It's Time to Shift the Paradigm: Translation and Clinical Application of Non-αvß3 Integrin Targeting Radiopharmaceuticals.

ABSTRACT

For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvß3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvß3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5ß1, αvß6, αvß8, α6ß1, α6ß4, α3ß1, α4ß1, and αMß2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvß6, αvß8, and α6ß1/ß4, were subsequently translated into humans during the last few years. αvß6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvß6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvß3 by αvß6 as the most popular integrin in theranostics.