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This Article Figures Only Full Text Full Text (PDF) Supplemental Data All Versions of this Article: jnumed.109.065623v1 50/11/1895    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zlatopolskiy, B. D. Articles by Reske, S. N. PubMed PubMed Citation Articles by Zlatopolskiy, B. D. Articles by Reske, S. N.

Synthesis and Biologic Study of IV-14, a New Ribonucleoside Radiotracer for Tumor Visualization

Klinik für Nuklearmedizin, Universität Ulm, Ulm, Germany

Correspondence: For correspondence or reprints contact: Sven N. Reske, Universität Ulm, Klinik für Nuklearmedizin, Albert-Einstein-Allee 23 D-89081, Ulm, Germany. E-mail: sven.reske{at}uniklinik-ulm.de

Uridine-cytidine kinase (UCK) 2, an enzyme normally expressed in human placenta and testis and highly overexpressed in many neoplasias of blood and solid tissues, catalyzes monophosphorylation of pyrimidine ribonucleosides with efficiency 15- to 20-fold higher than that of ubiquitously expressed isozyme UCK1. In this paper, we report the synthesis of 3'-(E)-(2-iodovinyl)uridine (IV-14) and its preclinical evaluation as a new radiotracer derived from a UCK2-selective antitumor agent, 3'-(ethynyl)uridine. Methods: Radioiodinated IV-14 was prepared from the respective stannyl precursor. ¹³¹I-IV-14 was studied in cellular uptake assays and tested for stability in serum as well as for stability to thymidine phosphorylase, liver-, and mucosa-specific murine uridine phosphorylases. UCK1 and UCK2 expression levels in different tumor cell lines were determined by Western blot. Cellular distribution of ¹³¹I-IV-14 was determined in HL60 cells. Biodistribution studies and -camera scintigraphy were performed on an HL60-xenografted severe combined immunodeficiency (SCID) mouse model. Results: ¹³¹I-IV-14 demonstrated excellent stability in serum. It was stable to human thymidine phosphorylase and to liver- and mucosa-specific murine uridine phosphorylases. Cellular uptake after 24 h of incubation with ¹³¹I-IV-14 was 4.27 ± 0.21, 3.66 ± 0.13, 2.69 ± 0.07, 2.24 ± 0.18, and 3.26 ± 0.18 percentage injected dose per 5 x 10⁵ Mia-PaCa-2, CX-1, HL60, Capan-1, and Panc-1 cells, respectively. Uptake and retention of IV-14 were regulated by 2 factors: UCK2 expression level and intracellular transport mediated partially via human equilibrating nucleoside transporter 1. A biodistribution study of ¹³¹I-IV-14 in an HL60-xenografted SCID mouse model showed that at 4 h after injection the greatest amount of retained radioactivity was in tumor. The tissue-to-tumor ratio 4 h after injection was 1.0 ± 0.24 for tumor, 0.40 ± 0.18 for spleen, 0.25 ± 0.12 for colon, 0.14 ± 0.07 for small intestine, and less than 0.1 for other sites. Scintigraphy with ¹²³I-IV-14 4 h after injection showed the tumor well. In addition, high accumulation of radioiodide in the stomach content was observed and was presumably due to metabolic degradation of IV-14. Conclusion: IV-14 is a UCK2-specific marker, allowing for in vivo addressing of tumors with high RNA synthesis independent of proliferation rate.

Key Words: tumor targeting • ribonucleosides • uridine/cytidine kinase 2

^* Contributed equally to this work.

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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JNM 2009 50: 11A-12A. [Full Text]