Edotreotide

Structural formula
General
Non-proprietary name	Edotreotide
other names	DOTATOC SMT487 (DOTA (0) -Phe (1) -Tyr (3)) octreotide 2- (4 - {[(1 R ) -1 - {[(4 S , 7 S , 10 S , 13 R , 16 S , 19 S ) -10- (4-aminobutyl) -4 - {[(2 R , 3 R ) -1,3-dihydroxybutan-2-yl] carbamoyl} -7- (1-hydroxyethyl) -16 - [(4-hydroxyphenyl) methyl] -13- (1 H -indol-3-ylmethyl) -6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl] carbamoyl} -2-phenyl-ethyl] carbamoylmethyl} -7.10 -bis (carboxymethyl) -1,4,7,10-tetrazacyclododec-1-yl) acetic acid ( IUPAC )
Molecular formula	C 65 H 92 N 14 O 18 S 2
External identifiers / databases
CAS number 204318-14-9 PubChem 158782 ChemSpider 139675 Wikidata Q908790
properties
Molar mass	1421.64 g mol −1
Physical state	firmly
safety instructions
GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Edotreotide is the international non-proprietary name for the medicinal substance (DOTA (0) -Phe (1) -Tyr (3)) octreotide. The designation DOTATOC is the most common among experts .

Edotreotide is used together with various radionuclides as a radiopharmaceutical in oncology for both diagnosis and therapy ( radionuclide therapy ).

The radiopeptide therapy (RPT) with ⁹⁰ Y-DOTATOC in particular in advanced neuroendocrine tumors (NET) as a palliative used treatment method and clinically tested.

construction

DOTATOC consists of two components that are chemically linked (conjugated) to one another by covalent bonds . The two components are:

• The complexing agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid , called DOTA and
• the octreotide - analogue D -Phe-cyclo [Cys-Tyr- D Trp-Lys-Thr-Cys] -Thr (ol), called TOC

As a chelating agent, DOTA is able to coordinate a large number of polyvalent metal ions very tightly. The DOTA is linked to the octapeptide TOC via one of the four acid groups of the molecule . TOC itself is very similar in structure to the somatostatin analogue octreotide ( D -Phe-c [Cys-Phe- D- Trp-Lys-Thr-Cys] -Thr (ol)). The amino acid phenylalanine of octreotide has been replaced by tyrosine in the TOC . The non-proteinogenic D- amino acid D- phenylalanine prevents premature metabolism (metabolism) of the TOC in the body.

While the endogenous , 14 amino acid somatostatin has a very short plasma half-life of 2 to 4 minutes, octreotide ( Greek prefix octa- = "eight"), made up of eight amino acids, has a significantly longer half-life of 1.5 to 2 hours .

Like octreotide, TOC binds to somatostatin receptors , also called SRIF receptors (from Somatropin Release Inhibiting Factor ). These receptors are overexpressed in a number of tumors , especially neuroendocrine tumors (NET), which means that there are above-average numbers of these receptors on the surface of the cancer cells .

So far, five different types of somatostatin receptors (SSTR1 to SSTR5, from somatostatin seven-transmembrane-domain receptor ) have been found, which are expressed to different degrees depending on the type of tumor. Gastro-entero-pancreatic neuro-endocrine tumors ( GEP-NET ), for example, preferentially express SSTR2 and, less strongly, SSTR1 and SSTR5.

Diagnosis

If DOTATOC is loaded with short-lived isotopes that emit gamma rays, such as ¹¹¹ indium , or with isotopes that are subject to beta-plus decay (β +), such as ⁶⁸ gallium , it is possible to use imaging methods such as SPECT or positron emission tomography (PET) to detect and localize the corresponding neuroendocrine tumors and their metastases .

Scintigraphy

DOTATOC is not approved for this application . In some clinics, however, studies are carried out with ¹¹¹ In-DOTATOC. The method has no significant advantages over the approved somatostatin receptor scintigraphy with ¹¹¹ indium pentetreotide (OctreoScan ^® ).

Positron emission tomography

⁶⁸ Ga-DOTATOC

If DOTATOC is loaded with a radioactive metal ion that is subject to β ⁺ decay, such as ⁶⁸ gallium from a gallium 68 generator , somatostatin-expressing tumors and their metastases can be detected with the aid of positron emission tomography. The ⁶⁸ Ga-DOTATOC accumulates on the correspondingly degenerated cells . These areas radiate much more strongly than normal tissue. The radiation is localized by means of detectors and processed into a three-dimensional representation using image processing.

The PET with ⁶⁸ Ga-DOTATOC enables the representation and quantitative evaluation of the receptor expression in tumor and normal tissue. The ⁶⁸ Ga-DOTATOC-PET is superior to the ¹¹¹ In-DTPA-octreotide scintigraphy (octreotide scan) in neuroendocrine tumors. ⁶⁸ Ga-DOTATOC is more hydrophilic than ¹¹¹ In-DTPA-octreotide, which is why unbound DOTATOC is excreted more quickly ( renal clearance ).

Neuroendocrine tumors and their metastases can be diagnosed with this method down to a diameter of 7 to 8 mm, while in comparison with ¹¹¹ In-DTPA-octreotide scintigraphy there are problems with the detection of malignant tissue below 25 mm in diameter.

The ⁶⁸ Ga-DOTATOC-PET technique can currently only be used in very few clinics. With this form of imaging, essentially only the tumor and any metastases that may be present are shown. Precise information about the anatomical position of these tissue changes is not obtained from PET alone. With the help of the combination of PET and computed tomography (PET / CT) this problem can be avoided.

therapy

Neuroendocrine tumors grow relatively slowly. They therefore do not respond to many conventional chemotherapeutic agents, which essentially only work against rapidly growing cells. In addition, in many patients symptoms only develop at a very late stage, when metastases are already present. This type of tumor is generally very difficult to treat.

The specific binding of DOTATOC to the somatostatin receptors of neuroendocrine tumors can also be used for therapeutic purposes. If DOTATOC is loaded with a beta emitter , the tumor cells can be killed by DNA damage induced by the beta radiation emitted. This radiopeptide therapy is a special form of endoradiotherapy . Since the range of beta radiation is only a few millimeters, the surrounding healthy tissue is largely spared.

Radionuclides used

⁹⁰ Y-DOTATOC

¹⁷⁷ Lu-DOTATOC

Essentially ⁹⁰ yttrium and ¹⁷⁷ lutetium have established themselves as possible radionuclides . ⁹⁰ Yttrium decays with a half-life of 64.1 hours, releasing an electron with an energy of 2.28 MeV . The range in human tissue is around 11 millimeters.

The decay of ¹⁷⁷ Lu, on the other hand, is significantly lower in energy at 0.5 MeV. Accordingly, the range of the electrons is reduced to around 1.5 millimeters. The half-life is 6.73 days. In addition to the release of an electron, gamma radiation is also released when ¹⁷⁷ Lu decays .

application

In addition to the therapy of neuroendocrine tumors, a number of other tumor types also express somatostatin receptors. One possible application is, for example, the therapy of prostate cancer . Further indications are currently in various clinical phases, for example for the treatment of lung cancer and metastatic breast cancer . Its use to treat gliomas is also being tested.

Limitations

Therapy with ⁹⁰ Y-DOTATOC only makes sense in those cases in which the tumor has the necessary somatostatin receptors on the cell surfaces that bind to the TOC.

Another limitation of radiopeptide therapy with ⁹⁰ Y or ¹⁷⁷ Lu is the radiation-induced nephrotoxicity (kidney toxicity). Infusions with the two amino acids arginine and lysine can reduce the absorption of DOTATOC in the kidneys. However, these infusions cause other side effects.

Therapy success

A cure is not possible with this form of therapy, but in most of the affected patients the growth of the tumors and metastases comes to a standstill. This can significantly improve the quality of life of the patient.

There is currently no official approval for this form of therapy. The application is essentially palliative.

In cases where the DOTATOC therapy is the only promising therapy, the health insurance company is obliged to reimburse the costs.

Development history

⁹⁰ Y-DOTATOC was developed by the Swiss company Novartis in the late 1990s under the name SMT487 . The brand name was initially OctreoTher ^® , later Onalta ^® . In September 2005, Novartis had significantly reduced or discontinued the activities of the compound in clinical phase II. In January 2007, the US company Molecular Insight Pharmaceuticals took over the worldwide rights to SMT487.

Related drugs

Several compounds related to the DOTATOC are in clinical testing.

DOTALAN

DOTALAN or also called DOTA-Lanreotid, like octreotide, has a similar ability to bind to the SST2 receptor. However, this somatostatin analog has a significantly higher affinity for SSTR5. With ⁹⁰ Y it is used as ⁹⁰ Y DOTA lanreotide.

DOTATATE

DOTATATE, also known as DOTA- [Tyr³] octreotate, has an affinity for SSTR2 that is about nine times higher than that of DOTATOC. Together with ¹⁷⁷ Lu it is used as ¹⁷⁷ Lu-DOTA-Tyr³-Octreotat. DOTATATE is approved as Lu 177 complex Lutathera ^® in Europe and the USA.

literature

• A. Otte et al .: Yttrium-90 DOTATOC: first clinical results. In: Eur J Nucl Med. 26/1999, pp. 1439-1447. PMID 10552085
• D. Storch: New, radioactively labeled and magnetically resonance active somatostatin analogues for better diagnosis and targeted radionuclide therapy of neuroendocrine tumors . S. l. 2005, doi : 10.5451 / unibas-003592299 (dissertation, University of Basel).
• A. Frilling et al .: Treatment with (90) Y- and (177) Lu-DOTATOC in patients with metastatic neuroendocrine tumors. In: Surgery. 140/2006, pp. 968-976. PMID 10552085 .
• SWJ Lamberts et al: Octreotide. In: NEJM. 334/1996, pp. 246-254.
• A. Otte et al: DOTATOC: a powerful new tool for receptor-mediated radionuclide therapy. In: European journal of nuclear medicine. 24/1997, pp. 792-795. PMID 9211767 .
• J. Rendl et al.: Somatostatin receptor scintigraphy (SRS) in malignant CNS tumors in children: first results and comparison with CT and MR. In: Nucl Med. 34/1995, pp. 50-78.
• R. Albert et al .: Direct synthesis of [DOTA-DPhe1] -octreotide and [DOTA-DPhe1, Tyr3] -octreotide (SMT487): two conjugates for systemic delivery of radiotherapeutical nuclides to somatostatin receptor positive tumors in man. In: Bioorg Med Chem Lett. 8/1998, pp. 1207-1210. PMID 9871736 .
• RE Weiner, ML Thakur: Radiolabeled peptides in the diagnosis and therapy of oncological diseases. In: Applied Radiation and Isotopes. 57/2002, pp. 749-763.
• C. Waldherr et al .: Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90) Y-DOTATOC. In: J Nucl Med. 43/2002, pp. 610-616.
• DV Beuter: Comparison of gastrin receptor scintigraphy with positron emission tomography, computed tomography, somatostatin receptor scintigraphy, bone marrow and bone scintigraphy in patients with metastatic medullary thyroid carcinoma. Dissertation, Philipps University of Marburg, 2007.
• C. Wängler et al: Radiolabeled peptides and proteins in cancer therapy. In: Protein Pept Lett. 14/2007, pp. 273-279. PMID 17346233 .
• D. Bushnell et al .: Assessment of hepatic toxicity from treatment with 90Y-SMT 487 (OctreoTher (TM)) in patients with diffuse somatostatin receptor positive liver metastases. In: Cancer Biotherapy & Radiopharmaceuticals. 18/2003, pp. 581-588.

Web links

• PET - modern diagnostic method in the fight against cancer German Society for Nuclear Medicine eV and the Professional Association of German Nuclear Medicine eV
• Peptides and Amines (Engl.)

Individual evidence

1. ↑ edotreotide - Drug information ( Memento of 5 September 2010 at the Internet Archive ), accessed on June 10 of 2008.
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ^ F. Forrer et al.: Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC. In: Journal of nuclear medicine. 46/2005, pp. 1310-1316. PMID 16085587 .
4. ↑ ^{a b} M. Neininger et al.: Studies on the nephrotoxicity of a radio-peptide therapy with 90-Y-DOTATOC. ( Memento of October 4, 2015 in the Internet Archive ) (PDF; 1.9 MB). In: Nuclear Medicine. 2/2008, A15.
5. ↑ ^{a b} R. E. Weiner et al. In: Appl Radiat Isot. 57/2002, pp. 749-763.
6. ↑ A. Janecka et al. In: J Pept Res. 58/2001, pp. 91-107.
7. ↑ A. Schmid: Modular synthesis and macrocyclization of ruthenium-labeled diaryl ether peptoids. (PDF; 5.6 MB) Dissertation, LMU Munich, 2005.
8. ^ V. Prasad et al.: Changing role of somatostatin receptor targeted drugs in NET: Nuclear Medicine's view. (PDF; 2.4 MB). In: J Pharm Pharmaceut Sci. 2007, pp. 321-337.
9. ↑ M. Ö. Öksüz et al: Therapy control of a radio-peptide therapy (Y-90 or Lu-177 DOTATOC) with Ga-68 DOTATOC-PET / CT. In: Nuclear Medicine. 2/2008, A15.
10. ^ V. Budach et al .: PET / CT as a therapy-controlling instrument in oncological diagnostics and as a therapy progress marker. In: 4th Berlin PET / (CT) Symposium. Pp. 22-26.
11. ↑ J. Kowalski et al: Evaluation of positron emission tomography imaging using [68Ga] -DOTA-D Phe (1) -Tyr (3) -Octreotide in comparison to [111In] -DTPAOC SPECT. First results in patients with neuroendocrine tumors. In: Mol Imaging Biol. 5/2003, pp. 42-48.
12. ↑ M. Henze et al .: Exceptional increase of Somatostatin receptor expression in pancreatic neuroendocrine tumor visualized with 68Ga-DOTATOC-PET. In: Eur J Nucl Med. 31/2004, p. 466.
13. ↑ S. Petersenn: Neuroendocrine Tumors. (PDF; 720 kB). In: Unique items from Essen. 25/2005, pp. 62-75.
14. ↑ Neuroendocrine tumors are often discovered very late. In: Doctors newspaper. July 3, 2006.
15. ↑ DJ Kwekkeboom et al .: Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake. In: J. Nucl. Med. 40/1999, pp. 762-767.
16. ↑ ^{a b} M. De Jong et al .: Radiolabelled peptides for tumor therapy: current status and future directions. In: Eur. J. Nucl. Med. 30/2003, pp. 463-469.
17. ↑ J. Kotzerke: Current developments in the field protstataspezifischer tracer. Pp. 9-11.
18. ^ ClinicalTrials.gov: Edotreotide , accessed June 10, 2008.
19. ↑ T. Schumacher et al .: Local injection of the 90Y-labeled peptidic vector DOTATOC to control gliomas of WHO grades II and III. An extended pilot study. In: Eur J Nucl Med Mol Imaging. 29/2002, pp. 486-493.
20. ↑ OC Boermann include: Between the Scylla and Charybdis of peptide radionuclide therapy: hitting the tumor and saving the kidney. In: Eur. J. Nucl. Med. 28/2001, pp. 1447-1449.
21. ↑ ^{a b} T. M. Behr et al.: Nephrotoxicity versus anti-tumor efficacy in radiopeptide therapy: facts and myths about the Scylla and Charybdis. In: Eur. J. Nucl. Med. 29/2002, pp. 277-279.
22. ↑ M. Béhé et al .: Kidney protections agents during radiopeptide therapy in mice. In: Eur. J. Nucl. Med. Mol. Imag. 29/2002, p. 301.
23. ↑ D. Bushnell et al .: Effects of intravenous amino acid administration with Y-90 DOTA-Phe1-Tyr3-Octreotide (SMT487, OctreoTher) treatment. In: Cancer Biother Radiopharm 19/2004, pp. 35-41. PMID 15068609 .
24. ↑ EJ Rolleman et al: Save and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. In: Eur. J. Nucl. Med. Mol. Imag. 30/2002, pp. 9-15.
25. ↑ University Hospital Basel: ( Page no longer available , search in web archives: New therapy options against lymphatic cancer ); Press release from April 28, 2005.
26. ↑ M. Pavel: Neuroendocrine tumors: presentation, rational diagnosis and therapy guidelines.
27. ↑ LSG North Rhine-Westphalia, judgment of January 17, 2007 - L 11 KR 6/06 (PDF; 899 kB) RID 07-01-143, p. 52.
28. ^ Molecular Insight Pharmaceuticals, Inc. Acquires Clinical Stage, Targeted Radiotherapeutic Candidate Onalta ™ (Formerly OctreoTher ™). In: evaluategroup.com. Evaluate Ltd., January 24, 2007, accessed February 14, 2017 . 
29. ↑ DJ Kwekkeboom et al .: Treatment of patients with gastroenteropancreatic (GEP) tumors with the novel radiolabelled somatostatin analogue [177Lu-DOTA, Tyr3] octreotate. In: Eur. J. Nucl. Med. Mol. Imag. 30/2003, pp. 417-422.

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