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: Sudipta Chakraborty, Jiyun Shi, Young-Seung Kim, Yang Zhou, Bing Jia, Fan Wang, Shuang Liu
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 21 Issue 5 Pg. 969-78 (May 19 2010) ISSN: 1520-4812 [Electronic] United States
• PMID: 20387808 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Heterocyclic Compounds, 1-Ring
• Indium Radioisotopes
• Integrin alphaVbeta3
• Oligopeptides
• Peptides, Cyclic
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• arginyl-glycyl-aspartic acid
• glycyl-glycyl-glycine

Topics

• Animals
• Cell Line, Tumor
• Glioma (diagnostic imaging)
• Heterocyclic Compounds, 1-Ring (chemistry, pharmacokinetics)
• Humans
• Indium Radioisotopes (chemistry, pharmacokinetics)
• Integrin alphaVbeta3 (metabolism)
• Mice
• Mice, Nude
• Oligopeptides (chemistry, pharmacokinetics)
• Peptides, Cyclic (chemistry, pharmacokinetics)
• Radionuclide Imaging