It’s Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals

SIMPLE SUMMARY: Cancer cells often present a different set of proteins on their surface than normal cells. This also applies to integrins, a class of 24 cell surface receptors which mainly are responsible for physically anchoring cells in tissues, but also fulfil a plethora of other functions. If a certain integrin is found on tumor cells but not on normal ones, radioactive molecules (named tracers) that specifically bind to this integrin will accumulate in the cancer lesion if injected into the blood stream. The emitted radiation can be detected from outside the body and allows for localization and thus, diagnosis, of cancer. Only one of the 24 integrins, the subtype αvβ3, has hitherto been thoroughly investigated in this context. We herein summarize the most recent, pertinent research on other integrins, and argue that some of these approaches might ultimately improve the clinical management of the most lethal cancers, such as pancreatic carcinoma. 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 αvβ3, 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 αvβ3-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 α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-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 αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.