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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.


Related in: MedlinePlus

Comparisons of the in vivo accumulation level of thymidine analogs in C6 tumor-bearing mice. Summed PET images (60 to 80 min) of C6 tumor-bearing mice after injection of 50 MBq of [11C]AZT, [11C]d4T or [11C]4DST (a). The color code for the standardized uptake value (SUV) is shown at the bottom. Arrowheads indicate the C6 tumors. Arrows indicate bone or bone marrow regions. The graph in (b) shows the SUVs from PET images for tumor tissue and bone. Data are presented as means ± S.D. (n = 4 to 6). One way ANOVA;**P < 0.01 vs. [11C]AZT and [11C]d4T injected mouse. †P < 0.01 vs. [11C]d4T injected mouse. The graph in (c) shows the ratio of tumor-to-bone uptake of the labeled probes. One way ANOVA;*P < 0.05 vs. [11C]4DST injected mouse. **P < 0.01 vs. [11C]d4T injected mouse
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Fig5: Comparisons of the in vivo accumulation level of thymidine analogs in C6 tumor-bearing mice. Summed PET images (60 to 80 min) of C6 tumor-bearing mice after injection of 50 MBq of [11C]AZT, [11C]d4T or [11C]4DST (a). The color code for the standardized uptake value (SUV) is shown at the bottom. Arrowheads indicate the C6 tumors. Arrows indicate bone or bone marrow regions. The graph in (b) shows the SUVs from PET images for tumor tissue and bone. Data are presented as means ± S.D. (n = 4 to 6). One way ANOVA;**P < 0.01 vs. [11C]AZT and [11C]d4T injected mouse. †P < 0.01 vs. [11C]d4T injected mouse. The graph in (c) shows the ratio of tumor-to-bone uptake of the labeled probes. One way ANOVA;*P < 0.05 vs. [11C]4DST injected mouse. **P < 0.01 vs. [11C]d4T injected mouse

Mentions: To compare the differences in the pattern of accumulation of three 11C-labeled thymidine analogs in normal proliferative tissues in vivo, we performed PET analysis of injected C6 tumor-bearing mice under the same conditions and analyzed the ratio of tumor accumulation to bone accumulation for each analog in PET images. As shown in Fig. 5a, b and Additional file 1: Figure S3A, although [11C]4DST showed the highest tumor accumulation (3.5 times higher than the tumor accumulation of [11C]AZT), it was also highly accumulated in the bone. Thus, of the two thymidine analogs examined, [11C]4DST and [11C]AZT showed the lowest and highest tumor-to-bone ratios, respectively (Fig. 5c and Additional file 1: Figure S3B, p < 0.05).Fig. 5


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)

Comparisons of the in vivo accumulation level of thymidine analogs in C6 tumor-bearing mice. Summed PET images (60 to 80 min) of C6 tumor-bearing mice after injection of 50 MBq of [11C]AZT, [11C]d4T or [11C]4DST (a). The color code for the standardized uptake value (SUV) is shown at the bottom. Arrowheads indicate the C6 tumors. Arrows indicate bone or bone marrow regions. The graph in (b) shows the SUVs from PET images for tumor tissue and bone. Data are presented as means ± S.D. (n = 4 to 6). One way ANOVA;**P < 0.01 vs. [11C]AZT and [11C]d4T injected mouse. †P < 0.01 vs. [11C]d4T injected mouse. The graph in (c) shows the ratio of tumor-to-bone uptake of the labeled probes. One way ANOVA;*P < 0.05 vs. [11C]4DST injected mouse. **P < 0.01 vs. [11C]d4T injected mouse
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Fig5: Comparisons of the in vivo accumulation level of thymidine analogs in C6 tumor-bearing mice. Summed PET images (60 to 80 min) of C6 tumor-bearing mice after injection of 50 MBq of [11C]AZT, [11C]d4T or [11C]4DST (a). The color code for the standardized uptake value (SUV) is shown at the bottom. Arrowheads indicate the C6 tumors. Arrows indicate bone or bone marrow regions. The graph in (b) shows the SUVs from PET images for tumor tissue and bone. Data are presented as means ± S.D. (n = 4 to 6). One way ANOVA;**P < 0.01 vs. [11C]AZT and [11C]d4T injected mouse. †P < 0.01 vs. [11C]d4T injected mouse. The graph in (c) shows the ratio of tumor-to-bone uptake of the labeled probes. One way ANOVA;*P < 0.05 vs. [11C]4DST injected mouse. **P < 0.01 vs. [11C]d4T injected mouse
Mentions: To compare the differences in the pattern of accumulation of three 11C-labeled thymidine analogs in normal proliferative tissues in vivo, we performed PET analysis of injected C6 tumor-bearing mice under the same conditions and analyzed the ratio of tumor accumulation to bone accumulation for each analog in PET images. As shown in Fig. 5a, b and Additional file 1: Figure S3A, although [11C]4DST showed the highest tumor accumulation (3.5 times higher than the tumor accumulation of [11C]AZT), it was also highly accumulated in the bone. Thus, of the two thymidine analogs examined, [11C]4DST and [11C]AZT showed the lowest and highest tumor-to-bone ratios, respectively (Fig. 5c and Additional file 1: Figure S3B, p < 0.05).Fig. 5

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