EMORY UNIVERSITY
Grant: $387,500 - National Institutes of Health - Sep. 4, 2009
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Award Description: Although Alzheimer?s Disease (AD) is an aggressive and devastating dementia that has an increased frequency with age and is one of the most common neurodegenerative diseases, it is remarkably difficult to diagnose with certainty, particularly in the earliest stages when significant presymptomatic changes are happening in specific cognitive and memory centers of the patients? brains. Several other neurodegenerative dementias have similar symptoms and conclusive diagnosis requires a postmortem neuropathological exam. The two hallmark defects of AD are senile plaques (SP) and neurofibrillary tangles (NFT). If one or both of these defects could be imaged in the living patient during the earliest disease stages, it would benefit both clinical treatment regimens and basic research. To develop a method for such imaging studies, radio-chemists have tried to model candidate tracers for neuroimaging on fluorescent dyes that bind to the beta-pleated sheet structures of the amyloid fibrils of SP. Several classes of tracers have met with a measure of success but lack a high signal-to-noise ratio and only one is labeled with 18F, a positron emitting isotope with a long enough half-life (110 minutes) to permit transportation to institutions lacking a cyclotron facility. We propose to develop a high-affinity, fluorinated radioligand for ß-amyloid that can be used as a radiotracer for PET neuroimaging. Analogs of several divergent prototypes from two different laboratories will be tested in both in vitro and in vivo assays for ß-amyloid binding in SP of AD brain tissue. In addition, we will determine the diagnostic specificity of ligand binding for two major subtypes of frontotemperal dementia classified according to deposits of ubiquitin versus tau. Finally, we will determine the aggregation state and peptide/protein composition of the binding site in AD brain tissue using photoaffinity labeling and affinity purification techniques combined with western blotting and mass spectroscopy.
Project Description: The purpose of this project is to develop improved ß-amyloid binding agents for imaging the disease process in the brains of living Alzheimer?s Disease patients using Positron Emission Tomography (PET). There are several such agents used clinically and they have produced valuble information about AD; however, they suffer from at least one of two specific limitations. The first is that they all have rather low sensitivity and the second is that some use a 11C isotope as their positron emitting label, which decays so quickly that it makes the binding agent difficult to work with. We will develop new agents that have better sensitivity and that use 18F as the positron emitting label, which has decays much more slowly. To accomplish this goal, we will test many new compounds for their ability to bind to ß-amyloid in a test tube and we will identify and study the chemical nature of the binding site for such agents located on the ß-amyloid molecule. STATUS: This project has just begun. We are currently designing new agents, including a special one that will allow us to purify the ß-amyloid in order to study its chemistry and binding properties. Dr. Ciliax is in the process of creating a technician position and interviews will begin shortly. Quotes for the primary probe have been obtained and an order for its synthesis will be submitted soon.
Infrastructure Description: N/A
Jobs Summary: Brian J. Ciliax, Ph.D., Principal Investigator (6.0 calendar months), Assistant Professor of Neurology. Dr. Ciliax has been working on developing amyloid radioligands for the past 5 years. He laboratory screens compounds using various binding experiments and can determine which are the best agents based on their affinity for the binding target. Dr. Ciliax will design all binding, immunostaining, and biochemistry experiments, analyze and interpret all data, and supervise a technician. Marla Gearing, Ph.D., Faculty (1.80 calendar months), Assistant Professor of Pathology. Dr. Gearing has expertise in neuropathology and will provide tissue samples from various neurodegenerative diseases stored in the Emory University Center for Neurodegenerative Diseases. She is the director of the Alzheimer?s Disease Brain Bank at Emory. She performs autopsies, archives the tissue, characterizes it via neuropathological exams, and distributes both fixed and frozen samples to investigators around the world for their research. She will oversee any immunostaining of tissues and provide relevant neuropathological information on the individual cases. Fanxing Zeng, Ph.D., Co-Investigator (4.56 calendar months), Assistant Professor of Radiology. Dr. Zeng has expertise in synthetic chemistry of radiotracers and has been synthesizing several IMPY derivatives for our preliminary studies. She will provide all [18F]radioligands to Dr. Ciliax?s lab as well as synthesize the affinity purification ligands. Outside this project, Dr. Zeng also generates PET agents for imaging neurotransmitter receptors and various transporters. Technician (12.0 calendar months), This person will be hired to work in Dr. Ciliax's laboratory. They will perform the basic binding, immunochemical, immunostaining, and biochemical assays. Small-scale binding assays will be translated into one or more high-throughput screening systems. The technician will log, store, and process brain specimens, log and manage radioactivity usage, log and manage a small library of chemical compounds, prepare buffers and reagents, conduct experiments with supervision from the Investigator, maintain the lab and its equipment, and order supplies. Technician, (1.80 calendar months Year 2) This person will perform mass spectroscopy experiments, which can determine the chemical identity of many proteins contained in a biological sample. This will allow us to determine the chemical nature of the ß-amyloid binding site recognized by currently available PET agents. Such knowledge will give us valuable information for designing better agents. (Total jobs reported: 0)
Project Status: Not Started
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