A Novel (11)C-labeled Thymidine Analog, [(11)C]AZT, for Tumor Imaging by Positron Emission Tomography

Overview

Journal EJNMMI Res

Date 2015 Sep 5

PMID 26337804

Citations 2

Authors

Tsuyoshi Tahara

Zhouen Zhang

Masahiro Ohno

Yukako Hirao

Nami Hosaka

Hisashi Doi

Masaaki Suzuki

Hirotaka Onoe

Affiliations

Soon will be listed here.

Abstract

Background: Nucleoside analogs labeled with positrons, such as (11)C and (18)F, are considered valuable in visualizing the proliferative activity of tumor cells in vivo using positron emission tomography (PET). We recently developed the (11)C-labeled thymidine analogs [(11)C]zidovudine ([(11)C]AZT) and [(11)C]stavudine ([(11)C]d4T) via the Pd(0)-Cu(I) co-mediated rapid C-C coupling reaction. In this study, to examine whether [(11)C]AZT and [(11)C]d4T might be useful for visualization of tumors in vivo, we performed PET imaging, tissue distribution studies, and metabolite analysis in tumor-bearing mice.

Methods: Mice bearing tumors (rat glioma C6 and human cervical adenocarcinoma HeLa cells) were injected with 50 MBq of [(11)C]AZT or [(11)C]d4T, and PET was performed immediately thereafter. After PET imaging, the radioactivity in several tissues, including tumor tissues, was measured using a γ-counter. In addition, radioactive metabolites in plasma, bile, intestinal contents, and tumor were analyzed using thin layer chromatography (TLC). Cellular uptake of [(11)C]AZT in C6 was measured in the presence or absence of non-labeled thymidine (0.1 mM).

Results: In PET studies, C6 and HeLa tumors in mice were clearly visualized using [(11)C]AZT. Time-activity curves using [(11)C]AZT showed that the accumulation of radioactivity in tumors plateaued at 10 min after injection and persisted for 60 min, while most of the radioactivity in other tissues was rapidly excreted into the urine. In various tissues of the body, tumor tissue showed the highest radioactivity at 80 min after injection (five to six times higher uptake than that of blood). Compared with tumor tissue, uptake was lower in other proliferative tissues such as the spleen, intestine, and bone marrow, resulting in a high tumor-to-bone marrow ratio. Cellular uptake of [(11)C]AZT in C6 cells was completely blocked by the application of thymidine, strongly indicating the specific involvement of nucleoside transporters. In contrast, the time-activity curve of [(11)C]d4T in the tumor showed transient and rapid excretion with almost no obvious tumor tissue accumulation.

Conclusions: Tumors can be detected by PET using [(11)C]AZT; therefore, [(11)C]AZT could be useful as a novel PET tracer for tumor imaging in vivo.

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References

Lynx M, Kang B, McKee E . Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines. Biochem Pharmacol. 2008; 75(8):1610-5. PMC: 2364649. DOI: 10.1016/j.bcp.2008.01.006. View

Smith G, Sala R, Carroll L, Behan K, Glaser M, Robins E . Synthesis and evaluation of nucleoside radiotracers for imaging proliferation. Nucl Med Biol. 2012; 39(5):652-65. DOI: 10.1016/j.nucmedbio.2011.12.002. View

Toyohara J, Okada M, Toramatsu C, Suzuki K, Irie T . Feasibility studies of 4'-[methyl-(11)C]thiothymidine as a tumor proliferation imaging agent in mice. Nucl Med Biol. 2007; 35(1):67-74. DOI: 10.1016/j.nucmedbio.2007.10.001. View

Morita N, Kusuhara H, Sekine T, Endou H, Sugiyama Y . Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J Pharmacol Exp Ther. 2001; 298(3):1179-84. View

Zhang Z, Doi H, Koyama H, Watanabe Y, Suzuki M . Efficient syntheses of [¹¹C]zidovudine and its analogs by convenient one-pot palladium(0)-copper(I) co-mediated rapid C-[¹¹C]methylation. J Labelled Comp Radiopharm. 2014; 57(8):540-9. DOI: 10.1002/jlcr.3213. View

Lynx M, Bentley A, McKee E . 3'-Azido-3'-deoxythymidine (AZT) inhibits thymidine phosphorylation in isolated rat liver mitochondria: a possible mechanism of AZT hepatotoxicity. Biochem Pharmacol. 2006; 71(9):1342-8. PMC: 1472706. DOI: 10.1016/j.bcp.2006.01.003. View

Good S, Koble C, Crouch R, Johnson R, Rideout J, de Miranda P . Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. Drug Metab Dispos. 1990; 18(3):321-6. View

Chen R, Nelson J . Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol. 2000; 60(2):215-9. DOI: 10.1016/s0006-2952(00)00334-8. View

Furman P, Fyfe J, St Clair M, Weinhold K, Rideout J, Freeman G . Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986; 83(21):8333-7. PMC: 386922. DOI: 10.1073/pnas.83.21.8333. View

10.

Grierson J, Shields A . Radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine: [(18)F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol. 2000; 27(2):143-56. DOI: 10.1016/s0969-8051(99)00104-3. View

11.

Elliott G, OHare P . Live-cell analysis of a green fluorescent protein-tagged herpes simplex virus infection. J Virol. 1999; 73(5):4110-9. PMC: 104190. DOI: 10.1128/JVI.73.5.4110-4119.1999. View

12.

Ritzel M, Ng A, Yao S, Graham K, Loewen S, Smith K . Recent molecular advances in studies of the concentrative Na+-dependent nucleoside transporter (CNT) family: identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine.... Mol Membr Biol. 2001; 18(1):65-72. DOI: 10.1080/09687680010026313. View

13.

Yao S, Cass C, Young J . Transport of the antiviral nucleoside analogs 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine by a recombinant nucleoside transporter (rCNT) expressed in Xenopus laevis oocytes. Mol Pharmacol. 1996; 50(2):388-93. View

14.

Wada S, Tsuda M, Sekine T, Cha S, Kimura M, Kanai Y . Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000; 294(3):844-9. View

15.

Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T . Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002; 300(3):918-24. DOI: 10.1124/jpet.300.3.918. View

16.

Conti P, Alauddin M, Fissekis J, Schmall B, WATANABE K . Synthesis of 2'-fluoro-5-[11C]-methyl-1-beta-D-arabinofuranosyluracil ([11C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PET. Nucl Med Biol. 1995; 22(6):783-9. DOI: 10.1016/0969-8051(95)00017-r. View

17.

Seitz U, Wagner M, Vogg A, Glatting G, Neumaier B, Greten F . In vivo evaluation of 5-[(18)F]fluoro-2'-deoxyuridine as tracer for positron emission tomography in a murine pancreatic cancer model. Cancer Res. 2001; 61(10):3853-7. View

18.

Georgi A, Warner A, Fields B, Chen L . Detection of individual fluorescently labeled reovirions in living cells. Proc Natl Acad Sci U S A. 1990; 87(17):6579-83. PMC: 54580. DOI: 10.1073/pnas.87.17.6579. View

19.

Toyohara J, Nariai T, Sakata M, Oda K, Ishii K, Kawabe T . Whole-body distribution and brain tumor imaging with (11)C-4DST: a pilot study. J Nucl Med. 2011; 52(8):1322-8. DOI: 10.2967/jnumed.111.088435. View

20.

Chow H, Li P, Brookshier G, Tang Y . In vivo tissue disposition of 3'-azido-3'-deoxythymidine and its anabolites in control and retrovirus-infected mice. Drug Metab Dispos. 1997; 25(4):412-22. View