Background

[PubMed]

Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α_vβ₃ integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α_vβ₃ integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α_vβ₃ are being studied as antitumor and antiangiogenic agents, and the agonists of α_vβ₃ are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α_vβ₃. Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10).

Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α_vβ₃ (inhibition concentration (IC₅₀), 7–40 nM) but not to integrins α_vβ₅ (IC₅₀, 600–4,000 nM) or α_IIbβ₃ (IC₅₀, 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Janssen et al. (13) reported the development of ¹¹¹In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]₂ (¹¹¹In-DOTA-E-[c(RGDfK)]₂) for single-photon emission computed tomography imaging α_vβ₃ receptors in nude mice bearing ovarian carcinoma tumors. Dijkgraaf et al. (14) also reported the evaluation of ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂ for positron emission tomography (PET) imaging α_vβ₃ receptors in tumor, which is the topic of this chapter.

Synthesis

[PubMed]

Dijkgraaf et al. (14) prepared the synthesis of ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂ by reacting DOTA-E-[c(RGDfK)]₂ with ⁶⁸Ga in ammonium acetate buffer (pH ~5.5) at 95°C for 20 min. Radiochemical purity was ~98% as determined by high-performance liquid chromatography. The maximum specific activity was 11.2 MBq/nmol (0.3 mCi/nmol). ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂ was stable in phosphate-buffered saline and human serum at 37°C for 2 h.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Dijkgraaf et al. (14) performed in vitro solid-phase binding assays of ¹¹¹In-DOTA-E-[c(RGDfK)]₂ with human α_vβ₃ integrin. ^natGa-DOTA-E-c(RGDfK) (monomer) had an IC₅₀ value of 23.9 ± 1.22 nM. ^natGa-DOTA-E-[c(RGDfK)]₂ (dimer) had an IC₅₀ value of 8.99 ± 1.20 nM. ^natGa-DOTA-E-{E-[c(RGDfK)]₂}₂ (tetramer) had an IC₅₀ value of 1.74 ± 1.18 nM.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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