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

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

The _Vß₃ integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the _Vß₃ integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed _Vß₃-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 _Vß₃ 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-ß-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 _IIbß₃, _Vß₅, and _Vß₃ 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 _Vß₃ in vitro (50% inhibitory concentration = 40 nmol/L). Pretreatment studies indicate specific binding of [¹²⁵I]GP2 on _Vß₃-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 _Vß₃-selective glycosylated radioiodinated second-generation tracer GP2 shows high tumor uptake and good tumor-to-organ ratios that allow noninvasive visualization of _Vß₃-expressing tumors and monitoring therapy with _Vß₃ antagonists. Finally, the favorable biokinetics make the glycosylated RGD-peptide a promising lead structure for tracers to quantify the _Vß₃ expression using PET.

Key Words: glycosylated RGD-peptides • _Vß₃ antagonists • integrin • angiogenesis • tumor targeting

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