Therapeutic Radiopharmaceuticals Targeting Integrin αvβ6

The epithelial integrin αvβ6 is expressed by many malignant carcinoma cell types, including pancreatic cancer, and thus represents a promising target for radionuclide therapy. The peptide cyclo­(FRGDLAFp­(<i>N</i>Me)­K) was decorated with different chelators (DOTPI, DOTAGA, and DOTA). The Lu­(III) complexes of these conjugates exhibited comparable αvβ6 integrin affinities (IC₅₀ ranging from 0.3 to 0.8 nM) and good selectivities against other integrins (IC₅₀ for αvβ8 >43 nM; for α5β1 >238 nM; and for αvβ3, αvβ5, and αIIbβ3 >1000 nM). Although different formal charges of the Lu­(III) chelates (ranging from 0 to 4) resulted in strongly varying degrees of hydrophilicity (log <i>D</i> ranging from −3.0 to −4.1), biodistributions in murine H2009 xenografts of the Lu-177-labeled compounds (except the DOTPI derivative) were quite similar and comparable to our previously reported αvβ6 integrin positron emission tomography tracer Ga-68-avebehexin. Hence, combinations of existing Ga-68- and Lu-177-labeled c­(FRGDLAFp­(<i>N</i>Me)­K) derivatives could be utilized for αvβ6 integrin-targeted theranostics, whereas our data nonetheless suggest that further improvement of pharmacokinetics might be necessary to ensure clinical success