Novel TSPO ligands to facilitate rapid tracer discovery and as precision imaging diagnostics of cancer

Abstract

Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships (SAR) related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and explored the impacts of these substituents on lipophilicity and plasma protein binding. Leveraging prior SAR on a series of novel pyrazolopyrimadines, we developed a series of new TSPO ligands with appended FITC fluorescence easily detectable by conventional optical imaging and microscopy. We further established the correlation between TSPO overexpression and pancreatic cancer, and developed a novel TSPO near-infrared probe that could allow surgeons to precisely locate and remove high-risk lesions. A small molecule TSPO PET tracer functionalized with Zirconium-89 was also utilized in pancreatic cancer imaging, which is ideal for the long circulation time required by high grade dense stromal. We envision these probes may help with pancreatic cancer diagnosis and surgery, and possibly be used for other TSPO related diseases, such as colon and breast cancers.