Synthesis and Biological Evaluation of A Tc-99m Labeled Cyclooxygenase-2 Inhibitor

Objectives: As a major disease, cancer is resulting in severe deaths of millions of people every year, and tends to be a greater problem in the future. Theranostic system has provided a new way for it could accurately diagnose the disease and synchronize the treatment. Here we would like to develop a molecule targeted COX-2, which expresses at low levels in most normal tissues and cells but at high levels in tumor tissues and cells¹. By conjugating a diagnostic or therapeutic nuclide, we hope this compound could show potentials in theranostic for cancer.

Methods: According to the extensive structure-activity relationship (SAR) work conduct by Penning T. D. and his coworks², we chose a compound exhibiting good potency and selectivity as substrate. After some designed modifications, we obtained our desired molecule which is suitable for labeling Tc-99m and Re-188. Blood kinetics studies of this probe were investigated in healthy rat. Results: We conjugated Tc-99m to our desired molecule for the synthesis of COX-2 targeting probe with a high radiochemical yield (>99%) and high radiochemical purity (>99%)(Figure 1). The probe showed good stability in 0.9% NaCl and 0.1% BSA for 18 h post labeling. After injected into the normal healthy male rat via caudal vein, the Tc-99m probe cleaned out slowly in blood, with a half-life of about 3 h. In addition, the results revealed that high radioactivity concentration was on liver and spleen and also cleaned out slowly.

Conclusions: The current study showed that T1-MAG₃ was not suitable for labeling Re-188 to treat cancer because of its long half-life in blood and other normal organs. But the results also prompt us to further modify the structure of this molecule by adding a hydrophilic functional group (PEG₃, Figure 2). Therefore, we would look forward to the better property of T2-MAG₃.[1] Zhang, H.; Fan, J.; Wang, J.; etc. J. Am. Chem. Soc. 2013, 135 (46), 17469-17475. [2] Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; etc. J. Med. Chem., 1997, 40 (9), 1347-1365.

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