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Radiolabeled _vß₃ Integrin Antagonists: A New Class of Tracers for Tumor Targeting

Department of Nuclear Medicine, Women's Hospital, Clinical Research Unit and Institute of Organic Chemistry and Biochemistry, Technische Universität München, Munich
Merck KGaA, Darmstadt, Germany

Correspondence: For correspondence or reprints contact: Roland Haubner, PhD, Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, D-81675 München, Germany.

ABSTRACT

The _vß₃ 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 a _vß₃ 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-Tyr⁴-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 _IIbß₃ and _vß₃ integrins. Expression of the _vß₃ receptor on the different tumors was validated by immunohistochemical methods using _v and _vß₃ 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 _vß₃. Immunohistochemical staining clearly indicates the presence of the _vß₃ 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 _Vß₃ integrin in vitro and in vivo and, thus, represents the first radiolabeled _vß₃ antagonist for the investigation of angiogenesis and metastasis in vivo.

Key Words: RGD peptides • alpha(v)beta(3) antagonists • integrins • ¹²⁵I labeling • tumor targeting

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