Research On Methods And Applications Of Dual-tracer PET Dynamic Imaging

Positron emission tomography (PET) is one of the ultrahigh sensitive and specific techniques for imaging molecular pathways in vivo, and has become the important tool for cancer research and clinical diagnosis and therapy. Moreover, the availability of tracers sensitive to different physiological and pharmacological variables enables PET to characterize multiple aspects of oncologic pathology, including metabolism, angiogenesis, cellular proliferation, blood flow and hypoxia and so on. Given the complexity and heterogeneity of malignant lesions, such complementary information can facilitate comprehensive evaluation of tumors, and improve early detection, staging, therapy, monitoring of therapeutic responses and prognosis evaluation. In comparison with multiple, separate single-tracer studies, PET imaging using multiple tracers in a single scan is expected to not only achieve this objective, but also reduce the cost, time and radiation dose, and avoid the variances of physiological conditions due to the delay between scans.In this dissertation, we performed18F-Fluorodeoxy glucose (18F-FDG) and18F-Arg-Gly-Asp (RGD) tripeptides dual tracer dynamic single PET scan to simultaneously observe the glucose metabolism and angiogenesis in tumor tissue. The dual tracer signal separation method was validated, and was used to monitor the therapy response. The overall summaries are outlined as following:1) The F-18labeling process was optimized for the RGD tripeptides and the in vitro/in vivo characteristics of F-RGD were evaluated. Three dimeric RGD peptides with or without PEGylation were synthesized to imaging αvβ3integrin. In vitro serum stability and cell binding assay, in vivo metabolic stability, PET static/dynamic imaging and biodistribution were conducted to compare the peptides to figure out the optimal one to do dual tracer imaging study. The optimal tracer was denoted as F-Alfatide Ⅱ.2)18F-Alfatide Ⅱ/18F-FDG dual tracer imaging TACs with10min,20min,30min and40min tracer injection separation were simulated and separated by both the compartment extrapolation and parallel compartment fitting method, whose results were compared. The known tracer kinetic parameters were utilized to generate the single tracer TACs by compartment modeling and then the noises were added to each TAC around a level similar to the experimental data. Simulated18F-Alfatiae Ⅱ and18F-FDG single tracer TACs were combined with different tracer injection separation to produce the simulated dual tracer TACs. The parallel compartment fitting method was used to directly obtain the kinetic parameters, while the compartment extrapolation method was carried out to recovery both18F-Alfatide Ⅱ and18F-FDG imaging TACs and then calculate the kinetic parameters. Results showed, the18F-Alfatide Ⅱ K1and all the18F-FDG kinetic parameters could be accurately calculated by the parallel compartment fitting method and almost unrelated to the injection time separation. The k2of18F-Alfatide Ⅱ was well recovered too and the separation performance for various time separation were similar. The k3、k4、volume of distribution (VT) and binding potential (Bp) of18F-Alfatide Ⅱ could be well recovered only at40min time separation. For40min time separation data, the performances of two signal recovery methods were very close.3) The18F-Alfatide Ⅱ/18F-FDG dual tracer in single dynamic PET scan was performed and the performance of signal separation by two signal separation method was validated by comparing with the single tracer dynamic PET imaging. Dual-tracer dynamic imaging in sessions lasted90min. F-Alfatide Ⅱ was first injected into the mice via tail vein catheters, followed40minutes later by18F-FDG injection. A three-compartment reversible model was used to fit the40min F-Alfatide Ⅱ time activity curve (TAC) prior to18F-FDG injection and then extrapolated to90min. The18F-FDG tumor TAC was isolated from the90min dual tracer TAC by subtracting the fitted18F-Alfatide Ⅱ tumor TAC. The comparison of TACs, tumor uptakes and kinetic parameters presented good significant correlation between single and dual tracer imaging, indicating the18F-Alfatide Ⅱ and18F-FDG signal can be well restored and used to image both the glucose metabolism and angiogenesis under quasi-consistent tumor physiological conditions. The parallel compartment fitting method was also applied to the same data and its separation results were consisting with that of compartment extrapolation method.4) The F-Alfatide Ⅱ/18F-FDG dual tracer imaging was applied to monitor tumor therapy response. Doxorubicin was administered to U87MG tumor bearing mice and the Abraxane to MDA-MB-435tumor bearing mice. The variance of tumor uptake, F-Alfatide Ⅱ Bp and18F-FDG influx rate demonstrated the quantitative kinetic parameters calculated from dynamic data are more sensitive than the tumor volume and static imaging, which may be helpful for predicting the early therapy response. And the dual tracer imaging provided richer tumor information than the single tracer imaging.