title: Linker effects on biological properties of 111In-labeled DTPA conjugates of a cyclic RGDfK dimer.
abstract: In this report, we present in vitro and in vivo evaluation of three 111 In-labeled DTPA conjugates of a cyclic RGDfK dimer: DTPA-Bn-SU016 (SU016 = E[c(RGDfK)] 2; DTPA-Bn = 2-( p-isothioureidobenzyl)diethylenetriaminepentaacetic acid), DTPA-Bn-E-SU016 ( E = glutamic acid) and DTPA-Bn-Cys-SU016 (Cys = cysteic acid). The integrin alpha vbeta 3 binding affinities of SU016, DTPA-Bn-SU016, DTPA-Bn-E-SU016, and DTPA-Bn-Cys-SU016 were determined to be 5.0 +/- 0.7 nM, 7.9 +/- 0.6 nM, 5.8 +/- 0.6 nM, and 6.9 +/- 0.9 nM, respectively, against 125 I-c(RGDyK) in binding to integrin alpha vbeta3, suggesting that E or Cys residue has little effect on the integrin alpha vbeta3 affinity of E[c(RGDfK)] 2. It was also found that the 111 In-labeling efficiency of DTPA-Bn-SU016 and DTPA-Bn-E-SU016 is 3-5 times better than that of DOTA analogues due to fast chelation kinetics and high-yield 111 In-labeling under mild conditions (e.g., room temperature). Biodistribution studies were performed using BALB/c nude mice bearing U87MG human glioma xenografts. 111 In-DTPA-Bn-SU016, 111 In-DTPA-Bn-E-SU016, and 111 In-DTPA-Bn-Cys-SU016 all displayed rapid blood clearance. Their tumor uptake was comparable between 0.5 and 4 h postinjection (p.i.) within experimental error. 111 In-DTPA-Bn-E-SU016 had a significantly lower ( p < 0.01) kidney uptake than 111 In-DTPA-Bn-SU016 and 111 In-DTPA-Bn-Cys-SU016. The liver uptake of 111 In-DTPA-Bn-SU016 was 1.69 +/- 0.18% ID/g at 24 h p.i., while the liver uptake values of 111 In-DTPA-Bn-E-SU016 and 111 In-DTPA-Bn-Cys-SU016 were 0.55 +/- 0.11% ID/g and 0.79 +/- 0.15% ID/g at 24 h p.i., respectively. Among the three 111 In radiotracers evaluated in this study, 111 In-DTPA-Bn-E-SU016 has the lowest liver and kidney uptake and the best tumor/liver and tumor/kidney ratios. Results from metabolism studies indicated that there is little metabolism (<10%) for three 111 In radiotracers at 1 h p.i. Imaging data showed that tumors can be clearly visualized at 4 h p.i. with good contrast in the tumor-bearing mice administered with 111 In-DTPA-Bn-E-SU016. It is concluded that using a glutamic acid linker can significantly improve excretion kinetics of the 111 In-labeled E[c(RGDfK)] 2 from liver and kidneys.
authors: Medical Isotopes Research Center, Peking University, Beijing 100083, China.
authors: Bing
authors: B
authors: Jia
authors: Zhaofei
authors: Z
authors: Liu
authors: Jiyun
authors: J
authors: Shi
authors: Zilin
authors: Z
authors: Yu
authors: Zhi
authors: Z
authors: Yang
authors: Huiyun
authors: H
authors: Zhao
authors: Zhengjie
authors: Z
authors: He
authors: Shuang
authors: S
authors: Liu
authors: Fan
authors: F
authors: Wang
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003544:Cysteic Acid / Q000378:metabolism; D019281:Dimerization; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D039564:Integrin alphaV / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D004369:Pentetic Acid / Q000737:chemistry* / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics*; D011854:Radiochemistry; D011877:Radionuclide Imaging; D012996:Solutions
chemical_list: D007205:Indium Radioisotopes; D039564:Integrin alphaV; D010456:Peptides, Cyclic; D012996:Solutions; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D018698:Glutamic Acid; D004369:Pentetic Acid; D003544:Cysteic Acid