Design, Synthesis, and Evaluation of a Novel-Labeled Small Molecule Inhibitor-Based PET/SPECT Tracer Targeting HSP90

Several HSP90 inhibitors are in use or late-stage trials: pimitespib is approved in Japan for intestinal tumors, hypericin sodium under US regulatory review, and WP-1303 in Phase III development. However, their efficacy depends on tumor HSP90 expression levels, necessitating probes for subtype-specific detection in vivo. Translation is limited by inadequate validation in specific subtypes and off-target accumulation in kidneys and liver. We developed and optimized an HSP90-targeted radiotracer addressing these limitations. Chemical modifications enhanced tumor uptake in colorectal and gastric cancer models (10.02 ± 2.05% and 5.02 ± 0.08% ID/g), while reducing liver and kidney retention (∼2% and ∼5% ID/g), yielding tumor/muscle ratios of 23.28 ± 9.70 and 16.73 ± 2.80. Clinical evaluation confirmed translational potential, enabling tumor delineation and high-contrast imaging (SUV_max ∼ 5). This probe supports comprehensive cancer management and may guide clinical application of emerging HSP90 inhibitors.