There is a world beyond αvß3-integrin: Multimeric ligands for imaging of the integrin subtypes αvß6, αvß8, αvß3, and α5ß1 by positron emission tomography.

BACKGROUND: In the context of nuclear medicine and theranostics, integrin-related research and development was, for most of the time, focused predominantly on 'RGD peptides' and the subtype αvß3-integrin. However, there are no less than 24 known integrins, and peptides without the RGD sequence as well as non-peptidic ligands play an equally important role as selective integrin ligands. On the other hand, multimerization is a well-established method to increase the avidity of binding structures, but multimeric radiopharmaceuticals have not made their way into clinics yet. In this review, we describe how these aspects have been interwoven in the framework of the German Research Foundation's multi-group interdisciplinary funding scheme CRC 824, yielding a series of potent PET imaging agents for selective imaging of various integrin subtypes. RESULTS: The gallium-68 chelator TRAP was utilized to elaborate symmetrical trimers of various peptidic and non-peptidic integrin ligands. Preclinical data suggested a high potential of the resulting Ga-68-tracers for PET-imaging of the integrins α5ß1, αvß8, αvß6, and αvß3. For the first three, we provide some additional immunohistochemistry data in human cancers, which suggest several future clinical applications. Finally, application of αvß3- and αvß6-integrin tracers in pancreatic carcinoma patients revealed that unlike αvß3-targeted PET, αvß6-integrin PET is not characterized by off-target uptake and thus, enables a substantially improved imaging of this type of cancer. CONCLUSIONS: Novel radiopharmaceuticals targeting a number of different integrins, above all, αvß6, have proven their clinical potential and will play an increasingly important role in future theranostics.