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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-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(D-diaminobutyric acid-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe)

111In-KE88
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: October 8, 2009.

Chemical name:111In-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(D-diaminobutyric acid-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe)
Abbreviated name:111In-KE88, 111In-DOTA-cyclo(dDab-RFFwKTF)
Synonym:
Agent category:Peptide
Target:Somatostatin receptors (SSRs)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), planar gamma imaging
Source of signal:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about somatostatin.

Background

[PubMed]

Somatostatin (SST) is an inhibitor of the release of somatotropin, glucagon, insulin, gastrointestinal hormones, and other secretory proteins (1). SST is also known as somatotropin release-inhibiting factor (SRIF). SST is a cyclic polypeptide with two biologically active isoforms, SRIF-14 and SRIF-28, of 14 and 28 amino acids, respectively. SRIF has a short plasma half-life of <3 min (2). SST receptors (SSTRs) (G-protein–coupled) have been found on a variety of neuroendocrine tumors and cells of the immune system, and five individual subtypes (sst1–sst5) have been identified and subsequently cloned from animal and human tissues (3, 4). SST also inhibits cell proliferation and promotes apoptosis through binding to specific cell-surface SSTRs (5).

111In-Labeled diethylenetriaminepentaacetic acid-octreotide ((111In-DTPA-OCT) is an SSTR analog that, over the last decade, has remained the most widely used radiopharmaceutical for the scintigraphic detection and staging of primary and metastatic neuroendocrine tumors bearing SSTRs with single-photon emission computed tomography (SPECT) (5). It has also showed promising results in peptide-receptor radionuclide therapy (6). 111In-DTPA-OCT binds with high affinity to SSTR subtypes 2 and 5 (sst2 and sst5) and to sst3 to a lesser degree, but it does not bind to sst1 or sst4 (7). Currently used targeting SSTR peptides mainly have affinity for sst2. However, sst1, sst3, sst4, and sst5 are also expressed in different tumors. Therefore, there is a need for pansomatostatin radioligands (8). Ginj et al. (9) has developed a series of pansomatostatin ligands. One of them, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(D-diaminobutyric acid-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe) (KE88) was found to be an agonist to all sst subtypes. For evaluation as a SPECT imaging agent for all sst subtypes, 111In has been attached to KE88 via 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) to form 111In-KE88.

Synthesis

[PubMed]

DOTA-tris(tert-butylester) was used to conjugate the N-terminal amino acid to form KE88 after standard solid-phase peptide synthesis of KE88 (9). KE88 was purified with high-performance liquid chromatography. 111InCl3 was conjugated to KE88 with a radiochemical yield of >95%. 111In-KE88 had a >97% radiochemical purity and a specific activity of ~37 GBq/µmol (1 Ci/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Ginj et al. (9) showed that KE88 exhibited an agonistic effect on forskolin-stimulated cAMP accumulation in CCL39 cells expressing sst1–sst5 with effective concentrations of 7.35, 9.73, 1.92, 0.47, and 2.66 nM, respectively. 111In-KE88 internalization into HEK-sst2, HEK-sst3, and HEK-sst5 cells was performed after 4 h of incubation at 37°C with <0.5, 32.2, and <0.1%, respectively.

Animal Studies

Rodents

[PubMed]

Ginj et al. (9) performed ex vivo biodistribution studies with 111In-KE88 in nude mice (n = 3/group) bearing xenografts of HEK-sst2 tumor cells on one flank and HEK-sst3 tumors on the other flank. The accumulation of 111In-KE88 in the HEK-sst3 tumors was 15.2% injected dose per gram (% ID/g) at 15 min, 22.9% ID/g at 1 h, 23.2% ID/g at 4 h, and 14.9% ID/g at 24 h after injection, whereas the accumulation in the HEK-sst2 tumors was 18.5, 13.6, 3.7, and 1.1% ID/g at the time points, respectively. Therefore, the sst3 tumors exhibited a higher 111In-KE88 accumulation and slower washout than the sst2 tumors. The kidney was the only organ that had a higher accumulation at 1 h after injection than the tumors with 64% ID/g, followed by the pituitary (9% ID/g) and liver (2.7% ID/g). Accumulation of radioactivity in the other tissues was low at I h after injection. The concentration in the blood was only 0.1% ID/g at 4 h after injection, with tumor/blood ratios of 232 for the sst3 tumors and 37 for the sst2 tumors. Co-injection with DOTA-TATE (sst2-selective ligand) reduced the accumulation of the radioactivity by 90% in the sst2 tumors at 1 h after injection. Co-injection with 111In-DTPA-TATE and KE88 reduced the accumulation of the radioactivity by 84% in the sst3 tumors. Whole-body SPECT imaging visualized the sst3 tumor as early as 1 h after 111In-KE88 injection with a strong radioactivity signal in the kidneys. In contrast, the sst2 tumor was barely visualized. By 4 h, only the sst3 tumor and kidneys were visible.

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.
Weckbecker G., Lewis I., Albert R., Schmid H.A., Hoyer D., Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov. 2003;2(12):999–1017. [PubMed: 14654798]
2.
Patel Y.C., Wheatley T. In vivo and in vitro plasma disappearance and metabolism of somatostatin-28 and somatostatin-14 in the rat. Endocrinology. 1983;112(1):220–5. [PubMed: 6128222]
3.
Corleto V.D., Nasoni S., Panzuto F., Cassetta S., Delle Fave G. Somatostatin receptor subtypes: basic pharmacology and tissue distribution. Dig Liver Dis. 2004;36 Suppl 1:S8–16. [PubMed: 15077906]
4.
Moller L.N., Stidsen C.E., Hartmann B., Holst J.J. Somatostatin receptors. Biochim Biophys Acta. 2003;1616(1):1–84. [PubMed: 14507421]
5.
Krenning E.P., Kwekkeboom D.J., Bakker W.H., Breeman W.A., Kooij P.P., Oei H.Y., van Hagen M., Postema P.T., de Jong M., Reubi J.C. et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716–31. [PubMed: 8404961]
6.
Kwekkeboom D.J., Mueller-Brand J., Paganelli G., Anthony L.B., Pauwels S., Kvols L.K. M. O'Dorisio T, R. Valkema, L. Bodei, M. Chinol, H.R. Maecke, and E.P. Krenning, Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med. 2005;46 Suppl 1:62S–6S. [PubMed: 15653653]
7.
Storch D., Behe M., Walter M.A., Chen J., Powell P., Mikolajczak R., Macke H.R. Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization? J Nucl Med. 2005;46(9):1561–9. [PubMed: 16157541]
8.
Reubi J.C., Schar J.C., Waser B., Wenger S., Heppeler A., Schmitt J.S., Macke H.R. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82. [PubMed: 10774879]
9.
Ginj M., Zhang H., Eisenwiener K.P., Wild D., Schulz S., Rink H., Cescato R., Reubi J.C., Maecke H.R. New pansomatostatin ligands and their chelated versions: affinity profile, agonist activity, internalization, and tumor targeting. Clin Cancer Res. 2008;14(7):2019–27. [PubMed: 18381940]

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