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Rationale of 5-¹²⁵I-Iodo-4'-Thio-2'-Deoxyuridine as a Potential Iodinated Proliferation Marker

¹ Research and Development Division, Research Center, Nihon Medi-Physics Company, Limited, Chiba, Japan
² School of Pharmaceutical Science, Showa University, Tokyo, Japan
³ Biomedical Imaging Research Center, Fukui Medical University, Fukui, Japan

The aim of this investigation was to synthesize and test a novel metabolically stable iodinated nucleoside as a proliferation-imaging agent for SPECT. Methods: 5-Iodo-4'-thio-2'-deoxyuridine (ITdU) and 5-iodo-1-(4-thio-ß-D-arabinofuranosyl)uracil (ITAU) were tested. The radiolabeling of ITdU and ITAU with ¹²⁵I was achieved by a destannylation reaction of the trimethylstannyl precursor of each nucleoside. The products were isolated in high yields and with >99% radiochemical purities. Results: ¹²⁵I-ITdU was effectively phosphorylated by cytosolic nucleoside kinases and specifically incorporated into a thymidine kinase-expressing L-M cell rather than a thymidine kinase-deficient mutant L-M (TK^-) cell. In addition, an in vitro cell metabolism study of ¹²⁵I-ITdU clarified that ¹²⁵I-ITdU was effectively and specifically incorporated into a DNA fraction (>90% at 60 min). Therefore, ¹²⁵I-ITdU was proven to be an ideal DNA synthesis marker such as 5-¹²⁵I-iodo-2'-deoxyuridine (IUdR). In contrast, ¹²⁵I-ITAU was neither remarkably phosphorylated by cytosolic nucleoside kinases nor notably incorporated into an L-M cell rather than an L-M (TK^-) cell. ¹²⁵I-ITdU and ¹²⁵I-ITAU showed a higher resistance to phosphorolytic cleavage by recombinant thymidine phosphorylase than did ¹²⁵I-IUdR. Furthermore, biodistribution of ¹²⁵I-ITdU and ¹²⁵I-ITAU revealed better in vivo stability of radioiodination than that of ¹²⁵I-IUdR. ¹²⁵I-ITdU also displayed a significantly higher uptake in proliferating organs (thymus, spleen, small intestine, and bone) than in nonproliferating organs (brain, muscle, liver, and lung), as did ¹²⁵I-IUdR, at 18 h after injection. As indicated by the in vitro study, ¹²⁵I-ITAU did not show any significant uptake in proliferating organs. Conclusion: Radioiodine-labeled ITdU is potentially useful as a proliferation-imaging agent, and further studies should clarify the usefulness of this compound as a tumor-imaging agent.

Key Words: 5-¹²⁵I-iodo-4'-thio-2'-deoxyuridine • 5-¹²⁵I-iodo-1-(4-thio-ß-D-arabinofuranosyl)uracil • 5-¹²⁵I-iodo-2'-deoxyuridine • nucleoside kinases • thymidine phosphorylase

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