Kinetic analysis of 2-[C-11]Thymidine PET imaging studies: Validation studies

2-[C-11]thymidine has been tested as a PET tracer of cellular proliferation . We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validat e some of the model's assumptions and to test the model's ability to predic t the time course of tracer incorporation into DNA in tumors. Methods: Thre e sets of studies were conducted: (a) The uptake of tracers in proliferativ e tissues of normal mice was measured early after injection to assess the r elative delivery of thymidine and metabolites of thymidine catabolism (thym ine and CO,) and calculate relative blood-tissue transfer rates (relative K (1)s). (b) By using sequential injections of [C-11]thymidine and [C-11]thym ine in normal human volunteers, the kinetics of the first labeled metabolit e were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[C-14]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. Results: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed red uced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bon e marrow in comparison to thymidine. This quantity of trapping could be exp lained by a small amount of fixation of labeled CO2 in tissue, a process th at is included as part of the model. Uptake experiments in rats showed earl y incorporation of label into DNA, and the model was able to fit the time c ourse of uptake. Conclusion: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidin e flux into DNA by using 2-[C-11]thymidine and PET. Results suggest that fu rther work will be necessary to investigate the effects of tumor heterogene ity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing the rapy.