• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

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

Show details

111In-DOTA-Gly-benzoyl-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2

111In-RM1
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: January 30, 2011.

Chemical name:111In-DOTA-Gly-benzoyl-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2
Abbreviated name:111In-RM1
Synonym:
Agent category:Peptide
Target:Gastrin-releasing peptide receptor (GRPR)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
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 receptors (GRPR) with high affinity and specificity (1). 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 (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (2). Specific BBN receptors (BBN-R) have been identified on CNS and GI tissuesincluding the pancreas and on a number of tumor cell lines. The BBN-R superfamily includes at least four different subtypes, namely neuromedin B (NMB or BB1), the GRPR subtype (BB2), the BB3 subtype, and the BB4 subtype (3). 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.

Currently used targeting GRPR peptides mainly are agonists. Therefore, there is a need for GRPR antagonist radioligands. Llinares et al. (4) has developed a series of GRPR peptide antagonists. One of them, D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM26), was found to be a selective GRPR antagonist. DOTA-Gly-benzoyl group was added to the C-terminus to form DOTA-Gly-benzoyl-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM1). For evaluation as a single-photon emission computed tomography (SPECT) imaging agent for GRPR, 111In has been attached to RM1 to form 111In-RM1 (5).

Synthesis

[PubMed]

RM1 was prepared by solid-phase peptide synthesis with a 30% yield (5). 111InCl3 was added to a solution of RM1 (~6 nmol) in sodium acetate (pH 5). The mixture was heated for 30 min at 95°C. The product, 111In-RM1, was identified with electrospray-mass spectrometry and used without further purification. The labeling yield of 111In-RM1 was >95% with a specific activity of 30 GBq/µmol (0.81 Ci/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Mansi et al. (5) performed in vitro inhibition studies of RM26, RM1 and natIn-RM1 in cultured PC-3 human prostate cells with 125I-BBN with the 50% inhibition concentration (IC50) values of 5.6 ± 1.8, 35.0 ± 13.0, and 14.0 ± 3.4 nM, respectively. The GRPR agonist, natLu-AMBA, showed the IC50 value of 0.8 ± 0.1 nM. 111In-RM1 showed a Kd (affinity constant) of 8.5 ± 2.7 nM and a Bmax (receptor density) of 2.4 ± 0.2 nM, whereas 111Lu-AMBA showed a higher affinity (Kd, 0.6 ± 0.3 nM) but a lower receptor density (Bmax, 0.7 ± 0.1 nM). PC-3 cells exhibited a 4.7% uptake of incubation dose (ID) of 111In-RM1 inside the cells at 4 h of incubation at 37°C with 21.8% of ID remained on the cell surface, indicating a lack of cell internalization of the radioligand. Only 10% of the internalized radioactivity remained inside the cells over 4 h of incubation in fresh medium. On the other hand, 29% of ID of 111Lu-AMBA was inside the cells with 4.3% of ID on the cell surface. About 40% of the internalized radioactivity remained inside the cells over 4 h of incubation in fresh medium. natIn-RM1 was able to inhibit the calcium release and receptor internalization induced by BBN.

Animal Studies

Rodents

[PubMed]

Mansi et al. (5) performed ex vivo biodistribution studies of 0.18 MBq (5 μCi) 111In-RM1 or 111Lu-AMBA in nude mice bearing PC-3 tumors. Tumor accumulation for 111In-RM1 was 14.2 ± 1.8, 13.5 ± 0.8, and 6.6 ± 1.1% ID/g at 1, 4, and 24 h after injection, respectively. Tumor accumulation for 111Lu-AMBA was 4.5 ± 0.7, 3.7 ± 0.8, and 3.0 ± 0.6% ID/g at 1, 4, and 24 h after injection, respectively. Both tracers exhibited a fast blood clearance with 0.05% ID/g at 4 h after injection. The tumor/blood ratios were 17, 336, and 658 for 111In-RM1 and 14, 74, and 147 for 111Lu-AMBA at 1, 4, and 24 h after injection, respectively. Preinjection of excess cold peptide (20 nmol, 5 min) inhibited the tumor, pancreas, small intestine, and large intestine accumulation by ~90% with little effect in the other tissues at 4 h after tracer injection. 111In-RM1 exhibited a faster washout from most of the normal organs and tissues than 111Lu-AMBA. SPECT imaging in nude mice bearing PC-3 xenografts was performed with 4 MBq (0.11 mCi) 111In-RM1 at 4, 24, 48 and 72 h after injection. The tumors were clearly visualized at these time points. Pretreatment with excess RM1 (20 nmol, 15 min) completely inhibit the accumulation of radioactivity in the tumor at 4 h after injection.

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.
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]
3.
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]
4.
Llinares M., Devin C., Chaloin O., Azay J., Noel-Artis A.M., Bernad N., Fehrentz J.A., Martinez J. Syntheses and biological activities of potent bombesin receptor antagonists. J Pept Res. 1999;53(3):275–83. [PubMed: 10231715]
5.
Mansi R., Wang X., Forrer F., Kneifel S., Tamma M.L., Waser B., Cescato R., Reubi J.C., Maecke H.R. Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides. Clin Cancer Res. 2009;15(16):5240–9. [PubMed: 19671861]
PubReader format: click here to try

Views

Search MICAD

Limit my Search:


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...