Design of a Tetravalent RGD Peptide Capable of Simultaneous Binding with Multiple Integrin αvβ3 for Targeted Radionuclide Therapy

For targeted radionuclide therapy, radioligands that exhibit high and persistent tumor uptake are indispensable. We previously synthesized a 99m Tc-labeled hexavalent RGD peptide ( 99m Tc-(RGD) 6 ) as a tumor imaging agent targeting integrin αvβ3. 99m Tc-(RGD) 6 showed high in vivo tumor uptake with long retention due to simultaneous binding to multiple integrin αvβ3 receptors. The purpose of this study was to apply this finding to the design of a multivalent RGD peptide labeled with 211 At, a promising α-emitting radionuclide for radionuclide therapy. As a candidate compound, a tetravalent RGD peptide (H 2 N-(RGD) 4 ) was synthesized and radiolabeled with 125 I, a homologous element of At, for basic studies. As expected, 125 I-(RGD) 4 retained the capability of simultaneous binding and showed comparable in vivo tumor uptake to 99m Tc-(RGD) 6 . Finally, 211 At-(RGD) 4 was synthesized with >95% radiochemical purity and exhibited an almost identical biodistribution pattern to 125 I-(RGD) 4 . These results indicate that 211 At-(RGD) 4 might be a potential radioligand for integrin αvβ3-targeted radionuclide therapy.