Nuclear Magnetic Resonance Analysis to Support Development of Alpha-Synuclein Imaging Agents

Study Rationale:
The Michael J. Fox Foundation Imaging Consortium has identified several promising compounds that bind specifically to alpha-synuclein fibrils, the clumps of protein that accumulate in the brains of people with Parkinson’s disease. We will perform experiments to determine where on the fibrils these agents interact with alpha-synuclein and whether all the agents interact in the same region. This information will aid the development of better imaging agents. 

Hypothesis:
The aim is to understand where on the alpha-synuclein fibrils the imaging agents bind, and whether there are multiple different locations. We hypothesize that this can be determined by identifying changes in the nuclear magnetic resonance (NMR) spectra of the fibrils upon addition of the imaging agents. 

Study Design:
We will prepare alpha-synuclein fibrils with isotopic labels (C-13 and N-15) that enable us to collect nuclear magnetic resonance (NMR) spectra. NMR is the sister technique of magnetic resonance imaging (MRI), in which high magnetic fields are used to observe the shape and position of molecules. We will characterize the spectra of the fibrils before and after adding each imaging agent; we expect that some of the signals will change position or intensity, indicating the locations where the agents bind. Then we will perform additional experiments to define the locations more precisely.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
As Parkinson’s disease (PD) develops, the protein called alpha-synuclein accumulates in the brain in clumps of material known as fibrils. Detecting the amount and location of these fibrils in the brain would potentially enable early detection of PD and better ways to evaluate the effect of PD drug therapies. 

Next Steps for Development:
Structural information will help to develop better imaging agents. For example, if two imaging agents interact with distinct sites on the alpha-synuclein fibrils, our data would help define the proper way to attach them together and maintain the favorable properties of each molecule, ultimately making a more powerful imaging agent.