Translational investigation of the role of Hsp90 in neurodegenerative proteinopathies using positron emission tomography (PET)

Heat Shock protein-90 (Hsp90) is an ubiquitous "chaperone" protein responsible for (re)folding of client proteins to prevent them from degradation. Hsp90 is expressed at high levels in brain and recent research suggests a role of Hsp90 in neurodegenerative diseases. Positron emission tomography (PET) is a molecular imaging technique that allows in vivo quantification of the body distribution of radioactive tracers. We recently developed PET tracers with high affinity for Hsp90 and identified [11C]YC as a PET tracer allowing in vivo visualization of Hsp90 in brain of mice, rats and a rhesus monkey. As we were able to block Hsp90 tracer binding in vivo we assume that a only small fraction of the large Hsp90 pool in brain adopts a high-affinity binding mode. In this project we aim to 
1. expand our library of PET tracers for in vivo visualization of Hsp90
2. identify the molecular form of Hsp90 adopting the high-affinity binding mode using advanced protein identification methodology and localize the tracer binding site(s) with sub-cellular resolution
3. use quantitative autoradiography to determine the contribution of the different Hsp90 isoforms to the global Hsp90 high-affinity binding
4. develop and validate a protocol for quantitative preclinical Hsp90 PET
5. translate the selected Hsp90 PET tracer to the clinic in order to quantify regional Hsp90 expression in brain of Alzheimer's and Parkinson's patients in comparison with healthy age-matched controls.