There is a world beyond alpha v beta 3-integrin: Multimeric ligands for imaging of the integrin subtypes alpha v beta 6, alpha v beta 8, alpha v beta 3, and alpha 5 beta 1 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 alpha v beta 3-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 alpha 5 beta 1, alpha v beta 8, alpha v beta 6, and alpha v beta 3. For the first three, we provide some additional immunohistochemistry data in human cancers, which suggest several future clinical applications. Finally, application of alpha v beta 3- and alpha v beta 6-integrin tracers in pancreatic carcinoma patients revealed that unlike alpha v beta 3-targeted PET, alpha v beta 6-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, alpha v beta 6, have proven their clinical potential and will play an increasingly important role in future theranostics.