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A novel (11)C-labeled thymidine analog, [(11)C]AZT, for tumor imaging by positron emission tomography.

Tahara T, Zhang Z, Ohno M, Hirao Y, Hosaka N, Doi H, Suzuki M, Onoe H - EJNMMI Res (2015)

Bottom Line: Cellular uptake of [(11)C]AZT in C6 was measured in the presence or absence of non-labeled thymidine (0.1 mM).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), 6-7-3 Minatojima, Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan, tsuyoshi.tahara@riken.jp.

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.

No MeSH data available.


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Metabolite analysis of injected [11C]AZT. a Representative TLC-radiochromatogram of plasma and tumor tissues at 30 min after i.v. injection and of the bile at 60 min after i.v. injection of [11C]AZT. * indicates unmetabolized [11C]AZT. Arrowhead, arrow, and † indicate the metabolites a, b and c, respectively. b The picture of TLC-chromatogram with unlabeled AZT metabolites visualized by ultraviolet (254 nm) irradiation
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Fig6: Metabolite analysis of injected [11C]AZT. a Representative TLC-radiochromatogram of plasma and tumor tissues at 30 min after i.v. injection and of the bile at 60 min after i.v. injection of [11C]AZT. * indicates unmetabolized [11C]AZT. Arrowhead, arrow, and † indicate the metabolites a, b and c, respectively. b The picture of TLC-chromatogram with unlabeled AZT metabolites visualized by ultraviolet (254 nm) irradiation

Mentions: Metabolite analysis of plasma, bile, intestinal contents, and tumor at 30 or 60 min after the injection of [11C]AZT was then performed using TLC (Fig. 6a). Three major hydrophilic metabolites were detected: metabolites a, b, and c. To identify these metabolites, we carried out TLC with major AZT metabolites, AZT-5′-monophosphate (AZT-P) and AZT-β-d-glucuronide (AZT-G) (Fig. 6b). In plasma, the unmetabolized form of [11C]AZT constituted 93.3 ± 2.4 % of the total radioactivity; in the tumors, it accounted for approximately 50 % of the total radioactivity, with large amounts of metabolite a (45.6 ± 3.1 %) being present. The other metabolites, metabolite b and c were observed in the bile. The percentages of metabolites b and c in the bile were 9.2 ± 2.3 % and 39.6 ± 5.5 %, respectively. The Rf values of metabolite a and b were consistent with that of AZT-P and AZT-G, respectively (Fig. 6a, b).Fig. 6


A novel (11)C-labeled thymidine analog, [(11)C]AZT, for tumor imaging by positron emission tomography.

Tahara T, Zhang Z, Ohno M, Hirao Y, Hosaka N, Doi H, Suzuki M, Onoe H - EJNMMI Res (2015)

Metabolite analysis of injected [11C]AZT. a Representative TLC-radiochromatogram of plasma and tumor tissues at 30 min after i.v. injection and of the bile at 60 min after i.v. injection of [11C]AZT. * indicates unmetabolized [11C]AZT. Arrowhead, arrow, and † indicate the metabolites a, b and c, respectively. b The picture of TLC-chromatogram with unlabeled AZT metabolites visualized by ultraviolet (254 nm) irradiation
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Fig6: Metabolite analysis of injected [11C]AZT. a Representative TLC-radiochromatogram of plasma and tumor tissues at 30 min after i.v. injection and of the bile at 60 min after i.v. injection of [11C]AZT. * indicates unmetabolized [11C]AZT. Arrowhead, arrow, and † indicate the metabolites a, b and c, respectively. b The picture of TLC-chromatogram with unlabeled AZT metabolites visualized by ultraviolet (254 nm) irradiation
Mentions: Metabolite analysis of plasma, bile, intestinal contents, and tumor at 30 or 60 min after the injection of [11C]AZT was then performed using TLC (Fig. 6a). Three major hydrophilic metabolites were detected: metabolites a, b, and c. To identify these metabolites, we carried out TLC with major AZT metabolites, AZT-5′-monophosphate (AZT-P) and AZT-β-d-glucuronide (AZT-G) (Fig. 6b). In plasma, the unmetabolized form of [11C]AZT constituted 93.3 ± 2.4 % of the total radioactivity; in the tumors, it accounted for approximately 50 % of the total radioactivity, with large amounts of metabolite a (45.6 ± 3.1 %) being present. The other metabolites, metabolite b and c were observed in the bile. The percentages of metabolites b and c in the bile were 9.2 ± 2.3 % and 39.6 ± 5.5 %, respectively. The Rf values of metabolite a and b were consistent with that of AZT-P and AZT-G, respectively (Fig. 6a, b).Fig. 6

Bottom Line: Cellular uptake of [(11)C]AZT in C6 was measured in the presence or absence of non-labeled thymidine (0.1 mM).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), 6-7-3 Minatojima, Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan, tsuyoshi.tahara@riken.jp.

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.

No MeSH data available.


Related in: MedlinePlus