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 ^99mTc-labeled hexavalent RGD peptide (^99mTc-(RGD)₆) as a tumor imaging agent targeting integrin αvβ3. ^99mTc-(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 ²¹¹At, a promising α-emitting radionuclide for radionuclide therapy. As a candidate compound, a tetravalent RGD peptide (H₂N-(RGD)₄) was synthesized and radiolabeled with ¹²⁵I, a homologous element of At, for basic studies. As expected, ¹²⁵I-(RGD)₄ retained the capability of simultaneous binding and showed comparable in vivo tumor uptake to ^99mTc-(RGD)₆. Finally, ²¹¹At-(RGD)₄ was synthesized with >95% radiochemical purity and exhibited an almost identical biodistribution pattern to ¹²⁵I-(RGD)₄. These results indicate that ²¹¹At-(RGD)₄ might be a potential radioligand for integrin αvβ3-targeted radionuclide therapy.