The potential of 2-deoxy-2[18F]fluoro-D-glucose (FDG) for the detection of tumor involvement in lymph nodes. To assess the potential of FDG for PET imaging of nodal tumor metastases, we evaluated its uptake into normal lymph nodes, tumor-involved lymph nodes, and subcutaneous tumor xenografts in rodents. Normal lymph nodes in mice and rats accumulate FDG moderately, developing node/blood ratios of 1.3-11.9/1 at 2 hr following i.v. injection. By contrast, FDG given subcutaneously to healthy Sprague Dawley rats developed very high normal draining lymph node/blood ratios (272/1) versus 7.7/1 by i.v. injection. In nude mice, subcutaneous human ovarian cancer xenografts had 1.27-fold more uptake relative to blood than did normal popliteal lymph nodes. Subcutaneous tumor xenografts of rat breast cancer developed tumor/normal node uptake ratios of 4.91 +/- 0.43/1 and tumor/blood ratios of 6.6 +/- 0.9 at 2 hr postinjection. Mouse nodes involved with 38C13 murine B-cell lymphoma had mean node/blood ratios of 42.9 +/- 6.7/1 and tumored node/normal lymph node uptake of 6.3/1. Thus, FDG given intravenously but not subcutaneusly (due to high normal nodal uptake) has potential as an agent for the detection of metastatic tumors in regional lymph nodes using PET scanning. 