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68Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Asp-cyclohexylalanine-Phe-d-Ser-d-Arg-Tyr-Leu-Trp-Ser-NH2 (AE105-NH2)

, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: August 23, 2012.

Chemical name:68Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Asp-cyclohexylalanine-Phe-d-Ser-d-Arg-Tyr-Leu-Trp-Ser-NH2 (AE105-NH2)
Abbreviated name:68Ga-NODAGA-AE105-NH2, 68Ga-NODAGA-d-Cha-F-s-r-Y-L-W-S-NH2
Agent category:Peptide
Target:Urokinase-type plasminogen activator receptor (uPAR)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal:68Ga
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about uPAR.



Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play an important role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Invasive tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degradation of the basement membrane and ECM (3). Several families of proteases are involved in atherogenesis, myocardial infarction, angiogenesis, and tumor invasion and metastasis (4-7).

Urokinase-type plasminogen activator (uPA) is a serine protease (8, 9). The uPA/uPA receptor (uPAR) system is responsible for tissue degradation after plasminogen activation to plasmin, which leads to a cascade of proteolysis or thrombolysis, depending on the physiological conditions. uPA also directly activates MMPs, vascular endothelial growth factor, and human growth factor (10). Malignant tumors often express high levels of uPA and uPAR (11); therefore, the uPA/uPAR system is linked to vascular diseases and cancer. The synthetic peptide Asp-cyclohexylalanine-Phe-d-Ser-d-Arg-Tyr-Leu-Trp-Ser (AE105) has been identified to have a high affinity for human uPAR (dissociation constant (Kd) = 0.4 nM) (12), and AE105 has been labeled with 64Cu (T1/2 = 12.7 h, β+ = 17.8%) as 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-AE105 (64Cu-DOTA-AE105) and 64Cu-DOTA-AE105-NH2 for use in positron emission tomography (PET) imaging of uPAR expression in tumors (13, 14). Persson et al. (15) also prepared 68Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-AE105-NH2 (68Ga-NODAGA-AE105-NH2) and 68Ga-DOTA-AE105-NH2 for evaluation as alternative PET agents (68Ga: T1/2 = 68 min, β+ = 89%).



Persson et al. (15) performed NODAGA chelation of the N-terminus of AE105-NH2via solid-phase synthesis. A mixture of AE105-NH2 and NODAGA-tris(tBu)ester in a molar ratio of 1:3 was incubated for 24–48 h at room temperature. The NODAGA-AE105-NH2 conjugate was purified with high-performance liquid chromatography (HPLC). The number of NODAGA molecules per peptide was ~1 as determined with mass spectroscopy. For radiolabeling, NODAGA-AE105-NH2 (5 nmol) was added to 68GaCl3 diluted in 0.1 M sodium acetate buffer (pH 5.0). The reaction mixture was incubated for 15 min at 25ºC. 68Ga-NODAGA-AE105-NH2 was purified with a Sep-Pak column (>95% radiochemical purity). 68Ga-DOTA-AE105-NH2 was prepared similarly. The specific activities of 68Ga-NODAGA-AE105-NH2 and 68Ga-DOTA-AE105-NH2 were ~20 GBq/μmol (0.54 Ci/μmol) at the end of synthesis. Total synthesis time and yields for both tracers were not reported. The log P values were –1.15 ± 0.1 and –1.75 ± 0.1 for 68Ga-NODAGA-AE105-NH2 and 68Ga-DOTA-AE105-NH2, respectively. Both tracers were >98% intact in both saline buffer and mouse plasma for 60 min at 37°C.

In Vitro Studies: Testing in Cells and Tissues


Persson et al. (15) performed binding experiments with AE105-NH2, NODAGA-AE105-NH2, and DOTA-AE105-NH2 with the use of a Biacore sensor chip immobilized with pro-uPA. The IC50 values for inhibiting the binding of 0.5 nM uPAR to pro-uPA were 7.6 ± 2.0 nM, 3.4 ± 0.4 nM, and 6.7 ± 0.9 nM for AE105-NH2, NODAGA-AE105-NH2, and DOTA-AE105-NH2, respectively. Cellular accumulation of 68Ga-NODAGA-AE105-NH2 and 68Ga-DOTA-AE105-NH2 was assessed by incubating the agents with U87MG human glioblastomas (uPAR-positive) cells for 120 min at 37°C. Both tracers reached a plateau accumulation at 60 min after incubation, with 1.46 ± 0.1% and 1.37 ± 0.1% incubation dose, respectively.

Animal Studies



Persson et al. (15) performed dynamic PET imaging studies for 60 min after injection of 5–7 MBq (0.135–0.189 mCi, 0.5 nmol) 68Ga-NODAGA-AE105-NH2 or 68Ga-DOTA-AE105-NH2 in mice (n = 3/group) bearing U87MG tumors in the left and right flanks. The tumors and kidneys were visualized for both tracers at 10–60 min. Region of interest (ROI) analysis showed that the tumor accumulation values of 68Ga-NODAGA-AE105-NH2 were 2.5% injected dose per gram (ID/g), 2.0% ID/g, and 2.0% ID/g at 10, 30, and 60 min after injection. The tumor/blood, tumor/muscle, and tumor/liver ratios at 60 min were 1, 5, and 1, respectively. The tumor accumulation values of 68Ga-DOTA-AE105-NH2 were 2.2% ID/g, 1.3% ID/g, and 1.0% ID/g at 10, 30, and 60 min after injection, respectively. The tumor/blood, tumor/muscle, and tumor/liver ratios at 60 min were 1, 3, and 1, respectively. 68Ga-NODAGA-AE105-NH2 and 68Ga-DOTA-AE105-NH2 exhibited lower tumor accumulation and a lower tumor/muscle ratio than 64Cu-DOTA-AE105-NH2 (4.8% ID/g and 16) at 60 min after injection, as reported previously in the same tumor model. No blocking studies and ex vivo biodistribution studies were performed with either tracer.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


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