PET imaging for TSPO in liver diseases

Translocator protein (18 kDa; TSPO) is the critical component of a multimeric 140-200-kDa complex located in the outer mitochondrial membrane and enriched in the outer/inner mitochondrial membrane contact sites. TSPO has broad functions related to the mitochondrial function regulation, steroid hormone synthesis, porphyrin and heme transport, apoptosis, cell proliferation, immunomodulation, and inflammation. TSPO is widely distributed in the peripheral tissues and the mRNA levels of TSPO are high in the adrenal glands, kidneys, spleen, heart, and lungs, and are low in the liver and brain. It has been demonstrated that TSPO expression increases in inflammatory cells during the occurrence and progression of inflammation. Because of low expression of TSPO in normal liver, we used positron emission tomography (PET) with a TSPO radioprobe [18F]FEDAC to visualize TSPO in liver diseases and to determine cellular sources enriching TSPO expression in the liver. We conducted PET imaging with [18F]FEDAC to noninvasively visualize and quantify TSPO in the peripheral tissues and monitor three liver diseases, such as nonalcoholic fatty liver disease, liver damage, liver fibrosis in animal models. The radioactive uptake of [18F]FEDAC increased with disease progression. Strong correlations were observed between radioactivity uptake ratio and disease severity in the liver. The in vivo specific binding of [18F]FEDAC to TSPO in the livers was demonstrated by competition experiments with the unlabeled TSPO selective PK11195. In vitro autoradiography and histopathology supported these PET imaging results. Further, we found that some of the PET images reflected increase of senescent cells in the livers and improvement of therapeutic effects of senolytics on the liver diseases. First-in-human PET study with [18F]FEDAC has been finished on volunteer peoples.