OBJECTIVE: To investigate the value of integrin α(v)β(3) targeted microPET/CT imaging with (68)Ga-NODAGA-RGD(2) as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis. METHODS: The (68)Ga-NODAGA-RGD(2) and (177)Lu-NODAGA-RGD(2) were prepared via one-step method and their stability and integrin α(v)β(3) binding specificity were investigated in vitro. Forty-one nude mice were injected with human MG63 osteosarcoma to established the animal model bearing subcutaneous osteosarcoma (n=21), osteosarcoma in tibia (n=5), and osteosarcoma pulmonary metastatic (n=15). The microPET-CT imaging was carried out in 3 animal models at 1 hour after tail vein injection of (68)Ga-NODAGA-RGD(2). Biodistribution study of (68)Ga-NODAGA-RGD(2) was performed in animal model bearing subcutaneous osteosarcoma at 10, 60, and 120 minutes. The animal model bearing pulmonary metastatic osteosarcoma was injected with (177)Lu-NODAGA-RGD(2) at 7 weeks after model establishment to observe the therapeutic effect of pulmonary metastatic osteosarcoma. Histological and immunohistochemistry examinations were also done to confirm the establishment of animal model and integrin β(3) expression in animal models bearing subcutaneous osteosarcoma and bearing pulmonary metastatic osteosarcoma. RESULTS: (68)Ga-NODAGA-RGD(2) and (177)Lu-NODAGA-RGD(2) had good stability in vitro with the 50% inhibitory concentration value of (5.0±1.1) and (6.5±0.8) nmol/L, respectively. The radiochemical purity of (68)Ga-NODAGA-RGD(2) at 1, 4, and 8 hours was 98.5%±0.3%, 98.3%±0.5%, and 97.9%±0.4%; while the radiochemical purity of (177)Lu-NODAGA-RGD(2) at 1, 7, and 14 days was 99.3%±0.7%, 98.7%±1.2%, and 96.0%±2.8%. (68)Ga-NODAGA-RGD(2) microPET-CT showed that the accumulation of (68)Ga-NODAGA-RGD(2) in animal models bearing subcutaneous osteosarcoma and osteosarcoma in tibia and in lung metastasis as small as 1-2 mm in diameter of animal model bearing pulmonary metastatic osteosarcoma. Biodistribution study of (68)Ga-NODAGA-RGD(2) in animal model bearing subcutaneous osteosarcoma revealed rapid clearance from blood with tumor peak uptake of (3.85±0.84) %ID/g at 120 minutes. The distribution of (177)Lu-NODAGA-RGD(2) in lung metastasis was similar with (68)Ga-NODAGA-RGD(2). The number and size of osteosarcoma metastasis decreased at 2 weeks after (177)Lu-NODAGA-RGD(2) administration and integrin targeting specificity was confirmed by pathology examination. CONCLUSION: (68)Ga-NODAGA-RGD(2) was potential for positive imaging and early detection of osteosarcoma and metastasis. Targeted radiotherapy with (177)Lu-NODAGA-RGD(2) was one potential alternative for osteosarcoma lung metastasis.