title: 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.affiliation: School of Health Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Xin
authors.initials: X
authors.lastname: Yan
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000031:analogs & derivatives / Q000737:chemistry; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003301:Copper Radioisotopes / Q000737:chemistry*; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D012235:Rhodamines / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D003301:Copper Radioisotopes; D012235:Rhodamines; C022027:lissamine rhodamine B; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone