Click‐Chemistry (CuAAC) Trimerization of an α(v)β(6) Integrin Targeting Ga‐68‐Peptide: Enhanced Contrast for in‐Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

α(v)β(6) 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 α(v)β(6) integrin‐dependent TGF‐β dysregulation, such as fibrosis. We have designed a trimeric Ga‐68‐labeled TRAP conjugate of the α(v)β(6)‐specific cyclic pentapeptide SDM17 (cyclo[RGD‐Chg‐E]‐CONH(2)) to enhance α(v)β(6) integrin affinity as well as target‐specific in‐vivo uptake. Ga‐68‐TRAP(SDM17)(3) showed a 28‐fold higher α(v)β(6) affinity than the corresponding monomer Ga‐68‐NOTA‐SDM17 (IC(50) of 0.26 vs. 7.4 nM, respectively), a 13‐fold higher IC(50)‐based selectivity over the related integrin α(v)β(8) (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with 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.