Synthesis and Evaluation of a Dimeric RGD Peptide as a Preliminary Study for Radiotheranostics with Radiohalogens

We recently developed (125)I- and (211)At-labeled monomer RGD peptides using a novel radiolabeling method. Both labeled peptides showed high accumulation in the tumor and exhibited similar biodistribution, demonstrating their usefulness for radiotheranostics. This study applied the labeling method to a dimer RGD peptide with the aim of gaining higher accumulation in tumor tissues based on improved affinity with α(v)β(3) integrin. We synthesized an iodine-introduced dimer RGD peptide, E[c(RGDfK)] (6), and an (125/131)I-labeled dimer RGD peptide, E[c(RGDfK)]{[(125/131)I]c[RGDf(4-I)K]} ([(125/131)I]6), and evaluated them as a preliminary step to the synthesis of an (211)At-labeled dimer RGD peptide. The affinity of 6 for α(v)β(3) integrin was higher than that of a monomer RGD peptide. In the biodistribution experiment at 4 h postinjection, the accumulation of [(125)I]6 (4.12 ± 0.42% ID/g) in the tumor was significantly increased compared with that of (125)I-labeled monomer RGD peptide (2.93 ± 0.08% ID/g). Moreover, the accumulation of [(125)I]6 in the tumor was greatly inhibited by co-injection of an excess RGD peptide. However, a single injection of [(131)I]6 (11.1 MBq) did not inhibit tumor growth in tumor-bearing mice. We expect that the labeling method for targeted alpha therapy with (211)At using a dimer RGD peptide could prove useful in future clinical applications.