Integrin αvβ6-targeted PET in Malignant Tumors

Malignant tumors are a significant disease that threatens human health and life, with high incidence and mortality rates. Molecular imaging plays an important role in the early diagnosis, staging, prognosis evaluation, and therapeutic efficacy assessment of major diseases such as tumors. Currently, 18F-FDG PET imaging is the most widely used molecular imaging, but there are still problems such as physiological uptake, false negatives, and false positives. It is urgent to explore and develop a new type of tumor-targeting PET imaging. Integrins are key members of the cell adhesion molecular family and play a central role in regulating cell-cell and cell-extracellular matrix interactions. They are highly expressed in a variety of malignant tumors and plays a vital role in the angiogenesis, invasion and metastasis of tumors, and the regulation of immune microenvironment. As such, integrins have emerged as potential targets for tumor-specific imaging. To date, PET tracers targeting integrin αvβ3 have been extensively studied for imaging tumor neovascularization. However, this integrin subtype also shows certain expression in normal tissue endothelial cells, posing a challenge to its clinical value as a specific marker for tumor imaging. In contrast, integrin αvβ6, another subtype of integrin known as "cancer integrin", is specifically expressed in epithelial-derived tumor cells, whereas it hardly expressed in human healthy tissues. Therefore, integrin αvβ6 has gained attention as an attractive and promising biomarker. In the past decade, some integrin αvβ6-targeting PET tracers have been synthesized, but these agents have shown relatively low affinity and specificity, with high nonspecific uptake in the gastrointestinal tract, which hinders their clinical translation. Recently, Quigley et al. introduced a novel αvβ6-targeted trimeric probe based on a cyclic peptide c\[YRGDLAYp(NMe)K\], named 68Ga-Trivehexin. This probe demonstrated favorable characteristics, including excellent targeting affinity (IC50 = 0.047 nM), enhanced tumor uptake, and longer retention time in preclinical study. The preliminary results from PET imaging in 4 cancer patients further demonstrated intense 68Ga-Trivehexin accumulation in head and neck squamous cell carcinoma, parotid adenocarcinoma and pancreatic ductal adenocarcinoma; moreover, there was almost no physiological uptake in normal tissues and organs, such as stomach, intestine, liver, and lung, except for kidney (the excretory organ), resulting in an excellent tumor-to-background ratio. The safety and metabolic stability of 68Ga-Trivehexin targeting integrin αvβ6 are currently supported by clinical data, and this project will further expand its application in various malignant tumors, clarify its diagnostic and staging value in different types of tumors, and qualitative and quantitative characteristics. This project is expected to provide a new and precise evaluation method for malignant tumors to compensate for the shortcomings of current imaging methods.