Glycosylated RGD-Containing Peptides: Tracer for Tumor Targeting and Angiogenesis Imaging with Improved Biokinetics

Journal of Nuclear Medicine

Markus Schwaiger¹  Roland Haubner¹  Wolfgang Weber¹  Reingard Senekowitsch-Schmidtke¹  Fred Burkhart¹  Hans-Jürgen Wester¹  Simon L. Goodman¹  Horst Kessler¹ 

[1] Department of Nuclear Medicine and Institute of Organic Chemistry and Biochemistry, Technische Universität München, Munich; and Department of Preclinical Oncology, Merck KGaA, Darmstadt, Germany Department of Nuclear Medicine and Institute of Organic Chemistry and Biochemistry, Technische Universität München, Munich; and Department of Preclinical Oncology, Merck KGaA, Darmstadt, Germany Department of Nuclear Medicine and Institute of Organic Chemistry and Biochemistry, Technische Universität München, Munich; and Department of Preclinical Oncology, Merck KGaA, Darmstadt, Germany

关键词: glycosylated RGD-peptides;    α_Vβ₃ antagonists;    integrin;    angiogenesis;    tumor targeting;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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-heptonic 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 αIIbβ3, 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 osteosarcoma-bearing 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.

【 授权许可】

Unknown