University of Washington Medical School

Funded in December, 2004: $120000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Molecular Imaging of Neurons in the Brain

Researchers will develop “smart contrast agents” that bind to specific brain cells involved in Parkinson’s and Huntington’s disease, enabling scientists to quantify brain cell loss in patients with these degenerative diseases.  If effective, this technique then could be used to assess the effects of therapies designed to prevent death of these cells. 

Smart contrast agents are tiny particles of iron oxide that are coated with drugs.  They travel to and bind with brain cells that use the neurotransmitter dopamine to communicate.  These are the cells that are progressively destroyed in Parkinson’s and Huntington’s diseases, and the contrast agents can be used with MRI imaging to measure the extent of cell loss over time.  Using MRI with this new tracer avoids the constraints incurred by PET scanning, which currently is the only way to image specific brain cell populations.  Moreover, the therapeutic drugs that are to be attached to the iron oxide smart contrast agent already have been approved for use in humans.  If these new smart contrast agents successfully identify and bind to dopamine-transmitting brain cells, the research would lead directly to the clinical use of this technique to assess the effectiveness of therapies designed to prevent cell death in these two devastating diseases.

Significance:  If this new tracer proves effective in enabling MRI imaging of cells that die as a result of Huntington’s and Parkinson’s diseases, it would be an advance over the use of PET.  Moreover, the new tracer could become a clinical tool for delivering therapeutic drugs to their target cells, and for imaging the drugs’ effectiveness in preventing cell loss.  This would be a major diagnostic and therapeutic advance that also might be adapted for use in combating other brain diseases.

ABSTRACT

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Molecular Imaging of Neurons in the Brain

Neurodegenerative diseases such as Huntington's disease and Parkinson's disease preferentially affect certain vulnerable neuronal populations in the brain. The ability to image these neuron populations in any hospital that has magnetic resonance imaging (MRI) capabilities would improve diagnosis, prognosis, and clinical trial endpoints for these diseases. We propose to develop "smart" contrast agents that target paramagnetic iron oxide nanoparticles to neurons that express D2 dopamine receptors. The nanoparticles will be coated with ligands that bind to D2 receptors with nanomolar affinity. The specificity of the ligand-conjugated nanoparticles for D2 receptors will be tested in immortalized rat striatal neuronal cell cultures. Nanoparticles that specifically bind to striatal neurons with nanomolar affinity will advance to in vivo studies in wild type and Huntington's disease R6/2 mice.

Wild type mice provide an opportunity to distinguish D2 receptor-rich striatum from overlying cerebral cortex that contains few D2 receptor-positive neurons. The R6/2 mice show markedly reduced D2 receptors in striatum, thus the striatum:cortex D2 receptor ratio is predicted to be smaller in these mice than in wild type littermate controls. D2 receptor ligands that have already been approved for use in humans will be used in this study so that successful "smart contrast" agents are optimally positioned to advance to human clinical trials.

HYPOTHESIS

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Hypothesis:
We hypothesize that superparamagnetic nanoparticle contrast agents will enable imaging of neuronal populations in brain.

Goals:
1. Generate nanoparticles that bind to D2 dopamine receptors with nanomolar affinity

2. Evaluate D2-targeting nanoparticles in mice

Methods:
We propose to develop "smart" contrast agents that target paramagnetic iron oxide nanoparticles to neurons that express D2 dopamine receptors.  The nanoparticles will be coated with ligands that bind to D2 receptors with nanomolar affinity. The specificity of the ligand-conjugated nanoparticles for D2 receptors will be tested in immortalized rat striatal neuronal cell cultures.  Nanoparticles that specifically bind to striatal neurons with nanomolar affinity will advance to in vivo studies in wild type and Huntington's disease R6/2 mice.

SELECTED PUBLICATIONS

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Kohler N., Fryxell G.E., and Zhang M.  A bifunctional poly(ethylene glycol) silane immobilized on metallic oxide-based nanoparticles for conjugation with cell targeting agents.  J Am Chem Soc. 2004 Jun 16;126(23):7206-11.

Zhang Y., Sun C., Kohler N., and Zhang M. Self-assembled coatings on individual monodisperse magnetite nanoparticles for efficient intracellular uptake. Biomed Microdevices. 2004 Mar;6(1):33-40.

Zhang Y., Kohler N., and Zhang M. Surface modification of superparamagnetic iron oxide nanoparticles and their uptake into the macrophage cells. Biomaterials. 2002 Apr;23(7):1553-61.

Zhao M., Beauregard D.A., Loizou L., Davletov B., and Brindle K.M. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med. 2001 Nov;7(11):1241-4.

Luthi-Carter R., Strand A., Peters N.L., Solano S.M., Hollingsworth Z.R., Menon A.S., Frey A.S., Spektor B.S., Penney E.B., Schilling G., Ross C.A., Borchelt D.R., Tapscott S.J., Young A.B., Cha J.H., and Olson J.M.  Decreased expression of striatal signaling genes in a mouse model of Huntington's disease.  Hum Mol Genet. 2000 May 22;9(9):1259-71.