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111In-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-NDECELCVNVACTGCL

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: June 25, 2010.

Chemical name:111In-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid- NDECELCVNVACTGCL
Abbreviated name:111In-DOTA-E3-uroguanylin
Agent category:Peptide
Target:Receptor guanylate cyclase C (GC-C)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar
Source of signal:111In
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Click on protein, nucleotide (RefSeq), and gene for more information about uroguanylin.



Receptor guanylate cyclase C (GC-C) is a type I transmembrane glycoprotein expressed on intestinal brush border membranes of intestinal epithelial cells and transformed human colon cancer cell lines (e.g., T84) (1). GC-C is expressed in very low levels on the other tissues and is highly expressed on the primary and metastatic colon cancer tissues (2). Peptides such as the Escherichia coli heat-stable enterotoxin (STh) and uroguanylin have been shown to inhibit the growth of colorectal cancer (CRC) cells in animal models (3-5). STh and uroguanylin are agonistic for the GC-C receptor with nanomolar affinity, resulting in activation of the guanylyl cyclase that increases the intracellular concentration of guanosine 3,5-cyclic monophosphate. Uroguanylin and guanylin are endogenous peptides, which are secreted into the lumen of the gut by enterochromaffin cells to regulate ion and fluid homeostasis (6). However, their expression is lost during cancer transformation (5, 7).

CRC is the second most common type of cancer in the United States (8). The United States Food and Drug Administration (FDA) has approved scintigraphic agents that are based on monoclonal antibodies (mAbs) for the imaging of colorectal cancers (9), but these agents have limitations because of a lack of penetration in tumors and prolonged blood circulation as a result of their large molecular size. Furthermore, the pharmacokinetics of intact radiolabeled mAbs, with high liver uptake and slow blood elimination, are generally not ideal for imaging. 1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA) derivatives of STh have been evaluated for in vivo imaging in nude mice bearing colorectal xenografts (10-12). Uroguanylin (NDDCELCVNVACTGCL) is a 16 amino acid peptide with two disulfide bonds and is less complex than STh, which contains three disulfide bonds. The N-terminal end of uroguanylin and E3-uroguanylin (NDECELCVNVACTGCL) was conjugated with DOTA for 111In-radiolabeling. 111In-DOTA-uroguanylin and 111In-DOTA-E3-uroguanylin have been evaluated in nude mice bearing human colon adenocarcinoma tumors (13).

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N-Hydroxysuccinimide (NHS) ester of DOTA (NHS-DOTA) was used in a 100-fold excess to conjugate the N-terminal end of uroguanylin and E3-uroguanylin to form DOTA-uroguanylin and DOTA-E3-uroguanylin after being incubated overnight at 4°C (13). DOTA-uroguanylin and DOTA-E3-uroguanylin were isolated with high-performance liquid chromatography (HPLC) and identified with mass spectroscopy. There was one DOTA molecule per peptide. DOTA-uroguanylin or DOTA-E3-uroguanylin (24 nmol) was mixed with 7.5–92.5 MBq (0.2–2.5 mCi) 111InCl3 and incubated for 60 min at 37°C. 111In-DOTA-uroguanylin and 111In-DOTA-E3-uroguanylin were purified with HPLC. The labeling yield and the radiochemical purity were not reported. The specific activity was not reported.

In Vitro Studies: Testing in Cells and Tissues


The binding affinities of uroguanylin, DOTA-uroguanylin, E3-uroguanylin, and DOTA-E3-uroguanylin for GC-C were determined using T84 cells (13). In this assay, 125I-F19-STh(1-19) was incubated with 3 × 106 cells in the presence of 0.1–1,000 nM corresponding peptide for 60 min at 37°C. The 50% inhibition concentration (IC50) values were 39.9, 34.5, 5.0, and 9.6 nM for uroguanylin, DOTA-uroguanylin, E3-uroguanylin, and DOTA-E3-uroguanylin, respectively.

Animal Studies



Liu et al. (13) performed ex vivo biodistribution studies of 111In-DOTA-E3-uroguanylin and 111In-DOTA- uroguanylin (7.4 MBq (0.2 μCi)) in SCID mice (n = 4/group) bearing T84 xenografts. Accumulation levels of the two tracers in the T84 tumors were 1.04 ± 0.07% injected dose per gram (ID/g) and 0.88 ± 0.33% ID/g at 1 h after injection, respectively. The radioactivity levels in tumors were higher than in other organs and tissues (e.g., the lung, liver, spleen, and intestines) except the kidneys (28% ID/g) at 1 h after injection. Blood levels were 0.2–0.4% ID/g at 1 h. Tumor/blood, tumor/muscle, and tumor/liver ratios for 111In-DOTA-E3-uroguanylin at 1 h after injection were 5, 21, and 6, respectively. These ratios were 61, 61, and 4 at 4 h after injection, respectively. Co-injection of 111In-DOTA-E3-uroguanylin with E3-uroguanylin reduced the radioactivity levels in the tumors and kidneys by 60–70% at 1 h after injection, whereas little inhibition was observed in other tissues. As a comparison with 111In-DOTA-R1,4-F19-STh(1-19), the kidney uptake of 111In-DOTA-E3-uroguanylin was ~10-fold greater than that of 111In-DOTA-R1,4-F19-STh(1-19) at 1 h after injection (12).

Single-photon emission computed tomography analysis was performed in nude mice bearing the T84 tumors after injection of 7.4 MBq (0.2 μCi) 111In-DOTA-E3-uroguanylin. The tumors were clearly visualized at 1 h along with the kidneys.

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

P50 CA103130-01


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