Assessment of DNA/RNA Deregulation in Cancer Using ^99mTc-Labeled Thiopurine

Background: DNA biomarkers are useful for the assessment of tumor cell proliferation. The authors aimed to synthesize a thiopurine-based ligand for evaluation of nuclear uptake and tumor localization. Materials and Methods: A 2-hydroxypropyl spacer was incorporated between a chelator (cyclam) and thiopurine ligand to produce SC-06-L1. In vitro cellular uptake and the cell/media ratios of [^99mTc]Tc-SC-06-L1 were assessed in breast (MCF-7, MDA-MB-231) and ovarian (TOV-112D, OVCAR3) cancer cells. The nuclear and cytosolic uptake ratio of [^99mTc]Tc-SC-06-L1 was determined in OVCAR-3 and MCF-7 cells. Cytotoxicity assays and flow cytometric analysis of cell cycle apoptosis were conducted in cancer cells treated with SC-06-L1. Imaging was conducted in tumor-bearing mice; fluorine-18-2¢-fluorodeoxyglucose ([¹⁸F]FDG) was used as a control. Results: The radiochemical purity of [^99mTc]Tc-SC-06-L1 was >95%. [^99mTc]Tc-SC-06-L1 exhibited higher cell-to-media ratios than [¹⁸F]FDG in cancer cells. [^99mTc]Tc-SC-06-L1 had high uptake in the nuclear fractions in OVCAR-3 and MCF-7 cells, with nuclear/cytosolic ratios of 8 and 2, respectively. Cytotoxicity assays showed that SC-06-L1 was non-toxic compared with azathioprine in breast and ovarian cancer cells. Conclusions: [^99mTc]Tc-SC-06-L1 was stable and involved in nuclear activities. [^99mTc]Tc-SC-06-L1 showed non-toxic to cancer cells and exhibited fast kinetic uptake patterns for tumor imaging. [^99mTc]Tc-SC-06-L1 represents a promising biomarker for imaging purine pathway-directed systems.