Clinical Study of Trap-(FAPI)3 PET Imaging in the Diagnosis of Pulmonary Nodules

Positron Emission Tomography (PET) is a functional imaging technology for the diagnosis and monitoring of tumors. The clinical applications of PET in malignant tumors, including staging, response evaluation, and efficacy prediction, provide attractive semi-quantitative biomarkers for clinical and research platforms. Understanding the advantages and limitations of fundamental imaging science and imaging modalities is crucial for optimizing research evaluations. With the widespread use of functional techniques and the development of novel PET biomarkers, PET research evaluations will be further improved.

The field of oncology has undergone a revolution due to molecular imaging, which evaluates tumor biology, while traditional radiological imaging focuses on morphological anatomy. Molecular imaging employs non-invasive visualization of physiological or pathological processes at the cellular or subcellular level. Positron Emission Tomography/Computed Tomography (PET/CT) is a hybrid imaging tool that provides complementary information on both function and structure. [18F]Fluorodeoxyglucose (FDG), first developed in the late 1970s as a tracer for brain metabolism, is now the most widely used PET tracer with applications in both oncological and non-oncological pathways. Although its clinical utility is undeniable, FDG uptake serves as a surrogate indicator for glucose transport/metabolism and is not specific to malignant tumors. The diagnostic accuracy of FDG for pulmonary nodules has long been a challenge, as tumor cells are scarce, solid components are minimal, and mucinous components are excessive. Multiple factors can lead to low uptake or no uptake of pulmonary nodules.

Through continuous exploration of cellular targets, fibroblast-activating protein (FAP) was identified. Cancer-associated fibroblasts are present in numerous tumors, particularly those with strong fibroblast proliferation responses, such as breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, and lung cancer. Consequently, FAP expression is detected in over 90% of epithelial tumors. To date, FAP expression has been reported to correlate with poor tumor prognosis, as observed in colorectal cancer, pancreatic cancer, hepatocellular carcinoma, and ovarian cancer. Although further research is required, this advantage positions cancer-associated fibroblasts as an ideal target for antitumor therapy. In practical applications, low FAP expression in fibroblasts or healthy tissues facilitates imaging of pathological changes with low background signals.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment, accounting for over half of the mass in various types of tumors. Previous studies have demonstrated that CAFs play significant roles in tumor growth, immunosuppression, and cancer invasion. Consequently, CAFs may emerge as a novel therapeutic target for lung tumor diagnosis and treatment. Fibroblast-activating protein (FAP) is overexpressed in CAFs of multiple epithelial cancers but weakly expressed in healthy tissues, making it an attractive target in cancer research. In recent years, molecular imaging targeting FAP has been extensively explored in the field of tumor diagnosis.

The excellent tumor-targeting efficacy of FAP has been confirmed by multiple clinical studies. The results unequivocally establish FAPI as a tumor-targeting ligand with significant potential, demonstrating important application prospects in translational oncology. However, its therapeutic effects remain under investigation. An ideal radiopharmaceutical for cancer treatment should possess outstanding targeting specificity and relatively prolonged tumor retention time. Previous studies have shown that radiolabeled FAPI variants (FAPI-04 and FAPI-46) rapidly and satisfactorily accumulate in tumors, while exhibiting low physiological uptake in normal tissues. However, prior FAP-related tracers demonstrated relatively short retention times in small pulmonary lesions. Our aim is to design a FAPI trimer, Trap-(FAPI)3, to optimize pharmacokinetics and evaluate whether this novel drug offers superior advantages over its monomer analogs in the imaging diagnosis and staging of pulmonary tumors.