18F-Alfatide II and 18F-FDG Dual-Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy

A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor's status under quasiconstant conditions. This study aimed to investigate the utility of dual-tracer dynamic PET imaging with F-18-alfatide II (F-18-AlF-NOTA-E[PEG(4)-c(RGDfk)](2)) and F-18-FDG for parametric monitoring of tumor responses to therapy. Methods: We administered doxorubicin to one group of athymic nude mice with U87MG tumors and paclitaxel protein-bound particles to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting with injection via the tail vein catheters with F-18-alfatide II, followed 40 min later by F-18-FDG. To achieve signal separation of the 2 tracers, we fit a 3-compartment reversible model to the time-activity curve of F-18-alfatide II for the 40 min before F-18-FDG injection and then extrapolated to 90 min. The F-18-FDG tumor time-activity curve was isolated from the 90min dual-tracer tumor time-activity curve by subtracting the fitted F-18-alfatide II tumor time-activity curve. With separated tumor time-activity curves, the F-18-alfatide II binding potential (Bp = k(3)/k(4)) and volume of distribution (VD) and F-18-FDG influx rate ((K-1 x k(3))/(k(2) + k(3))) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single-tracer imaging and to monitor therapeutic response. Results: The transport and binding rate parameters K-1-k(3) of F-18-alfatide II, calculated from the first 40 min of the dual-tracer dynamic scan, as well as Bp and VD correlated well with the parameters from the 60-min single-tracer scan (R-2 > 0.95). Compared with the results of single-tracer PET imaging, F-18-FDG tumor uptake and influx were recovered well from dualtracer imaging. On doxorubicin treatment, whereas no significant changes in static tracer uptake values of F-18-alfatide II or F-18-FDG were observed, both F-18-alfatide II Bp and F-18-FDG influx from kinetic analysis in tumors showed significant decreases. For therapy of MDA-MB-435 tumors with paclitaxel protein-bound particles, a significant decrease was observed only with F-18-alfatide II Bp value from kinetic analysis but not F-18-FDG influx. Conclusion: The parameters fitted with compartmental modeling from the dual-tracer dynamic imaging are consistent with those from single-tracer imaging, substantiating the feasibility of this methodology. Even though no significant differences in tumor size were found until 5 d after doxorubicin treatment started, at day 3 there were already substantial differences in F-18-alfatide II Bp and F-18-FDG influx rate. Dual-tracer imaging can measure F-18-alfatide II Bp value and F-18-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomic changes, and thus parametric imaging may offer the promise of early prediction of therapy response.