In vivo imaging of heat shock protein 90: Diagnostic tool and support for Hsp90-targeted therapy

The molecular chaperone heat shock protein 90 (Hsp90), essential for protein homeostasis and cellular stress response, has emerged as a promising therapeutic target across various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions. Although numerous Hsp90 inhibitors have been developed and extensively evaluated in clinical studies, progress has been impeded by limited clinical efficacy, narrow therapeutic windows, and challenges in assessing target engagement. These limitations highlight the importance of developing complementary noninvasive molecular imaging tools to better understand Hsp90 function in vivo and optimize therapeutic strategies, including assessing target engagement, refining dosing strategies, monitoring treatment response, and enabling patient stratification. This review provides a comprehensive overview of the current landscape of Hsp90-targeted molecular imaging. We discuss imaging modalities applicable to Hsp90, optical imaging, single-photon emission computed tomography, and positron emission tomography, and highlight key molecular probes developed to visualize Hsp90 expression and function in vivo using these modalities. Furthermore, we summarize significant findings that have deepened our fundamental understanding of Hsp90's role in disease, supported the development of novel therapeutic approaches, demonstrated imaging effectiveness in preclinical models, and suggested potential for integration into clinical research. We also address current challenges and propose future directions for the field. Through this review, we aim to illustrate the translational potential of molecular imaging in advancing our understanding of Hsp90 in disease and optimizing Hsp90-targeted therapeutics, thereby contributing to precision medicine approaches.