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64Cu-1,4,7-Triazacyclononane-1,4-diacetate-8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

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

Created: ; Last Update: July 23, 2009.

Chemical name:64Cu-1,4,7-Triazacyclononane-1,4-diacetate-8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2
Abbreviated name:64Cu-NO2A-8-Aoc-BBN[7-14]NH2
Agent category:Peptide
Target:Gastrin-releasing peptide receptor (GRPR)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal\contrast:64Cu
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about gastrin-releasing peptide receptor.



The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptors (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH2. BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system and the gastrointestinal system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-R) have been identified on central nervous system and gastrointestinal tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B (NMB) receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6).

Prasanphanich et al. (7) used 1,4,7-triazacyclononane-1,4-diacetate (NO2A) as a bifunctional chelator for labeling 8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (8-Aoc-BBN[7-14]NH2) with 64Cu. 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 has been evaluated as a positron emission tomography (PET) imaging agent of GRPR in nude mice bearing T-47D human breast cancer cells.



8-Aoc-BBN[7-14]NH2 was prepared with solid-phase peptide synthesis with subsequent addition of NO2A group to form NO2A-8-Aoc-BBN[7-14]NH2 (7). 64CuCl2 was added to a solution of NO2A-8-Aoc-BBN[7-14]NH2 in ammonium acetate (pH 7.1). The mixture was heated for 30 min at 70°C. The product, 64Cu-NO2A-8-Aoc-BBN[7-14]NH2, was purified with high-performance liquid chromatography with a yield of >90% and a radiochemical purity of >99%. The specific activity of 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 was not reported.

In Vitro Studies: Testing in Cells and Tissues


Prasanphanich et al. (7) performed in vitro inhibition studies of NO2A-8-Aoc-BBN[7-14]NH2 and 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 in cultured T-47D cells with 125I-BBN. The 50% inhibition concentration (IC50) values were 5.99 for NO2A-8-Aoc-BBN[7-14]NH2 and 7.56 nM for 64Cu-NO2A-8-Aoc-BBN[7-14]NH2. T-47D cells exhibited a 90% uptake of incubation dose of 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 within 60 min of incubation at 37°C, indicating cell internalization of the radioligand. More than 90% of the internalized radioactivity remained inside the cells over 90 min of incubation in fresh medium.

Animal Studies



Prasanphanich et al. (7) performed ex vivo biodistribution studies of 0.26 MBq (7 μCi) 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 in normal mice. The heart, lung, spleen, stomach, muscle, bone, brain, and blood exhibited very little (<0.5% injected dose per gram (ID/g)) of the accumulated conjugate at 1, 4, and 24 h after injection. Pancreatic accumulation was 27.0, 9.1, and 1.4% ID/g at the respective time points. The small intestine showed accumulation of 10.8, 1.9, and 0.4% ID/g, while the large intestine accumulated 2.1, 15.1, and 0.5% ID/g at these time points. Radioactivity accumulation in the kidney was 2.9, 0.7, and 0.4% ID/g, respectively. Accumulation in the liver was 1.5, 1.1, and 0.7% ID/g, respectively. The urinary excretion was 63, 77, and 81% ID. Administration of D-lysine (15 mg/mouse) had little effect on the biodistribution of 64Cu-NO2A-8-Aoc-BBN[7-14]NH2. Ex vivo biodistribution studies of 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 were performed in nude mice bearing T-47D xenografts. Tumor accumulation at these time points was 2.27 ± 0.08, 1.35 ± 0.14, and 0.28 ± 0.07% ID/g, while the biodistribution pattern in the other tissues was similar to that of the normal mice. The tumor/muscle ratios were 9.5, 7.5, and 5.6 at 1, 4, and 24 h after injection, respectively. Pretreatment of excess BBN[1-14] (100 µg/mouse) inhibited the tumor accumulation by 75%, whereas the accumulation in the pancreas, small intestine, and large intestine was inhibited by ~90% with little effect in the other tissues at 1 h after tracer injection. PET imaging in nude mice bearing T-47D xenografts was performed with 189 MBq (5.1 mCi) 64Cu-NO2A-8-Aoc-BBN[7-14]NH2 at 24 h after injection. The tumors were clearly visualized, as were the pancreas, liver, and 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.


Gonzalez N., Moody T.W., Igarashi H., Ito T., Jensen R.T. Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):58–64. [PMC free article: PMC2631407] [PubMed: 18185064]
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Chung D.H., Evers B.M., Beauchamp R.D., Upp J.R. Jr, Rajaraman S., Townsend C.M. Jr, Thompson J.C. Bombesin stimulates growth of human gastrinoma. Surgery. 1992;112(6):1059–65. [PubMed: 1455308]
Benya R.V., Kusui T., Pradhan T.K., Battey J.F., Jensen R.T. Expression and characterization of cloned human bombesin receptors. Mol Pharmacol. 1995;47(1):10–20. [PubMed: 7838118]
Reubi J.C., Wenger S., Schmuckli-Maurer J., Schaer J.C., Gugger M. Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[D-TYR(6), beta-ALA(11), PHE(13), NLE(14)] bombesin(6-14). Clin Cancer Res. 2002;8(4):1139–46. [PubMed: 11948125]
Smith C.J., Volkert W.A., Hoffman T.J. Radiolabeled peptide conjugates for targeting of the bombesin receptor superfamily subtypes. Nucl Med Biol. 2005;32(7):733–40. [PubMed: 16243649]
Prasanphanich A.F., Retzloff L., Lane S.R., Nanda P.K., Sieckman G.L., Rold T.L., Ma L., Figueroa S.D., Sublett S.V., Hoffman T.J., Smith C.J. In vitro and in vivo analysis of [(64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2)]: a site-directed radiopharmaceutical for positron-emission tomography imaging of T-47D human breast cancer tumors. Nucl Med Biol. 2009;36(2):171–81. [PMC free article: PMC2756974] [PubMed: 19217529]


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