title: Evaluation of the angiogenesis inhibitor KR-31831 in SKOV-3 tumor-bearing mice using (64)Cu-DOTA-VEGF(121) and microPET.
abstract: KR-31831 ((2R,3R,4S)-6-amino-4-[N-(4-chloropheyl)-N-(1H-imidazol-2ylmethyl)amino]-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran), an angiogenesis inhibitor, was evaluated in tumor-bearing mice using molecular imaging technology. Pre-treatment microPET images were acquired on SKOV-3 cell-implanted nude mice after injection with (64)Cu-DOTA-VEGF(121). KR-31831 (50 mg/kg) was then injected intraperitoneally into the treatment group (n=3), while injection vehicle was injected into the control (n=4) and blocking (n=3) groups. After injections occurred daily for 28 days, all groups of mice underwent post-treatment microPET imaging after injection with (64)Cu-DOTA-VEGF(121). The post-treatment images showed high tumor uptake in the control group and reduced tumor uptake in both the blocking and treatment groups. ROI analysis of the tumor images revealed 6.25%±1.18% ID/g at 1 h, 6.55%±0.69% ID/g at 2 h, and 4.68%±0.63% ID/g at 16 h in the control group; 3.87%±0.45% ID/g at 1 h, 4.50%±0.44% ID/g at 2 h, and 3.63%±0.25% ID/g at 16 h in the blocking group; and 4.03%±0.74% ID/g at 1 h, 4.37%±0.67% ID/g at 2 h, and 3.83%±0.90% ID/g at 16 h in the treatment group. Biodistribution obtained after the post-treatment microPET imaging also demonstrated high tumor uptake (3.74%±0.27% ID/g) in the control group and reduced uptakes in both the blocking group (2.69%±0.73% ID/g, P<.05) and the treatment group (3.11%±0.25% ID/g, P<.05), which correlated well with microPET imaging data. Immunofluorescence analysis showed higher levels of VEGFR2 and CD31 expressions in tumor tissues of the control and blocking groups than in tumor tissues of the treatment group. These results suggest that the antiangiogenic activity of KR-31831 is mediated through VEGFR2 and microPET serves as a useful molecular imaging tool for evaluation of a newly developed angiogenesis inhibitor, KR-31831.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul, Korea.
authors.forename: Iljung
authors.initials: I
authors.lastname: Lee
authors.forename: Kwang Yup
authors.initials: KY
authors.lastname: Yoon
authors.forename: Choong Mo
authors.initials: CM
authors.lastname: Kang
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
authors.forename: Yearn Seong
authors.initials: YS
authors.lastname: Choe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009942:Organometallic Compounds; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D042461:Vascular Endothelial Growth Factor A; D023041:Xenograft Model Antitumor Assays
chemical_list: C529227:64Cu-DOTA-VEGF(DEE); D020533:Angiogenesis Inhibitors; D001578:Benzopyrans; D007093:Imidazoles; C503693:KR 31831; D009942:Organometallic Compounds; D042461:Vascular Endothelial Growth Factor A