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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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111In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-c(D-Cys-Phe-Tyr-D-AgI8(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH

111In-DOTA-sst3-ODN-8
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: October 15, 2009.

Chemical name:111In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-c(D-Cys-Phe-Tyr-D-Agl8(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH
Abbreviated name:111In-DOTA-sst3-ODN-8
Synonym:
Agent category:Peptide
Target:Somatostatin receptor (sst3)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar 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 SST 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) (6). It has also shown promising results in peptide-receptor radionuclide therapy (7). Octreotide (OCT) is a cyclic peptide with eight amino acids. 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 and sst4 (8). 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 (9). Ginj et al. (10) have developed a series of sst3 antagonist ligands. One of them, c(D-Cys-Phe-Tyr-D-Agl8(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst3-ODN-8), was found to be a selective sst3 antagonist. For evaluation as a SPECT imaging agent for sst3, 111In has been attached to sst3-ODN-8 via tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) to form 111In-DOTA-sst3-ODN-8.

Synthesis

[PubMed]

DOTA-sst3-ODN-8 was synthesized via standard solid-phase peptide synthesis (10). DOTA was incorporated at the N-terminus of the peptide. DOTA-sst3-ODN-8 was purified with high-performance liquid chromatography. Neither the radiolabeling procedure for DOTA-sst3-ODN-8 with 111In nor the radiochemical yield or radiochemical purity was reported. 111In-DOTA-sst3-ODN-8 had a specific activity of ~20 GBq/µmol (0.54 Ci/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

111In-DOTA-sst3-ODN-8 showed a Bmax (receptor density) of 5,180 pmol/mg protein in HEK-sst3 cells (10). On the other hand, 111In-DOTA-NOC (sst2, sst3, and sst5 agonist) exhibited a Bmax of 68 pmol/mg protein. Hence, the antagonist labeled 75-fold more sst3 receptor sites than the agonist. DOTA-sst3-ODN-8 showed 50% inhibition concentration (IC50) values of >1,000, 5.2 ± 1.3, >1,000, >1,000, and >1,000 nM for human sst1, sst2, sst3, sst4, and sst5 receptors in competition with 125I-SRIF-28, respectively. DOTA-sst3-ODN-8 was not internalized in cultured HEK-sst3 cells, whereas In-DOTA-NOC and SRIF-28 were internalized. However, DOTA-sst3-ODN-8 inhibited the internalization of the two agonists.

Animal Studies

Rodents

[PubMed]

Ginj et al. (10) performed ex vivo biodistribution studies with 0.2 MBq (5.4 µCi, 0.01 nmol) 111In-DOTA-sst3-ODN-8 in HEK-sst3 tumor-bearing nude mice (n = 3/group). The accumulation of radioactivity in the sst3 tumors was 22.1% injected dose per gram (% ID/g) at 0.25 h, 34.8% ID/g at 0.5 h, 61.3% ID/g at 1 h, 49.7% ID/g at 4 h, and 30.8% ID/g at 24 h after injection. The kidney was the organ that had the highest accumulation (15.8% ID/g) at 1 h after injection, followed by the pituitary (5.3% ID/g), blood (1.8% ID/g), liver (1.3% ID/g), and pancreas (0.5% ID/g). Accumulation of radioactivity in the other tissues was low. The concentration in the blood was 0.1% ID/g at 4 h after injection, with tumor/blood ratios of 34, 497, and 1,026 at 1, 4, and 24 h, respectively. Tumor/muscle ratios were 68, 248, and 342 at 1, 4, and 24 h, respectively. Co-injection with sst3-ODN-8 (50 nmol) reduced the accumulation of radioactivity by 60% in the tumors, 20% in the adrenal, 28% in the pancreas, and 70% in the pituitary at 15 min after injection. Little or no inhibition was observed in the stomach, kidney, spleen, liver, and bone. On the other hand, accumulation of 111In-DOTA-NOC was only 17.5, 6.5, and 3.5% ID/g at 0.5, 1, and 24 h, respectively. The accumulation of the agonist was less than the antagonist in the sst3 tumors. Co-injection with In-DOTA-NOC (50 nmol) reduced the accumulation of radioactivity by 37% in the tumors, 86% in the stomach, 80% in the adrenal, 90% in the pancreas, and 60% in the pituitary at 4 h after injection. Mice bearing both the HEK-sst2 and the HEK-sst3 tumors were injected with 111In-DOTA-sst3-ODN-8 or 111In-DOTA-NOC, whole-body SPECT imaging was performed. The HEK-sst3 tumor was clearly visualized with 111In-DOTA-sst3-ODN-8 at 0.5 and 4 h after injection, but the HEK-sst2 tumor was not. On the other hand, 111In-DOTA-NOC showed only a weak accumulation in both tumors.

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

R01 DK59953

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.
Barnett P. Somatostatin and somatostatin receptor physiology. Endocrine. 2003;20(3):255–64. [PubMed: 12721505]
6.
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]
7.
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]
8.
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]
9.
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]
10.
Ginj M., Zhang H., Waser B., Cescato R., Wild D., Wang X., Erchegyi J., Rivier J., Macke H.R., Reubi J.C. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103(44):16436–41. [PMC free article: PMC1618814] [PubMed: 17056720]

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