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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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68Ga-1,4,7-Triazacyclononane-1,4-diacetic acid-8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2

68Ga-NOTA-8-Aoc-BBN[7-14]NH2
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: October 4, 2012.

Chemical name:68Ga-1,4,7-Triazacyclononane-1.4-diacetic acid-8-aminooctanoic acid-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2
Abbreviated name:68Ga-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:68Ga
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).

Various BBN analogs has been label with 99mTc and 111In for single-photon emission computed tomography imaging studies (7) and 64Cu, 68Ga, and 86Y for positron emission tomography imaging studies (8, 9). Dijkgraaf et al. (10) 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 68Ga. 68Ga-NOTA-8-Aoc-BBN[7-14]NH2 was evaluated as a PET imaging agent of GRPR in nude mice bearing human PC-3 prostate cancer cells.

Related Resource Links:

  • Chapters in MICAD (GRPR, bombesin)
  • Gene information in NCBI (GRPR, GRP)
  • Articles in Online Mendelian Inheritance in Man (OMIM) (GRPR, GRP)
  • Clinical trials (GRPR)

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 (10). 68GaCl3 was added to a solution of NOTA-8-Aoc-BBN[7-14]NH2 in sodium acetate buffer (pH 4.1). The mixture was heated for 10 min at 95°C. The product, 68Ga-NOTA-8-Aoc-BBN[7-14]NH2, was purified with cartridge chromatography with 50-90% yield and a radiochemical purity of >95%. The specific activity of 68Ga-NOTA-8-Aoc-BBN[7-14]NH2 was >10 MBq/nmol (0.27 mCi/nmol) at the end of synthesis. Total preparation time was ~45 min. 68Ga-NOTA-8-Aoc-BBN[7-14]NH2 exhibited a Log P value of -1.98 ± 0.03.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Dijkgraaf et al. (10) performed in vitro inhibition studies of NOTA-8-Aoc-BBN[7-14]NH2 and natGa-NOTA-8-Aoc-BBN[7-14]NH2 in cultured human prostate PC-3 tumor cells with 111In-NOTA-8-Aoc-BBN[7-14]NH2. The 50% inhibition concentration (IC50) values for NOTA-8-Aoc-BBN[7-14]NH2 and natGa-NOTA-8-Aoc-BBN[7-14]NH2 were 0.37 ± 0.15 nM and 0.41 ± 0.15 nM, respectively.

Animal Studies

Rodents

[PubMed]

Dijkgraaf et al. (10) performed ex vivo biodistribution studies of 68Ga-NOTA-8-Aoc-BBN[7-14]NH2 (~0.3 nmol) in nude mice bearing PC-3 xenografts with (n = 6) or without (n = 3) coinjection of 100-fold excess unlabeled NOTA-8-Aoc-BBN[7-14]NH2 at 1 h after injection. Tumor accumulation was 1.24 ± 0.26% injected dose per gram (ID/g). The organ with the highest accumulation was the pancreas (6% ID/g), followed by the colon (1% ID/g), small intestine (2% ID/g), liver (1% ID/g), kidney (1% ID/g), and stomach (0.5% ID/g). Little accumulation was observed in the spleen, lung, blood and muscle (<0.5% ID/g). NOTA-8-Aoc-BBN[7-14]NH2 blocked tumor accumulation by 83%. Significant inhibition (>90%) was also observed in the pancreas, stomach and colon. PET imaging studies were not performed.

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.
Varvarigou A., Bouziotis P., Zikos C., Scopinaro F., De Vincentis G. Gastrin-releasing peptide (GRP) analogues for cancer imaging. Cancer Biother Radiopharm. 2004;19(2):219–29. [PubMed: 15186603]
8.
Biddlecombe G.B., Rogers B.E., de Visser M., Parry J.J., de Jong M., Erion J.L., Lewis J.S. Molecular imaging of gastrin-releasing peptide receptor-positive tumors in mice using 64Cu- and 86Y-DOTA-(Pro1,Tyr4)-bombesin(1-14). Bioconjug Chem. 2007;18(3):724–30. [PubMed: 17378600]
9.
Schuhmacher J., Zhang H., Doll J., Macke H.R., Matys R., Hauser H., Henze M., Haberkorn U., Eisenhut M. GRP receptor-targeted PET of a rat pancreas carcinoma xenograft in nude mice with a 68Ga-labeled bombesin(6-14) analog. J Nucl Med. 2005;46(4):691–9. [PubMed: 15809493]
10.
Dijkgraaf I., Franssen G.M., McBride W.J., D'Souza C.A., Laverman P., Smith C.J., Goldenberg D.M., Oyen W.J., Boerman O.C. PET of Tumors Expressing Gastrin-Releasing Peptide Receptor with an 18F-Labeled Bombesin Analog. J Nucl Med. 2012;53(6):947–52. [PubMed: 22570329]

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