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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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111In-Diethylenetriamine pentaacetic acid-QKYGNQWAVGHLM-NH2

111In-[DTPA1-Lys3,Tyr4]-BN
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: June 25, 2010.

Chemical name:111In-Diethylenetriamine pentaacetic acid-QKYGNQWAVGHLM-NH2
Abbreviated name:111In-[DTPA1-Lys3,Tyr4]-BN
Synonym:
Agent category:Peptide
Target:Gastrin-releasing peptide receptor (GRPR)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT)
Source of signal\contrast:111In
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 receptor (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).

Prostate cancer is the third most common type of cancer in men in the United States. GRPR is overexpressed on human androgen-independent prostate PC-3 cancer cells. Ho et al. (7) radiolabeled diethylenetriamine pentaacetic acid-QKYGNQWAVGHLM-NH2 ([DTPA1-Lys3,Tyr4]-BN) with 111In. 111In-[DTPA1-Lys3,Tyr4]-BN has been evaluated as a single-photon emission computed tomography imaging agent of GRPR in nude mice bearing human PC-3 prostate cancer cells.

Synthesis

[PubMed]

[DTPA1-Lys3,Tyr4]-BN was prepared with solid-phase peptide synthesis (7). A mixture of [DTPA1-Lys3,Tyr4]-BN (0.525 nmol) and 111InCl3 (105 MBq (2.84 mCi)) was allowed to react for 10 min at 25°C. The product, 111In-[DTPA1-Lys3,Tyr4]-BN, was obtained with a yield of 97% and a radiochemical purity of >97%. The specific activity of 111In-[DTPA1-Lys3,Tyr4]-BN was 200 GBq/µmol (5.4 Ci/µmol). 111In-[DTPA1-Lys3,Tyr4]-BN was relatively stable in saline (99% intact), human plasma (83% intact), and rat plasma (76% intact) after 4 h of incubation.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Ho et al. (7) performed in vitro inhibition studies of [DTPA1-Lys3,Tyr4]-BN and BN using recombinant human BB2 receptor with 125I-Tyr4-BN. The 50% inhibition concentration (IC50) values for [DTPA1-Lys3,Tyr4]-BN and BN were 1.05 ± 0.46 nM and 0.05 ± 0.02 nM, respectively. The Kd and Bmax values of 111In-[DTPA1-Lys3,Tyr4]-BN using PC-3 cells were determined to be 22.9 ± 6.8 nM and 880 fmol (~5 × 105 receptor sites) per 106 cells, respectively. PC-3 cells exhibited 26% uptake of the incubation dose of 111In-[DTPA1-Lys3,Tyr4]-BN within 60 min of incubation at 37°C, and 60% of radioactivity remained internalized after 120 min incubation in fresh medium.

Animal Studies

Rodents

[PubMed]

Ho et al. (7) performed ex vivo biodistribution studies of 0.37 MBq (10 μCi) 111In-[DTPA1-Lys3,Tyr4]-BN in mice (n = 4–5/group) bearing PC-3 xenografts at 1, 4, 8, 24, and 48 h after injection. Tumor accumulation levels at these time points were 1.93 ± 0.25%, 1.60 ± 0.21%, 2.48 ± 0.48%, 1.23 ± 0.19%, and 0.93 ± 0.16% injected dose per gram (ID/g). The tumor/muscle ratio of 5.4 peaked at 8 h and decreased to 1.29 at 48 h. Pretreatment with excess [DTPA1-Lys3,Tyr4]-BN (1.05 nmol/mouse) inhibited accumulation in the tumor by 51% at 4 h and 66% at 24 h after injection, whereas accumulation in the pancreas was inhibited by 81% and 84%, respectively. The intestines also showed >50% inhibition at these time points. The organ with the highest uptake at 8 h after injection was the pancreas (32% ID/g), followed by the kidney (22% ID/g), adrenal (8% ID/g), small intestine (8% ID/g), and large intestine (7% ID/g). The heart, lung, stomach, muscle, bone, brain, and blood exhibited little accumulation of radioactivity at 8–48 h after injection.

Positron emission tomography imaging in nude mice (n = 4) bearing PC-3 xenografts was performed with 10 MBq (0.27 mCi) 111In-[DTPA1-Lys3,Tyr4]-BN at 1, 4, 8, 24, and 48 h after injection. The tumors were clearly visualized, as were the pancreas, intestines, and kidneys. Tumor standard uptake values at these time points were 1.60 ± 0.62, 1.62 ± 0.46, 2.48 ± 0.48, 1.47 ± 0.44, and 1.50 ± 0.49, respectively.

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.
Weiner R.E., Thakur M.L. Radiolabeled peptides in oncology: role in diagnosis and treatment. BioDrugs. 2005;19(3):145–63. [PubMed: 15984900]
7.
Ho C.L., Chen L.C., Lee W.C., Chiu S.P., Hsu W.C., Wu Y.H., Yeh C.H., Stabin M.G., Jan M.L., Lin W.J., Lee T.W., Chang C.H. Receptor-binding, biodistribution, dosimetry, and micro-SPECT/CT imaging of 111In-[DTPA(1), Lys(3), Tyr(4)]-bombesin analog in human prostate tumor-bearing mice. Cancer Biother Radiopharm. 2009;24(4):435–43. [PubMed: 19694578]

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