Glycosylated RGD-containing peptides: Tracer for tumor targeting and angiogenesis imaging with improved biokinetics

R. Haubner, H. J. Wester, F. Burkhart, R. Senekowitsch-Schmidtke, W. Weber, S. L. Goodman, H. Kessler, M. Schwaiger

Research output: Contribution to journalArticlepeer-review

421 Scopus citations


The αvβ3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the αvβ3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed αvβ3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of αvβ3 expression are described. Methods: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-β-D-glycero-D-gulo-he ptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)- Gly-Asp(OtBu)-D-Tyr(tBu)-Lys-) and subsequent removal of the protection groups. Iodine labeling was performed by the Iodo-Gen method (radiochemical yield > 50%). The in vitro binding assays were performed using purified immobilized αllbβ3, αvβ5, and αvβ3 integrins. For in vivo experiments, nude mice bearing xenotransplanted melanomas and mice with osteosarcomas were used. Results: The glycosylated peptide 3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP2 showed high affinity and selectivity for αvβ3 in vitro (50% inhibitory concentration = 40 nmol/L). Pretreatment studies indicate specific binding of [125I]GP2 on αvβ3-expressing tumors in vivo. Comparison of the pharmacokinetics of [125I]GP2 and [125I]-3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) [125I]P2 revealed for [125I]GP2 an increased activity concentration in the blood (e.g., 3.59 ± 0.35 percentage injected dose [%ID]/g vs. 1.72 ± 0.44 %ID/g at 10 min postinjection) and a significantly reduced uptake in the liver (e.g., 2.59 ± 0.24 %ID/g vs. 21.96 ± 2.78 %ID/g at 10 min postinjection). Furthermore, a clearly increased activity accumulation in the tumor was found (e.g., 3.05 ± 0.31%ID/g vs. 0.92 ± 0.16 %ID/g at 240 min postinjection), which remained almost constant between 60 and 240 min postinjection. This resulted in good tumor-to-organ ratios for the glycosylated tracer (e.g., 240-min postinjection osteosarcoma model: tumor-to-blood = 16; tumor-to-muscle = 7; tumor-to-liver = 2.5), which were confirmed by the first gamma-camera images of osteosarcomabearing mice at 240 min postinjection. Conclusion: This study demonstrates that the introduction of a sugar moiety improves the pharmakokinetic behavior of a hydrophobic peptide-based tracer. Additionally, this αvβ3-selective glycosylated radioiodinated second-generation tracer GP2 shows high tumor uptake and good tumor-to-organ ratios that allow noninvasive visualization of αvβ3-expressing tumors and monitoring therapy with αvβ3 antagonists. Finally, the favorable biokinetics make the glycosylated RGD-peptide a promising lead structure for tracers to quantify the αvβ3 expression using PET.

Original languageEnglish
Pages (from-to)326-336
Number of pages11
JournalJournal of Nuclear Medicine
Issue number2
StatePublished - 2001
Externally publishedYes


  • Angiogenesis
  • Glycosylated RGD-peptides
  • Integrin
  • Tumor targeting
  • αβ antagonists


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