Supramolecular Hosts as Combined Protein Aggregation Inhibitors and Hyperpolarized MRI Reporters

Study Rationale:
Amyloid fibrils play a key role in Parkinson's disease (PD) and monitoring of their formation from self‐assembled insoluble molecular aggregates would be extremely valuable as a diagnostic tool in living tissue. Despite the progress in understanding these aggregations processes in a test tube, visualization of the involved compounds in a diagnostic imaging approach has not yet been achieved in a satisfactory way. We will develop a contrast agent with protective effects based on a molecule that has recently been postulated to interact with the related molecules.

Hypothesis:
This project aims to develop a novel type of magnetic resonance imaging (MRI) reporter that a) specifically binds to alpha-synuclein as a disease‐modifying molecular target for Parkinson's disease (PD) and b) inhibits further fibril formation to interrupt the disease progress at an early stage.

Study Design:
This project relies on the recently developed concept of xenon biosensors that consist of container molecules for temporarily trapping the harmless noble gas xenon which enables MRI scans at unprecedented sensitivity. We will synthesize a novel sensor type where the molecular container can trap alternatively xenon or alpha-synuclein. It therefore changes its signal at the onset of fibril formation but also inhibits further progression. This study will explore the MRI capabilities of such a sensor in cell cultures specifically used in PD research. MRI detection will be co-validated with optical imaging methods for further optimization prior to clinical translation.

Impact on Diagnosis/Treatment of Parkinson's disease:
This project has a twofold impact because we will simultaneously get information about the therapeutic effect postulated earlier for the molecular container used here (CB7) and use its affinity for designing a contrast agent that is sensitive to the early onset of PD before amyloid fibril formation.

Next Steps for Development:
We plan rapid translation into preclinical tests upon successful completion of this sensor design. Such a step will already foster monitoring of therapy outcome for drug development that focuses on such early molecular events during the onset of PD in animal models. This will eventually lead to a perspective for clinical applications in humans.