title: 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.affiliation: School of Health Sciences, Purdue University , West Lafayette, Indiana, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
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; D002412:Cations / Q000737:chemistry / Q000493:pharmacokinetics; D056831:Coordination Complexes / Q000737:chemistry / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005910:Glioma / Q000737:chemistry / Q000000981:diagnostic imaging*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000378:metabolism; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C561041:(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); D002412:Cations; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals