Ontwikkeling van radiotracers voor in vivo visualisatie van Heat Shock Protein 90 met positronemissietomografie: van lab naar kliniek

Our cells have built-in systems to keep proteins functional. A key player in this system is Heat Shock Protein 90 (Hsp90), a protein that helps other proteins fold correctly, stay stable, and perform their normal tasks, especially when cells are under stress. Because of its essential role, Hsp90 is involved in many diseases where proteins become damaged or behave abnormally. In cancer, for example, Hsp90 supports proteins that help tumor cells grow and survive. In brain disorders such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis (ALS), it interacts with toxic proteins that accumulate in the brain. Therefore, Hsp90 has attracted growing interest as a therapeutic target that could influence several disease mechanisms. However, targeting Hsp90 is not straightforward. Since it is also important in healthy cells, developing drugs that selectively affect only the harmful activity of Hsp90, without disrupting its normal functions, has proven challenging. To improve treatment strategies, researchers need reliable tools to measure how much Hsp90 is present in the body and where it is active. One powerful method is PET (positron emission tomography) imaging, which uses very small mass amounts of radioactive substances, called tracers, to visualize biological activity inside the body. These tracers are designed to bind to specific proteins like Hsp90, allowing scientists to see where the protein is located, how much is present, and how it changes with disease or treatment. PET imaging has long been used, especially for cancer, brain, and heart conditions, to support diagnosis, monitor disease progression, and guide therapy decisions. Applying PET to Hsp90 could help us better understand its role in both health and disease. It could also aid in the development of new treatments by helping identify patients that may benefit from Hsp90 targeted therapy, tracking how a disease evolves, and showing whether Hsp90-targeting drugs are effectively reaching their target. This information is essential to adjust drug dosing and minimize side effects, common obstacles in Hsp90-related drug development. In this research, we developed and tested three new PET tracers that specifically bind to Hsp90, two labeled with carbon-11 and one with fluorine-18. These tracers were evaluated in cells, tissues, and small animal models to determine how specifacally they target Hsp90 and how they behave in the body. One of the tracers showed strong potential and is now being tested in a clinical study to explore its usefulness in imaging Hsp90 in patients with Alzheimer's disease, Parkinson's disease, and ALS. These new imaging tools could deepen our understanding of Hsp90's role in brain disorders and may support the development and monitoring of new Hsp90-targeted therapies in the future.