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

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86Y-DOTA-[Pro1,Tyr4]-Bombesin[1-14]

86Y-MP2346

, PhD, , PhD, and , MS.

Author Information
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim
, PhD
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, Corresponding Author, ude.ltsuw@siwel.s.j
, MS
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, ude.ltsuw.rim@gebmocelddib

Created: ; Last Update: January 8, 2008.

Chemical name:86Y-DOTA-[Pro1,Tyr4]-Bombesin[1-14]image 26675368 in the ncbi pubchem database
Abbreviated name:86Y-MP2346
Synonym:86Y-Bombesin, 86Y-BN, 86Y-BNN
Agent Category:Peptide
Target:Gastrin-releasing peptide receptor (GRP-R)
Target Category:Receptor binding
Method of detection:Positron emission tomography (PET) imaging
Source of signal/ contrast:86Y
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents

Click on the above structure for additional information in PubChem.
Click on protein, nucleotide (RefSeq), and gene for more information about BN and GRP.

Background

[PubMed]

86Y-DOTA-[Pro1,Tyr4]-Bombesin[1-14] (86Y-MP2346) is a peptide analog of human gastrin-releasing peptide (GRP) conjugated with 86Y, and it was developed for positron emission tomography (PET) imaging of tumors with overexpressed GRP receptors (GRP-R) (1). 86Y is a positron emitter with a 33% abundance and a physical half-life (t½) of 14.7 h.

The amphibian bombesin (BBN or BN), a peptide of 14 amino acids, is an analog of human GRP, a peptide of 27 amino acids, that binds to GRP-R with high affinity and specificity (2, 3). Both GRP and BN share an amidated C-terminus sequence homology of 7 amino acids, -Trp-Ala-Val-Gly-His-Leu-Met-NH2. BN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system (4, 5). They also act as potential growth factors for both normal and neoplastic tissue. Specific BN receptors (BN-R) have been identified in CNS and GI tissues and a number of tumor cell lines. The BN-R superfamily includes at least 4 different subtypes, namely the GRP-R subtype (BB2), the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype (6). Overexpression of GRP-R in various human tumors (e.g., breast, prostate, lung, colon, ovarian, and pancreatic cancers) provides opportunities to image tumors with the use of specific molecular imaging agents designed to target the GRP-R (1, 3, 7-9).

There have been varying degrees of success in the current development of GRP-R–targeted radiopharmaceuticals for diagnostic or therapeutic applications (9). Various BN analogs have been labeled with 99mTc and 111In for single-photon emission computed tomography (SPECT) imaging (10, 11). BN Analogs labeled with 68Ga, 18F, or 64Cu have been studied for PET imaging (1, 12, 13). Breeman et al. (14, 15) prepared two GRP-R agonists, diethylene triamine pentaacetic acid (DTPA)-[Pro1,Tyr4]BN[1-14] and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-[Pro1,Tyr4]BN[1-14] (MP2346), for radiometal labeling by replacing pGlu1 and Leu4 in the native BN with DTPA-Pro or DOTA-Pro and with Tyr, respectively. Both MP2346 and DTPA-[Pro1,Tyr4]BN[1-14] were readily labeled with 111In and appeared to be promising radioligands for SPECT imaging. For PET imaging, Biddlecombe et al. (1) prepared and evaluated 86Y-MP2346 because yttrium-DTPA–conjugated peptides are not stable in vivo (15). In comparison with 64Cu-MP2346. Biddlecombe et al. (1) reported distinct differences in the in vivo pharmacokinetics and tumor uptake of these two radioligands. The authors suggested that this may be the result of their differences in peptide to receptor affinity, overall chemical charge, and radiometal-chelate stability.

Synthesis

[PubMed]

Biddlecombe et al. (1) reported the synthesis of 86Y-MP2346. The [Pro1,Tyr4]BN[1-14] peptide was synthesized by the standard 9-fluorenylmethyloxycarbonyl (Fmoc) solid-phase chemistry and Rink amide resin. The DOTA conjugation with [Pro1,Tyr4]BN[1-14] was not reported, but the standard method involved use of the sulfosuccinimidyl ester of DOTA (16). The resulting MP2346 was purified with high-performance liquid chromatography (HPLC), and the identity was confirmed by mass spectrometry. The radiolabeling involved mixing MP2346 with 86Y chloride (86YCl3) in 0.5 M ammonium acetate (pH 6.5). The reaction mixture was incubated at 80ºC for 30 min. Reaction progress and purity were analyzed by analytical reverse-phase HPLC. Based on the HPLC analysis, the radiochemical yield and radiochemical purity were >94%. The specific activity was 37 MBq/μg (1 mCi/μg) or 74 GBq/μmol (2 Ci/μmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Biddlecombe et al. (1) performed in vitro internalization studies (n = 3) of 86Y-MP2346 in human prostate adenocarcinoma PC-3 cells. The amount of specifically internalized 86Y-MP2346 was 28.09 ± 30.76 fmol/mg protein content of the cells at 15 min after incubation and increased steadily to 1,420.42 ± 129.94 fmol/mg at 20 h. The amount of surface-bound radioactivity was <100 fmol/mg at all times, and the maximum internalized radioactivity was 1,945 fmol/mg.

Animal Studies

Rodents

[PubMed]

Biodistribution studies of 86Y-MP2346 were performed in nude mice (n = 5) bearing human prostate adenocarcinoma PC-3 tumors in their flanks (1). Each mouse received 0.22–0.27 kBq (8–10 μCi) radioactivity in 8–10 ng of 86Y-MP2346 by i.v. administration. 86Y-MP2346 showed rapid clearance of radioactivity from the blood over 24 h. The tumor radioactivity levels in percentage injected dose per gram (% ID/g) were 2.646 ± 1.228 (1 h), 1.243 ± 0.658 (4 h), and 1.405 ± 0.222 (24 h). The tumor/blood ratios were 12.074 (1 h), 134.3 (4 h), and 1,680 (24 h), and the tumor/muscle ratios were 29.89 (1 h), 79.20 (4 h), and 271.4 (24 h). At 1 h, the radioactivity levels (% ID/g) for major organs were 0.219 ± 0.098 (blood), 0.302 ± 0.062 (lung), 0.170 ± 0.027 (liver), 8.309 ± 2.412 (kidney), 0.089 ± 0.010 (muscle), 0.091 ± 0.030 (heart), 0.336 ± 0.228 (bone), and 14.456 ± 5.719 (pancreas). At 24 h, these levels changed to 0.001 ± 0.001 (blood), 0.030 ± 0.020 (lung), 0.152 ± 0.069 (liver), 2.623 ± 0.391 (kidney), 0.005 ± 0.004 (muscle), 0.002 ± 0.002 (heart), 0.044 ± 0.012 (bone), and 12.965 ± 2.229 (pancreas). Blocking studies with preinjection of 100 μg of [Tyr4]-BN immediately before radioligand injection were performed, and the mice were euthanized 1 h after injection. Radioactivity levels of both the tumor and GRP-R–rich pancreas decreased significantly (P < 0.0005) to 0.667 ± 0.179% ID/g and 0.304 ± 0.018% ID/g, respectively. Similar trends were observed in other GRP-R–rich organs.

PET imaging of 86Y-MP2346 was conducted in mice bearing PC-3 tumors (n = 3) with a 7.4 MBq (0.2 mCi) dose in 200-ng peptide by i.v. administration (1). The images showed that the radioactivity distribution pattern was similar to that of the biodistribution studies. Background activity was low, and the tumor was clearly visualized for 1–24 h. The imaging study of Lewis rats bearing AR42J tumors showed similar results. The blocking study of mice coinjected with 100 μg [Tyr4]-BN and imaged side by side with mice that received 86Y-MP2346 showed a significant reduction of tumor radioactivity.

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.

NIH Support

NCI R24 CA86307, NIH/NCI SAIRP grant R24 CA83060, NCI Cancer Center Support Grant 1 P30 CA91842.

References

1.
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]
2.
Smith C.J., Gali H., Sieckman G.L., Higginbotham C., Volkert W.A., Hoffman T.J. Radiochemical investigations of (99m)Tc-N(3)S-X-BBN[7-14]NH(2): an in vitro/in vivo structure-activity relationship study where X = 0-, 3-, 5-, 8-, and 11-carbon tethering moieties. Bioconjug Chem. 2003;14(1):93–102. [PubMed: 12526698]
3.
Ma L., Yu P., Veerendra B., Rold T.L., Retzloff L., Prasanphanich A., Sieckman G., Hoffman T.J., Volkert W.A., Smith C.J. In Vitro and In Vivo Evaluation of Alexa Fluor 680-Bombesin[7-14]NH(2) Peptide Conjugate, a High-Affinity Fluorescent Probe with High Selectivity for the Gastrin-Releasing Peptide Receptor. Mol Imaging. 2007;6(3):171–80. [PubMed: 17532883]
4.
Mantey S., Frucht H., Coy D.H., Jensen R.T. Characterization of bombesin receptors using a novel, potent, radiolabeled antagonist that distinguishes bombesin receptor subtypes. Mol Pharmacol. 1993;43(5):762–74. [PubMed: 7684815]
5.
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]
6.
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]
7.
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]
8.
Nock B., Nikolopoulou A., Chiotellis E., Loudos G., Maintas D., Reubi J.C., Maina T. [99mTc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging. Eur J Nucl Med Mol Imaging. 2003;30(2):247–58. [PubMed: 12552343]
9.
Smith C.J., Volkert W.A., Hoffman T.J. Gastrin releasing peptide (GRP) receptor targeted radiopharmaceuticals: a concise update. Nucl Med Biol. 2003;30(8):861–8. [PubMed: 14698790]
  • 10. de Visser, M., H.F. Bernard, J.L. Erion, M.A. Schmidt, A. Srinivasan, B. Waser, J.C. Reubi, E.P. Krenning, and M. de Jong, Novel (111)In-labelled bombesin analogues for molecular imaging of prostate tumours. Eur J Nucl Med Mol Imaging, 2007. [PubMed: 17287960]
  • 11.
    Ferro-Flores G., Arteaga de Murphy C., Rodriguez-Cortes J., Pedraza-Lopez M., Ramirez-Iglesias M.T. Preparation and evaluation of 99mTc-EDDA/HYNIC-[Lys 3]-bombesin for imaging gastrin-releasing peptide receptor-positive tumours. Nucl Med Commun. 2006;27(4):371–6. [PubMed: 16531924]
    12.
    Breeman W.A., Bakker W.H., De Jong M., Hofland L.J., Kwekkeboom D.J., Kooij P.P., Visser T.J., Krenning E.P. Studies on radiolabeled somatostatin analogues in rats and in patients. Q J Nucl Med. 1996;40(3):209–20. [PubMed: 8961800]
    13.
    Zhang X., Cai W., Cao F., Schreibmann E., Wu Y., Wu J.C., Xing L., Chen X. 18F-labeled bombesin analogs for targeting GRP receptor-expressing prostate cancer. J Nucl Med. 2006;47(3):492–501. [PubMed: 16513619]
    14.
    Breeman W.A., De Jong M., Bernard B.F., Kwekkeboom D.J., Srinivasan A., van der Pluijm M.E., Hofland L.J., Visser T.J., Krenning E.P. Pre-clinical evaluation of [(111)In-DTPA-Pro(1), Tyr(4)]bombesin, a new radioligand for bombesin-receptor scintigraphy. Int J Cancer. 1999;83(5):657–63. [PubMed: 10521803]
    15.
    Breeman W.A., de Jong M., Erion J.L., Bugaj J.E., Srinivasan A., Bernard B.F., Kwekkeboom D.J., Visser T.J., Krenning E.P. Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy. J Nucl Med. 2002;43(12):1650–6. [PubMed: 12468515]
    16.
    Chen X., Park R., Hou Y., Tohme M., Shahinian A.H., Bading J.R., Conti P.S. microPET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts. J Nucl Med. 2004;45(8):1390–7. [PubMed: 15299066]

    This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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