Introduction: 18F-5-fluoro-N-(2-(Diethylamino)ethyl)picolinamide (F-18-5-FPN) is a new positron-emission tomography (PET) radiopharmaceutical with potential for the detection of lymph node (LN) and pulmonary metastatic lesions of melanoma. We compared its performance with that of F-18-deoxyglucose (F-18-FDG). Methods: Cervical LN and lung melanoma metastasis models were established in C57BL/6 mice. Primary tumors were created by injection of melanoma cells into the pinna, and the resulting cervical LN metastases were evaluated. Lung metastases were created by intravenous injection of melanoma cells. The mice underwent F-18-FDG and 18F-5-FPN positron emission tomography (PET) imaging. A biodistribution study was conducted after imaging. Histopathologic evaluation of the tumors was also performed. Results: LN metastases with a diameter < 1 cm were more visible on 18F-5-FPN PET imaging than F-18-FDG imaging. Quantitative analysis showed that the uptake of 18F-5-FPN was significantly higher than that of F-18-FDG, with values of 13.29 3.80% ID/g and 7.24 +/- 1.95% ID/g (n = 5, P < 0.05), respectively. LN-to-muscle ratios were 21.23 +/- 6.02 and 4.50 2.11 (n = 5, P < 0.01) for F-18-5-FPN and F-18-FDG, respectively. Biodistribution results were similar, with high uptake of 18F-5-FPN in the LN. F-18-5-FPN imaging manifested the pulmonary lesions clearly, while the 18F-FDG imaging showed no uptake in lesions <2 mm. The related uptakes of F-18-5-FPN and F-18-FDG were 3.12 +/- 1.17% ID/g and 1.48 +/- 0.15% ID/g, respectively (n = 5, P < 0.05), with lung metastasis to -muscle ratios of 8.16 +/- 3.12 and 128 +/- 0.18 (n = 5, P < 0.01), respectively. H&E and Prussian blue staining displayed pluri nucleated or mega nucleus cells and dark brown granules in the metastatic tissues, characteristic of melanoma. Conclusions: F-18-5-FPN targeted small metastatic lesions with a higher target-to-normal ratio of uptake than those of F-18-FDG, which suggests its ability to detect metastatic lesions earlier than 18F-FDG. Further studies with a wide range of melanoma cell lines should be needed to confirm the similar performance. 2017 Elsevier Inc. All rights reserved.