Click-chemistry (CuAAC) trimerization of an αvβ6-integrin targeting Ga-68-peptide: Enhanced contrast for in-vivo PET imaging of human lung adenocarcinoma xenografts.

: αvβ6-Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with αvβ6-integrin dependent TGF-β dysregulation, such as fibrosis. We designed a trimeric Ga-68-labeled TRAP-conjugate of the αvβ6-specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH 2 ) to enhance αvβ6-integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17) 3 showed a 28-fold higher αvβ6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC50 of 0.26 vs. 7.4 nM, respectively), a 13-times higher IC50-based selectivity over the related integrin αvβ8 (factors of 662 vs. 49), and a 3-times higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments using H2009-tumor bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17) 3 holds promise for improved clinical PET-diagnostics of carcinomas and fibrosis.