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64Cu-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2

, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: August 16, 2012.

Chemical name:64Cu-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2
Abbreviated name:64Cu-NODAGA-LM3
Agent category:Peptide
Target:Somatostatin receptor 2 (SSTR2)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:64Cu
  • Checkbox In vitro
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Click on protein, nucleotide (RefSeq), and gene for more information about somatostatin.



Somatostatin (SST) is an inhibitor of the release of somatotropin, glucagon, insulin, gastrointestinal hormones, and other secretory proteins (1). SST is also known as somatotropin release-inhibiting factor (SRIF). SST is a cyclic polypeptide with two biologically active isoforms, SRIF-14 and SRIF-28, of 14 and 28 amino acids, respectively. SRIF has a short plasma half-life of <3 min (2). SST receptors (SSTRs) (G-protein–coupled) have been found on a variety of neuroendocrine tumors and cells of the immune system, and five individual subtypes (SSTR1–SSTR5) have been identified and subsequently cloned from animal and human tissues (3, 4). SSTR also inhibits cell proliferation and promotes apoptosis through binding to specific cell-surface SSTRs (5).

111In-Diethylenetriamine pentaacetic acid-octreotide (111In-DTPA-OCT) is an SST analog that, over the last decade, has remained the most widely used radiopharmaceutical and the only FDA approved radiotracer for the scintigraphic detection and staging of primary and metastatic neuroendocrine tumors bearing SSTRs with single-photon emission computed tomography (SPECT) (6). It has also shown promising results in peptide-receptor radionuclide therapy (7). Octreotide (OCT) is a cyclic peptide with eight amino acids. 111In-DTPA-OCT binds with high affinity to SSTR2 and SSTR5 and to SSTR3 to a lesser degree, but it does not bind to SSTR1 and SSTR4 (8). A large number of radiolabeled SST analogs have been reported using different radionuclides and different linkers. Currently used targeting SSTR peptides are mainly SSTR2 agonists. Therefore, there is a need for SSTR2 antagonist radioligands (9). p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) is a novel selective SSTR2 antagonist. Fani et al. (10) prepared 64Cu-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-LM3 (64Cu-NODAGA-LM3) as a positron emission tomography (PET) imaging agent for SSTR2.



NODAGA-LM3 was synthesized via standard solid-phase peptide synthesis with a calculated mass of 1,522.6 Da in agreement with mass spectrometry (10). NODAGA was incorporated at the N-terminus of the peptide. NODAGA-LM3 was purified with high-performance liquid chromatography. 64Cu was complexed to NODAGA-LM3 by reaction of 3.3 nmol NODAGA-LM3 with 37 MBq (1 mCi) 64CuCl2 in ammonium acetate (pH 8.0) for 10 min at room temperature. 64Cu-NODAGA-LM3 had a >95% radiochemical purity and specific activity of 20 MBq/nmol (0.54 mCi/nmol), with a labeling yield >97%. 64Cu-NODAGA-LM3 had a log D value of –2.02 ± 0.01 and a net charge of zero.

In Vitro Studies: Testing in Cells and Tissues


Fani et al. (10) reported that natCu-NODAGA-LM3 had 50% inhibition concentration (IC50) values of >1,000, 6.7 ± 1.5, >1,000, >1,000, and >1,000 nM for human SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 receptors in competition with 125I-SRIF-28, respectively. 64Cu-NODAGA-LM3 bound to the cell surface of HEK-sst2 cells with ~30% of the incubation dose at 30 min and ~40% incubation dose at 4 h. Internalization of 64Cu-NODAGA-LM3 was ~12% and was inhibited to 1% incubation dose with excess unlabeled ligand. After 4 h in fresh medium, 55% of radioactivity remained on the cell surface, 16% was internalized, and 26% was found in the medium. Immunofluorescence studies showed that [Tyr3]octreotide (10 nM) triggers receptor internalization whereas natGa-NODAGA-LM3 at a much higher concentration (1,000 nM) does not stimulate receptor internalization in HEK-sst2 cells. natCu-NODAGA-LM3 was able to inhibit receptor internalization induced by [Tyr3]octreotide.

Animal Studies



Fani et al. (10) performed ex vivo biodistribution studies with 5.55 MBq (0.15 mCi) 64Cu-NODAGA-LM3 in nude mice (n = 3–7/group) bearing HEK-sst2 xenografts at 1, 4, and 24 h after injection. The accumulation of radioactivity in the SSTR2 tumor was 35.46 ± 5.70% injected dose per gram (% ID/g) at 1 h, 37.88% ID/g at 4 h, and 14.79% ID/g at 24 h after injection. The pancreas had the highest accumulation (16.26% ID/g) at 1 h after injection, followed by the kidney (10.90% ID/g), stomach (9.17% ID/g), lung (5.89% ID/g), and liver (2.23% ID/g). Accumulation of radioactivity in the other tissues was low. The concentration in the blood was 0.11% ID/g at 4 h after injection, with tumor/blood ratios of 42, 344, and 123 at 1, 4, and 24 h, respectively. Co-injection with 2,000-fold excess DOTA-LM3 reduced the accumulation of radioactivity by 98% in the tumor, 67% in the stomach, and 78% in the pancreas at 4 h after injection (all known to contain SSTR). Little or no inhibition was observed in the other tissues. In comparison, 64Cu-NODAGA-LM3 accumulation in the kidney was 1-, 3-, and 8- fold lower than that of 64Cu-CB-TE2A-LM3 at 1, 4, and 24 h, respectively. The tumor/tissue ratios (blood, kidney, liver, and muscle) were significantly higher for 64Cu-NODAGA-LM3 than for 64Cu-CB-TE2A-LM3 (P < 0.01).

Whole-body PET imaging visualized the SSTR2 tumor at 4 h and 24 h after injection of 6 MBq (0.16 mCi) 64Cu-NODAGA-LM3 (n=1). No blocking studies were carried out.

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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