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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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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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

64Cu-NOTA-8-Aoc-BBN[7-14]NH2
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: July 24, 2009.

Chemical name:64Cu-1,4,7-Triazacyclononane- triacetic acid-8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2
Abbreviated name:64Cu-NOTA-8-Aoc-BBN[7-14]NH2
Synonym:
Agent category:Peptide
Target:Gastrin-releasing peptide receptor (GRPR)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal\contrast:64Cu
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about gastrin-releasing peptide receptor.

Background

[PubMed]

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-1,4-7-triacetic acid (NOTA) 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-NOTA-8-Aoc-BBN[7-14]NH2 has been evaluated as a positron emission tomography (PET) imaging agent of GRPR in nude mice bearing human PC-3 prostate cancer cells.

Synthesis

[PubMed]

8-Aoc-BBN[7-14]NH2 was prepared with solid-phase peptide synthesis with subsequent addition of NOTA group to form NOTA-8-Aoc-BBN[7-14]NH2 (7). 64CuCl2 was added to a solution of NOTA-8-Aoc-BBN[7-14]NH2 in ammonium acetate (pH 7.0). The mixture was heated for 60 min at 70°C. The product, 64Cu-NOTA-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-NOTA-8-Aoc-BBN[7-14]NH2 was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Prasanphanich et al. (7) performed in vitro inhibition studies of NOTA-8-Aoc-BBN[7-14]NH2 in cultured human prostate PC-3 tumor cells with 125I-BBN. The 50% inhibition concentration (IC50) value was 3.1 ± 0.5 nM.

Animal Studies

Rodents

[PubMed]

Prasanphanich et al. (7) performed ex vivo biodistribution studies of 0.26 MBq (7 μCi) 64Cu-NOTA-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 ± 3.2, 9.1 ± 1.4, and 1.42 ± 0.13% ID/g at the respective time points. The small intestine showed accumulation of 10.8 ± 1.1, 1.87 ± 0.51, and 0.37 ± 0.06% ID/g, while the large intestine accumulated 2.14 ± 0.35, 15.1 ± 3.9, and 0.53 ± 0.16% ID/g at these time points. Radioactivity accumulation in the kidney was 2.92 ± 0.64, 0.72 ± 0.07, and 0.42 ± 0.05% ID/g, respectively. Accumulation in the liver was 1.54 ± 0.59, 1.07 ± 0.10, and 0.73 ± 0.09% ID/g, respectively. The urinary excretion was 76% ID at 4 h after injection. Administration of D-lysine (15 mg/mouse) had little effect on the biodistribution of 64Cu-NOTA-8-Aoc-BBN[7-14]NH2. Ex vivo biodistribution studies of 64Cu-NOTA-8-Aoc-BBN[7-14]NH2 were performed in nude mice bearing PC-3 xenografts. Tumor accumulation at these time points was 3.59 ± 0.70 and 1.00 ± 0.19% 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 with excess BBN[1-14] (100 µg/mouse) inhibited the tumor accumulation by 40%, whereas the accumulation in the pancreas and intestines at 1 h after tracer injection was inhibited by 95% and 75%, respectively. Little effect was observed in the other tissues. PET imaging in nude mice bearing PC-3 xenografts was performed with 55.5 MBq (1.5 mCi) 64Cu-NOTA-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

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
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]
2.
Bertaccini G. Active polypeptides of nonmammalian origin. Pharmacol Rev. 1976;28(2):127–77. [PubMed: 794887]
3.
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]
4.
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]
5.
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]
6.
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]
7.
Prasanphanich A.F., Nanda P.K., Rold T.L., Ma L., Lewis M.R., Garrison J.C., Hoffman T.J., Sieckman G.L., Figueroa S.D., Smith C.J. [64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues. Proc Natl Acad Sci U S A. 2007;104(30):12462–7. [PMC free article: PMC1914305] [PubMed: 17626788]
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