Synthesis of radiolabeled cytarabine conjugates.

N4-Modified, novel Ara-C conjugate capable of radiolabeling with gamma ray-emitting ((99m)Tc) as well as positron emitting ((18)F) radionuclides, that is, N4-hydrazine derivative was synthesized. The radiolabeling of N4-(hydrazinonicotinyl)-1-beta-arabinofuranosyl cytosine (HAra-C) with (99m)Tc was performed with over 95% labeling yield. To label HAra-C with (18)F, 4-fluoro((18)F)-benzaldehyde was synthesized from 4-formyl-N,N,N-trimethylanilinium triflate in 30% radiochemical yield; it quantitatively formed hydrazone derivative with HAra-C within 45min. The radiolabeled conjugates were analyzed by radio-UV-RP-HPLC. The cold precursors were characterized by (1)H, (13)C NMR. Additionally, HAra-C was evaluated for cytotoxicity in lung adenocarcinoma (H441) cells and found to be comparable in cell killing efficiency to that of Ara-C. Uptake of (99m)Tc-HAra-C in cultures of H441 cells and sensitive pancreatic cancer cells (MIAPaCa-2) was inhibited by nucleoside transporter inhibitor nitrobenzylthioinosine. The results suggest that (99m)Tc-labeled HAra-C is a substrate for the membrane nucleoside transporters, and that it may be used in molecular imaging of nucleoside transporter expression for the verification of potential anticancer efficacy of nucleoside drugs, such as Ara-C and gemcitabine.