title: Evaluation of 111In-labeled cyclic RGD peptides: tetrameric not tetravalent.
abstract: This report presents the synthesis and evaluation of (111)In(DOTA-6G-RGD(4)) (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid; 6G-RGD(4) = E{G(3)-E[G(3)-c(RGDfK)](2)}(2) and G(3) = Gly-Gly-Gly), (111)In(DOTA-RGD(4)) (RGD(4) = E{E[c(RGDfK)](2)}(2)) and (111)In(DOTA-3G-RGD(2)) (3G-RGD(2) = G(3)-E[G(3)-c(RGDfK)](2)) as new radiotracers for imaging integrin alpha(v)beta(3)-positive tumors. The IC(50) values of DOTA-6G-RGD(4), DOTA-RGD(4), and DOTA-3G-RGD(2) were determined to be 0.4 +/- 0.1, 1.4 +/- 0.1 and 1.1 +/- 0.1 nM against (125)I-c(RGDyK) bound to integrin alpha(v)beta(3)-positive U87MG human glioma cells. (111)In(DOTA-6G-RGD(4)), (111)In(DOTA-RGD(4)), and (111)In(DOTA-3G-RGD(2)) were prepared by reacting (111)InCl(3) with the respective DOTA conjugate in NH(4)OAc buffer (100 mM, pH = 5.5). Radiolabeling could be completed by heating the reaction mixture at 100 degrees C for 15-20 min. The specific activity was approximately 1850 MBq/micromol for (111)In(DOTA-3G-RGD(2)) and approximately 1480 MBq/micromol for (111)In(DOTA-6G-RGD(4)). The athymic nude mice bearing U87MG human glioma xenografts were used to evaluate tumor uptake and excretion kinetics of (111)In(DOTA-6G-RGD(4)), (111)In(DOTA-RGD(4)), and (111)In(DOTA-3G-RGD(2)). The results from both the integrin alpha(v)beta(3) binding assay and biodistribution studies suggest that the tetrameric cyclic RGD peptides, such as RGD(4) and 6G-RGD(4), are most likely bivalent in binding to the integrin alpha(v)beta(3). Both (111)In(DOTA-6G-RGD(4)) and (111)In(DOTA-RGD(4)) had significantly higher tumor uptake than (111)In(DOTA-3G-RGD(2)) at 24-72 h postinjection due to the extra RGD motifs in RGD(4) and 6G-RGD(4). (111)In(DOTA-3G-RGD(2)) had very little metabolism, while (111)In(DOTA-6G-RGD(4)) had significant metabolism during its excretion via both renal and hepatobiliary routes over the 2 h period, probably due to its much larger size. The combination of high tumor uptake with long tumor retention suggests that their corresponding (90)Y and (177)Lu analogues M(DOTA-6G-RGD(4)) (M = (90)Y and (177)Lu) might be useful as therapeutic radiotracers for treatment of integrin alpha(v)beta(3)-positive solid tumors.
authors.affiliation: School of Health Sciences, Purdue University, Indiana 47907, USA.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005910:Glioma / Q000000981:diagnostic imaging*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics; D011877:Radionuclide Imaging
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010456:Peptides, Cyclic; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C047981:arginyl-glycyl-aspartic acid; C035647:glycyl-glycyl-glycine
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