Rationale of 5-(125)I-iodo-4'-thio-2'-deoxyuridine as a potential iodinated proliferation marker

The aim of this investigation was to synthesize and test a novel metabolically stable iodinated nucleoside as a proliferation-imaging agent for SPECT. 5-Iodo-4'-thio-2'-deoxyuridine (ITdU) and 5-iodo-1-(4-thio-beta-D-arabinofuranosyl)uracil (ITAU) were tested. The radiolabeling of ITdU and ITAU with (125)I 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. (125)I-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 (125)I-ITdU clarified that (125)I-ITdU was effectively and specifically incorporated into a DNA fraction (>90% at 60 min). Therefore, (125)I-ITdU was proven to be an ideal DNA synthesis marker such as 5-(125)I-iodo-2'-deoxyuridine (IUdR). In contrast, (125)I-ITAU was neither remarkably phosphorylated by cytosolic nucleoside kinases nor notably incorporated into an L-M cell rather than an L-M (TK(-)) cell. (125)I-ITdU and (125)I-ITAU showed a higher resistance to phosphorolytic cleavage by recombinant thymidine phosphorylase than did (125)I-IUdR. Furthermore, biodistribution of (125)I-ITdU and (125)I-ITAU revealed better in vivo stability of radioiodination than that of (125)I-IUdR. (125)I-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 (125)I-IUdR, at 18 h after injection. As indicated by the in vitro study, (125)I-ITAU did not show any significant uptake in proliferating organs. 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.