64Cu-labeled lissamine rhodamine B: a promising PET radiotracer targeting tumor mitochondria.

Abstract

Enhanced mitochondrial potential in carcinoma cells is an important characteristic of cancer. It is of great current interest to develop a radiotracer that is sensitive to mitochondrial potential changes at the early stage of tumor growth. In this report, we present the synthesis and evaluation of (64)Cu-labeled Lissamine rhodamine B (LRB), (64)Cu(DOTA-LRB) (DOTA-LRB = 2-(6-(diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-(2-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclo-dodecan-1-yl)acetamido)ethyl)sulfamoyl)benzenesulfonate) as a new radiotracer for imaging tumors in athymic nude mice bearing U87MG human glioma xenografts by positron emission tomography (PET). We also explored its localization mechanism using Cu(DOTA-LRB) as the fluorescent probe in both the U87MG human glioma cell line and the cultured primary U87MG glioma cells. It was found that (64)Cu(DOTA-LRB) had the highest tumor uptake (6.54 ± 1.50, 6.91 ± 1.26, 5.68 ± 1.13, 7.58 ± 1.96, and 5.14 ± 1.50%ID/g at 0.5, 1, 2, 4, and 24 h postinjection, respectively) among many (64)Cu-labeled organic cations evaluated in the same animal model. The cellular staining study indicated that Cu(DOTA-LRB) was able to localize in mitochondria of U87MG glioma cells due to the enhanced negative mitochondrial potential. This statement is completely supported by the results from decoupling experiment with carbonylcyanide-m-chlorophenylhydrazone (CCCP). MicroPET data showed that the U87MG glioma tumors were clearly visualized as early as 30 min postinjection with (64)Cu(DOTA-LRB). (64)Cu(DOTA-LRB) remained stable during renal excretion, but underwent extensive degradation during hepatobiliary excretion. On the basis of the results from this study, it was concluded that (64)Cu(DOTA-LRB) represents a new class of promising PET radiotracers for noninvasive imaging of the MDR-negative tumors.

• Authors: Yang Zhou, Young-Seung Kim, Xin Yan, Orit Jacobson, Xiaoyuan Chen, Shuang Liu
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 8 Issue 4 Pg. 1198-208 (Aug 01 2011) ISSN: 1543-8392 [Electronic] United States
• PMID: 21545131 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Copper Radioisotopes
• Rhodamines
• lissamine rhodamine B
• Carbonyl Cyanide m-Chlorophenyl Hydrazone

Topics

• Animals
• Carbonyl Cyanide m-Chlorophenyl Hydrazone (analogs & derivatives, chemistry)
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Copper Radioisotopes (chemistry)
• Female
• Glioma (diagnostic imaging, metabolism)
• Humans
• Mice
• Mice, Nude
• Mitochondria (metabolism)
• Molecular Structure
• Positron-Emission Tomography (methods)
• Rhodamines (chemistry)
• Tumor Cells, Cultured