Evaluation of 64Cu-labeled acridinium cation: a PET radiotracer targeting tumor mitochondria.

Abstract

This report presents the synthesis and evaluation of (64)Cu(DO3A-xy-ACR) (DO3A-xy-ACR = 2,6-bis(dimethylamino)-10-(4-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)benzyl)acridin-10-ium) as a radiotracer for imaging tumors in athymic nude mice bearing U87MG glioma xenografts by PET (positron emission tomography). The biodistribution data suggested that (64)Cu(DO3A-xy-ACR) was excreted mainly through the renal system with >65% of injected radioactivity being recovered from urine samples at 1 h postinjection (p.i.). The tumor uptake of (64)Cu(DO3A-xy-ACR) was 1.07 ± 0.23, 1.58 ± 0.55, 2.71 ± 0.66, 3.47 ± 1.19, and 3.52 ± 1.72%ID/g at 0.5, 1, 2, 4, and 24 h p.i., respectively. (64)Cu(DO3A-xy-ACR) had very high liver uptake (31.90 ± 3.98, 24.95 ± 5.64, 15.20 ± 4.29, 14.09 ± 6.82, and 8.18 ± 1.27%ID/g at 0.5, 1, 2, 4, and 24 h p.i., respectively) with low tumor/liver ratios. MicroPET studies showed that the tumors were clearly visualized as early as 30 min p.i. in the glioma-bearing mouse administered with (64)Cu(DO3A-xy-ACR). The high liver radioactivity accumulation was also seen. (64)Cu(DO3A-xy-ACR) had a relatively high metabolic stability during excretion via both renal and hepatobiliary routes, but it was completely decomposed in the liver homogenate. We explored the localization mechanism of Cu(DO3A-xy-ACR) using both U87MG human glioma and the cultured primary U87MG glioma cells. The results from the cellular staining assays showed that (64)Cu(DO3A-xy-ACR) is able to localize in the mitochondria of living U87MG glioma cells due to the enhanced negative mitochondrial potential as compared to normal cells. Although (64)Cu(DO3A-xy-ACR) is not an ideal PET radiotracer for tumor imaging due to its high liver uptake, the results from this study strongly suggest that (64)Cu-labeled acridinium cations are indeed able to localize in the energized mitochondria of tumor cells.

• Authors: Yang Zhou, Young-Seung Kim, Jiyun Shi, Orit Jacobson, Xiaoyuan Chen, Shuang Liu
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 22 Issue 4 Pg. 700-8 (Apr 20 2011) ISSN: 1520-4812 [Electronic] United States
• PMID: 21413736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• (2,6-bis(dimethylamino)-10-(4-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)benzyl)acridin-10-ium)copper(II)
• Cations
• Coordination Complexes
• Copper Radioisotopes
• Organometallic Compounds
• Radiopharmaceuticals

Topics

• Animals
• Cations (chemistry, pharmacokinetics)
• Coordination Complexes (chemistry, pharmacokinetics)
• Copper Radioisotopes (chemistry, pharmacokinetics)
• Glioma (chemistry, diagnostic imaging)
• Mice
• Mice, Nude
• Mitochondria (chemistry, diagnostic imaging, metabolism)
• Molecular Structure
• Organometallic Compounds (chemistry, pharmacokinetics)
• Positron-Emission Tomography
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Stereoisomerism
• Tissue Distribution
• Xenograft Model Antitumor Assays