Radiolabeled α(ν)β3 integrin antagonists: A new class of tracers for tumor targeting

Roland Haubner, Hans Jürgen Wester, Ute Reuning, Reingard Senekowitsch-Schmidtke, Beate Diefenbach, Horst Kessler, Gerhard Stöcklin, Markus Schwaiger

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386 Scopus citations


The α(ν)β3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective c{ν)β3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D- Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5- cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [125I]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). Methods: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized α(IIb)β3 and α(ν)β3 integrins. Expression of the α(ν)β3 receptor on the different tumors was validated by immunohistochemical methods using α(ν) and α(ν)β3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. Results: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for α(ν)β3. Immunohistochemical staining clearly indicates the presence of the α(ν)β3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 ± 0.32 %ID/g for the melanoma M21 and 3.50 ± 0.49 %ID/g for the osteosarcoma and decreases to 1.30 ± 0.13 %ID/g and 2.03 ± 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 ± 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [125I]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. Conclusion: [125I]P2 exhibits high affinity and selectivity for the α(ν)β3 integrin in vitro and in vivo and, thus, represents the first radiolabeled α(ν)β3 antagonist for the investigation of angiogenesis and metastasis in vivo.

Original languageEnglish
Pages (from-to)1061-1071
Number of pages11
JournalJournal of Nuclear Medicine
Issue number6
StatePublished - Jun 1999


  • Alpha(v)beta(3 antagonists
  • I labeling
  • Integrins;
  • RGD peptides
  • Tumor targeting


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