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Expression of the cellular transmembrane receptor αvβ6 integrin is essentially restricted to malignant epithelial cells in carcinomas of a broad variety of lineages, whereas it is virtually absent in normal adult tissues. Thus, it is a highly attractive target for tumor imaging and therapy. Furthermore, αvβ6 integrin plays an important role for the epithelial-mesenchymal interaction and the development of fibrosis. Methods: On the basis of the 68 Ga chelators TRAP (triazacyclononane-triphosphinate) and NODAGA, we synthesized mono-, di-, and trimeric conjugates of the αvβ6 integrin-selective peptide cyclo(FRGDLAFp( N Me)K) via click chemistry. These were labeled with 68 Ga and screened regarding their suitability for in vivo imaging of αvβ6 integrin expression by PET and ex vivo biodistribution in severe combined immunodeficiency mice bearing H2009 tumor (human lung adenocarcinoma) xenografts. For these, αvβ6 integrin expression in tumor and other tissues was determined by β6 immunohistochemistry. Results: Despite the multimers showing higher αvβ6 integrin affinities (23-120 pM) than the monomers (260 pM), the best results-that is, low background uptake and excellent tumor delineation-were obtained with the TRAP-based monomer 68 Ga-avebehexin. This compound showed the most favorable pharmacokinetics because of its high polarity (log D = -3.7) and presence of additional negative charges (carboxylates) on the chelator, promoting renal clearance. Although tumor uptake was low (0.65% ± 0.04% injected dose per gram tissue [%ID/g]), it was still higher than in all other organs except the kidneys, ranging from a maximum for the stomach (0.52 ± 0.04 %ID/g) to almost negligible for the pancreas (0.07 ± 0.01 %ID/g). A low but significant target expression in tumor, lung, and stomach was confirmed by immunohistochemistry. Conclusion: Because of highly sensitive PET imaging even of tissues with low αvβ6 integrin expression density, we anticipate clinical applicability of 68 Ga-avebehexin for imaging of αvβ6 tumors and fibrosis by PET.

In Vivo PET Imaging of the Cancer Integrin αvβ6 Using 68Ga-Labeled Cyclic RGD Nonapeptides

In Vivo PET Imaging of the Cancer Integrin αvβ6 Using ⁶⁸Ga-Labeled Cyclic RGD Nonapeptides