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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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64Cu-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522

, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: June 30, 2011.

Chemical name:64Cu-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522
Abbreviated name:64Cu-DOTA-MEDI-522
Synonym:64Cu-DOTA-Abegrin, 64Cu-DOTA-Vitaxin
Agent category:Antibody
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:64Cu
  • Checkbox In vitro
  • Checkbox Rodents
Structure is not available in PubChem.



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 αvβ3 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 αvβ3 integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of αvβ3 are being studied as antitumor and antiangiogenic agents, and the agonists of αvβ3 are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including αvβ3. 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 αvβ3 (inhibition concentration (IC50), 7–40 nM) but not to integrins αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). In addition to RGD peptides, a humanized anti-human integrin αvβ3 monoclonal antibody (MEDI-522) was identified to be unique in that it recognizes either the human αv or β3 subunit. MEDI-522 cross-reacts with integrin αvβ3 from rabbits, chickens, and hamsters but not with integrin αvβ3 from mice or rats (13). MEDI-522 is being evaluated as an antiangiogenic agent for cancer therapy (14-16). Cai et al. (17) reported the development of 64Cu-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522 (64Cu-DOTA-MEDI-522) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing tumors.



DOTA was incubated with EDC and SNHS for 30 min at pH 5.5 with a molar ratio of 10:5:4 (17). The product, DOTA-N-hydroxysulfosuccinimidyl (DOTA-OSSu), was added to MEDI-522 in a molar ratio of 1,000:1 (DOTA-OSSu/MEDI-522). The reaction mixture was adjusted to pH 8.5 and incubated for ~18 h at 4°C. DOTA-MEDI-522 was purified with column chromatography. DOTA-MEDI-522 (0.33 nmol) was incubated with 74 MBq (2 mCi) 64CuCl2 in sodium acetate buffer (pH 6.5) for 1 h at 40°C. 64Cu-DOTA-MEDI-522 was purified with column chromatography. This procedure provided a radiolabeling yield of 88% with a specific activity of 148 MBq/nmol (4 mCi/nmol). There were ~39 DOTA moieties per 64Cu-DOTA-MEDI-522. The immunoreactivity was determined to be 63% with integrin αvβ3-positive U87MG human glioblastoma cells. Control 64Cu-DOTA-IgG was prepared similarly. Decreasing the DOTA-OSSu/MEDI-522 molar ratios to 200:1 and 100:1 yielded final labeled 64Cu-DOTA-MEDI-522 conjugates that contained 10 and 6 DOTA moieties, respectively, with similar immunoreactivity.

In Vitro Studies: Testing in Cells and Tissues


Liu et al. (18) performed saturation binding studies of 125I-MEDI-522 on U87MG cells. 125I-MEDI-522 showed a Kd value (affinity constant) of 0.35 ± 0.06 nM and a Bmax value (receptor density) of 2.5 × 105 sites per cell. MEDI-522 and DOTA-MEDI-522 exhibited an inhibition curve similar to that of 125I-MEDI-522 binding to U87MG cells.

Animal Studies



Cai et al. (17) performed PET and ex vivo biodistribution studies of 64Cu-DOTA-MEDI-522 in nude mice (n = 3/group) bearing MDA-MB-435 human breast carcinoma tumors at 18 h and 46 h after injection. Ex vivo tumor accumulation was 4.54 ± 0.39% injected dose/gram (ID/g) and 5.40 ± 0.75% ID/g at 18 h and 44 h after injection, respectively. PET imaging revealed estimated tumor accumulation values of 5.63 ± 1.16% injected dose/gram (ID/g) and 7.04 ± 1.47% at 18 h and 46 h after injection, respectively. There was no significant difference between the two methods of measurement (P = 0.16). Accumulation in the liver and spleen was approximately two-fold higher than in the tumor. The other normal tissues showed less accumulation than the tumor. Co-injection of excess MEDI-522 inhibited tumor accumulation by ~70% at 46 h after injection as measured with PET imaging.

Another PET imaging study was performed with mice (n = 3/group) bearing tumors with different αvβ3 expression levels. U87MG tumor cells showed higher signal at 17–71 h after injection than MDA-MB-435 cells, GL-26 mouse glioblastoma, and PC-3 human prostate adenocarcinoma tumors, agreeing with their degree of human αvβ3 expression. Immunofluorescence staining of tumor sections confirmed MEDI-522 binding in human tumor cells but not in mouse tumor cells or in mouse tumor vasculature because MEDI-522 does not cross-react with mouse β3. Anti-mouse β3 antibody binding was observed only in mouse tumor cells and mouse tumor vasculature.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.

NIH Support

R21 EB001785, R21 CA102123, P50 CA114747, R24 CA93862, 1U54 CA119367-01


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