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Multivalent RGD peptides have been used as an excellent targeting vector to integrin α v β 3 -positive tumors. However, little attention has been paid to the influence of linker molecules in multivalent RGD peptides on their dissociation kinetics from tumor cells. In this study, we evaluated the dissociation kinetics of 99m Tc-labeled hexavalent RGD peptides which have (CH 2 -CH 2 -O) n (n = 4, [ 99m Tc][Tc(L1) 6 ] + and n = 12, [ 99m Tc][Tc(L2) 6 ] + ) or ( D Pro-Gly) n (n = 1, [ 99m Tc][Tc(L3) 6 ] + ; n = 6, [ 99m Tc][Tc(L4) 6 ] + ; and n = 9, [ 99m Tc][Tc(L5) 6 ] + ) as a linker molecule. The results showed that [ 99m Tc][Tc(L4) 6 ] + and [ 99m Tc][Tc(L5) 6 ] + displayed slower dissociation kinetics and [ 99m Tc][Tc(L4) 6 ] + showed exceptionally high in vitro cellular uptake (203.1 ± 16.7% dose/mg protein) and the highest tumor to blood ratio (138.1 ± 26.3 at 4 h p.i.) in tumor bearing nude mice. These findings indicate that the use of appropriate length of ( D Pro-Gly) n would maximize the binding of multivalent RGD peptides to clustered integrin α v β 3 .

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