α β integrins play an important role in angiogenesis and cell migration in cancer and are highly expressed on the activated endothelial cells of newly formed blood vessels. Here, we compare the targeting characteristics of 4 Ga-labeled multimeric cyclic arginine-glycine-aspartate (RGD)-based tracers in an α β integrin-expressing tumor model and a tumor model in which α β integrin is expressed solely on the neovasculature. Female BALB/c nude mice were subcutaneously injected with SK-RC-52 (α β integrin-positive) or FaDu (α β integrin-negative) tumor cells. Ga-labeled DOTA-(RGD) , TRAP-(RGD) , FSC-(RGD) , or THP-(RGD) was intravenously administered to the mice (0.5 nmol per mouse, 10-20 MBq), followed by small-animal PET/CT imaging and ex vivo biodistribution studies 1 h after injection. Nonspecific uptake of the tracers in both models was determined by coinjecting an excess of unlabeled DOTA-(RGD) (50 nmol) along with the radiolabeled tracers. Imaging and biodistribution data showed specific uptake in the tumors for each tracer in both models. Tumor uptake of Ga-FSC-(RGD) was significantly higher than that of Ga-DOTA-(RGD) , Ga-TRAP-(RGD) , or Ga-THP-(RGD) in the SK-RC-52 model but not in the FaDu model, in which Ga-FSC-(RGD) showed significantly higher tumor uptake than Ga-TRAP-(RGD) Most importantly, differences were also observed in normal tissues and in tumor-to-blood ratios. All tracers showed sufficient targeting of α β integrin expression to allow for tumor detection. Although the highest tumor uptake was found for Ga-FSC-(RGD) and Ga-THP-(RGD) in the SK-RC-52 and FaDu models, respectively, selection of the optimal tracer for specific diagnostic applications also depends on tumor-to-blood ratio and uptake in normal tissues; these factors should therefore also be considered.