Study Rationale: Glucocerebrosidase is an enzyme that is essential for maintaining healthy lipid metabolism throughout the human body. In Parkinson’s disease (PD), the efficiency of this protein is impaired, contributing to pathological changes in the brain. Enhancing glucocerebrosidase efficiency is a promising new treatment approach to slow disease progression; however, the development of such drugs is hampered by the lack of tools to investigate their effectiveness. We therefore propose to develop a radiotracer that – much like a chemical dye – allows us to monitor the performance of glucocerebrosidase in the body using a type of medical imaging called positron emission tomography (PET).
Hypothesis: We hypothesize that chemicals that are known to strongly bind to glucocerebrosidase in experimental cellular systems can be converted into radiotracers suitable for tracking glucocerebrosidase impairment in people with PD via PET scanning.
Study Design: We will investigate the effectiveness of two different types of chemicals for monitoring glucocerebrosidase in the human brain. To achieve this, we will work with brain tissue donated for research by people with PD as well as healthy volunteers, and we will quantify binding of each chemical using a tissue imaging technique called autoradiography. If the compounds demonstrate specificity for glucocerebrosidase binding, we will assess their ability to reach the brain. Guided by the results of these tests, we will optimize the structure of one selected chemical to work towards the characteristics required of a PET tracer.
Impact on Diagnosis/Treatment of Parkinson’s disease: Glucocerebrosidase-PET could accelerate the development of new PD therapeutics by facilitating the visualization and quantification of their effects in the living brain. In a clinical setting, such a tool would allow doctors to identify patients that are likely to benefit the most from glucocerebrosidase enhancing drugs, once these are available.
Next Steps for Development: If successful, the results will be used to support a PET tracer discovery program. This program would include radiochemistry development and exhaustive characterization of the PET tracer candidate in preclinical (animal) models of PD, to prepare for first-in-human studies.