EP0975670A1

EP0975670A1 - Radiolabelled somatostatin receptor ligands for diagnosis and therapy

Info

Publication number: EP0975670A1
Application number: EP98907750A
Authority: EP
Inventors: Irene Virgolini; Peter Smith-Jones; Peter Angelberger
Original assignee: Individual
Current assignee: Individual
Priority date: 1997-03-14
Filing date: 1998-03-12
Publication date: 2000-02-02
Also published as: ATA45197A; WO1998041540A1; AT405906B; AU6602198A; JP2001515494A; CA2284581A1

Abstract

The invention relates to a carrier substance for radionuclides used in the diagnosis and/or radiotherapy of somatostatin receptor-positive tumors or target cells. Said conjugate consists of somatostatin 14 agonists, lanreotide and a macrocyclic chelating agent former which forms stable chelates with metallic radionuclides in physiological conditions.

Description

RADIO-MARKED SOMATOSTATIN RECEPTOR LIGANDS FOR DIAGNOSIS AND THERAPY

The invention relates to a carrier substance for metal compounds for diagnosis and / or destruction of tumor tissue, which selectively binds the substance to the somatostatin-binding surface receptors of the affected cells, a macrocyclic chelating agent being bound to a somatostatin 14 agonist

The increased expression of peptide receptors on various tumor cells forms the molecular basis for the use of radiolabeled peptides in the nuclear medical localization diagnosis. One of the first molecules of this type, radio-iodinated N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys (1), was developed for the localization of abscesses based on its binding to chemotactic receptors on neutrophil blood cells. Subsequently, peptides such as (D) Phe-Cys-Tyr- (D) Trp-Lys-Thr-Cys-Thr (ol) (Tyr ³ -Octreotide, 2) and ^m In-DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr (ol) ((DTPA) - (D) Phe ¹ -Octreotide, 3) used to localize malignancies such as neuroendocrine tumors, breast cancer and lymphomas

Another technique for displaying tumors is the scintigraphy technique developed in Vienna with radioiodinated NDP (vasoactive intestinal peptide, 4), which is a naturally occurring peptide.This radioligand (ie ¹²³ I-VIP) not only binds to neuroendocrine tumors with high affinity, but also especially on a variety of adenocarcinomas that cannot be visualized with ¹¹¹ In-DTPA- (D) Phe ¹ octreotide. However, it is noteworthy that a number of primary tumors, such as carcinoids and insulinomas, are caused by both ¹²³ I-NIP and by ¹¹¹ In-DTPA- (D) Phe ¹ - octreotide An interesting phenomenon was observed in Vienna, namely that VTP and octreotide / somatostatin are cross-competitive for binding to tumor cell membranes

So far, five different human somatostatin receptors (hSSTRl-5) and two different VIP receptors have been characterized and cloned. Using transfected peptide receptors, the SSTR3 subtype has been found to be the most widely used among somatostatin receptors Binding site for somatostatin in the tumor tissue is. It was also shown that VIP binds to SSTR3 and that the binding of somatostatin and VIP is cross-competitive to primary tumor cells.

The binding of peptides to tumor receptors can not only be used to diagnose the location of tumors and their metastases. The ¹¹¹ In-DTPA (D) Phe ¹ octreotide used for diagnostic purposes has already been used in high doses as a receptor ligand for targeted radiotherapy.

EP 0 714 911 A2 shows that a conjugate of an octapeptide with the common name octreotide and a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' -tetraacetic acid (DOTA ), a radionuclide can complex so that it can be used in vivo for the therapy of tumors. This patent is limited to the therapeutic use of said substance. Octreotide only binds to some of the high affinity somatostatin 14 subtype receptors that have now been found. In vivo, ¹¹¹ In-DTPA- (D) Phe ¹ -octreotide is also taken up in kidney, liver and spleen, which leads to an unnecessarily high radiation exposure of these organs.

The invention is based on the object of creating a carrier molecule of the type mentioned at the outset which has the broadest possible somatostatin 14 receptor subtype recognition profile (hSSTR2-5) and has little stress on healthy body tissue and thus has better biodistribution. The effect would be a higher dose in the tumor tissue and a lower radiation exposure of the healthy tissue, especially of the spleen and kidney.

The same should also apply if heavy metal atoms or paramagnetic metals are used instead of radionuclides. The invention solves this problem in that as a somatostatin 14 agonist

Octapeptide of the general formula

(D) ßNal-Cys-Tyr- (D) Trp-Lys-Val-Cys-Thr-NHR ₁ (I) is bound to the macrocyclic chelating agent via its C or N terminus (example 1). This octapeptide is known under the name "lanreotide", but not in connection with a macrocyclic chelating agent. The peptide of the invention can be labeled with salts of radionuclides in metal-free buffers at elevated temperature (Examples 2-4). The high labeling efficiency is that The peptide of the invention forms a stable chelate with In, ⁹⁰ Y or ^67/68 Ga under physiological conditions. For example, these chelates are in human serum or in the presence of a 10,000-fold excess of diethylenetriamine-pentaacetic acid ( DTPA) The peptide of the invention also forms stable chelates with rare earths ( ¹⁶¹ Tb, ¹⁵³ Sm, etc.).

EP 0 714911A2 covers the use of DOTA octreotide in a form labeled with ⁹⁰ Y or ¹⁶¹ Tb and with radionuclides which emit alpha, beta particles or Auger electrons. In the specific radionuclides that capture an isomeric transition by making (such as ^99m Tc), electrons (ie ⁶⁷ Ga, In ^ιn) or positron proposed ⁽⁶⁸ Ga) is not mentioned (Example 8). The peptide of the invention can be based on

1 1 1 Λ7 / ΛR must be marked stable with In or Ga and is therefore not only suitable for therapy, but also for use as a radio diagnostic agent (both for SPECT and PET).

The octapeptide according to the invention has a broad somatostatin receptor recognition profile. Specifically, the radioactively labeled peptide with K values in the low nanomolar range binds to SSTR2, SSTR3, SSTR4 and also SSTR5 (Example 5). The radiolabeled ligand also shows high affinity binding for PC3 and DU145 prostate cancer cells, PANC1 and HT29 adenocarcinoma cells, A431 epithelial cells, ZR75-1 and T47D breast cancer cells and for 518A2 melanoma cells. The peptide also binds to a number of primary tumors such as breast cancer, melanoma, adenocarcinoma, lymphoma, liver cell tumor, thyroid tumor and various neuroendocrine tumors. The most important somatostatin receptor expressed in the tumor appears to be SSTR3, which is a target R for the peptide of the invention (Example 6). The experiments have shown that the binding behavior of the octapeptide on the one hand and that of the octapeptide associated with the macrocyclic chelating agent on the other hand is somewhat was different, which may be due to the different lipophilicity of the octapeptide in the unbound or bound state.

Biodistribution of the ⁹⁰ Y-labeled peptide in Sprague Dawley rats (180-220g, 4 MBq, 160 pmol) showed rapid elimination of the substance from the blood and high uptake and retention in tissues that physiologically express SSTR (such as pancreas). In contrast, the uptake in organs that normally express little or no SSTR was characterized by a very low uptake of radioactivity. For example, the calculation for the bone 48 hours after the injection resulted in an intake of only about 0.01% / g of the injected dose (example 7).

Instead of the radionuclides mentioned, heavy metal atoms or metal ions with atomic numbers 20-32, 42-44, 45 and 57 to 83 can also be used for the medical imaging diagnosis. Paramagnetic metals or metal ions with atomic numbers 21-29, 42, 44 or 57-71, in particular Gd ³⁺ , Mn ²⁺ or Dy ³⁺ , can be used for a magnetic resonance display. Alkali, alkaline earth or transition metals or metal ions, in particular Na ⁺ , K ⁺ , Ca ²⁺ , Fe ^{2 + / 3 +} , Zn ²⁺ and Mn ²⁺ can also be used for pharmaceutical purposes.

The compound 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' tetraacetic acid (DOTA) was advantageously used as the chelating agent. The conjugate resulting from Lanreotide and DOTA is relatively lipophilic and shows slower blood clearance and higher tumor accumulation than other somatostatin 14 analogues in humans. Due to the hydrophilicity of DOTA, the lipophilicity of the octapeptide used is reduced, which means that the tumors can be better displayed on the one hand, and on the other hand a lower absorption of this substance is achieved in the non-diseased organs, i.e. the non-target organs such as the spleen and kidney. In humans, the ^lu In-labeled peptide of the invention was directly compared to ^{ι π} In-DTPA- (D) Phe ¹ octreotide. After intravenous application of the peptide of the invention (3 mCi, 6 nmol) compared to the ^lu In-DTPA- (D) Phe ¹ -octreotide, there was a higher tumor uptake, a lower retention in the kidneys and a reduced uptake in the spleen (example 8th).

Advantageously, the diagnosis as a radionuclide ^{ι n} In or Ga ^67/68 be bound to the chelating agent, which has the advantage that this radionuclide Gamma radiation emitted, which is suitable for diagnosis, with less radiation exposure for the body. To destroy tumor tissue, the radionuclide ⁹⁰ Y can be bound to the chelating agent, which is known to emit beta radiation which serves to destroy the tumor cells, the effect of the radionuclide essentially being restricted to the diseased cells due to the specific binding of the octapeptide ). While ⁹⁰ Y is well suited for the treatment of larger tumors due to its radiation range (ß ^" radiation, 2.3 MeV), smaller tumors can be treated with other beta-emitting radionuclides such as ¹⁶¹ Tb (ß ^" radiation, 0.5 and 0.6 MeV) or ¹⁵³ Sm (β ^" radiation, 0.7 and 0.8 MeV), which can also be bound to the peptide of the invention, can theoretically be treated better. For this reason, treatment of tumor patients (whose tumors express SSTR2-5, but above all SSTR3) with a Mixture to think of the peptide of the invention ("cocktail" of radionuclides such as the ⁹⁰ Y-labeled and the ¹⁶¹ Tb-labeled peptide of the invention for radiotherapy). A "cocktail" of radioisotopes (such as ⁸⁶ Y-labeled peptide and ⁹⁰ Y-labeled peptide) or radionuclides (such as ^{U1 In} -labeled peptide and ⁹⁰ Y-labeled peptide) for simultaneous diagnosis and radiotherapy can also be produced.

For accompanying control during therapy, the radioactively labeled peptide can be used repeatedly to evaluate somatostatin receptor-positive tumor diseases or endocrinological diseases.

Examples:

Example 1: Chemical synthesis of the peptide

Abbreviations:

DOTA: l, 4,7,10-tetraazacyclododecane-N, N \ N ', N'-tetraacetic acid

LANREOTID: (D) _ß NaI-Cys-Tyr- (D) Trp-Lys-Val-Cys-Thr-NH ₂ II

BOC: tert-butyloxycarbonyl 80 mg of DOTA, 74 mg of N-hydroxysuccinimide and 80 mg of [ε-Boc-Lys ⁵ ] lanreotide are dissolved in 15 mL H ₂ O and 30 mL N, N-dimethylformamide. One hundred mg of NjN'-dicyclohexylcarbodiimide are added and the resulting solution is stirred at room temperature for 16 hours. The product, [α-DOTA- (D) - ßNal ¹ , ε-Boc-Lys ⁵ ] -lanreotide, is isolated and isolated on a silica gel 60 column using methylene chloride: methanol: 50% acetic acid (9: 1: 0.125 - »7: 3: 1) cleaned as a solvent. The Boc-protected group is cleaved from the [α-DOTA- (D) -ßNal ¹ , ε-Boc-Lys ⁵ ] - lanreotide product using 30 mL methylene chloride and 2 mL trifluoroacetic acid (30 minutes at room temperature). The resulting product, [α-DOTA- (D) -ßNal ¹ ] -lanreotide is precipitated using ether and purified by means of a C18 reverse phase HPLC column using a water / acetonitrile 1 / 0.1% trifluoroacetic acid solvent mixture. A second HPLC purification step is followed using a water / acetonitrile / 1% acetic acid solvent mixture to obtain the pure product of the invention as the acetate salt. FAB-MNH +: 1482

Conjugation at the N-terminus

Conjugation at the C-terminus

Example 2: Radiolabeling of the peptide with In

The peptide of the invention is dissolved in 0.2 mol / L ammonium acetate buffer (metal-free, pH 7) and incubated with ^m InCl ₃ (carrier-free, Me ⁺⁺ <0.1 μg / mCi, <1 μg / mL) in 0.05 mol / L HC1 . A ratio of 0.5 mCi ^{π π} In: 1 nmol DOTA lanotide is produced and the reaction mixture is boiled at 100 ° C. for 30 minutes. An aliquot is checked for purity by means of thin layer chromatography. The radiochemical purity of the product is typically> 99%. If it is less, the product is cleaned with reversed phase LC or HPLC. The radioligand is taken up in a solution of 0.075 mol / L NaCl, 0.05 mol / 1 NHUOAc, 0.2 mol / L ascorbic acid and 0.1% human serum albumin and sterilized by filtration through a 0.2 μm membrane. Example 3: Radiolabeling of the peptide with ⁹⁰ Y

As Example 2 but instead of ^lu InCl _3, ⁹⁰ ₃ YC1 used (1 mCi: 1 nmol DOTA-lanreotide).

Example 4 - Radiolabeling of the peptide with 67/68 _/ Ga

Instead of ^lu InCl ₃ , ⁶⁷⁶⁸ GaCl _{3 is used} to radiolabel the peptide of the invention.

Example 5: In vitro binding of the "'in / ^ Y-labeled peptide

The labeled and unlabelled substance of the invention was examined in saturation studies and in competition studies in vitro for its binding to various tumor cells (primary tumors, immortal cells) and also to the somatostatin receptor subtypes SSTR1-SSTR5. For this purpose, the subtype receptors were expressed on COS-7 cells using cDNA samples. Comparative studies were carried out with other somatostatin receptor agonists. In comparative studies, ¹²⁵ I-Tyr ⁿ -somatostatin-14 was also used as the radioligand. There was no significant difference in binding behavior between the ^{m In} and ⁹⁰ Y-labeled peptide of the invention. However, the data below clearly show that there is a significant difference in binding to the SSTR3 as well as the SSTR4 between the peptide of the invention and the ^{n ι} In-DTPA- (D) Phe ¹ -ctreotide.

Binding of [ ^{1 1} ln] / r ^ Vj-DOTA-Lanreotide, [ ¹¹¹ lπ] -DTPA-D-Phe ¹ -Octreotide / [ ¹²³ l] -Tyr ³ -Octreotide and [ ²⁵ l] -Tyr ¹¹ -SST- 14 on somatostatin

Receptor subtypes hSSTR1 to hSSTRδ.

Saturation study displacement study (ICso values for unlabeled peptides)

(K _d value)

Kd SST-14 DOTA- Lanreotide DOTA-Tyr ³ - Tyr3- DOTA- IP Lanreotide Octreotide Octreotide Vapreotide hSSTR (nM) (nM) (nM) (nM) (nM) (nM) (nM) (nM) hSSTRl

'"In-DOTA Lanreotide 15 0.1 309 ND ND ND ND 232

¹¹¹ ln-OCT / ^{1 3} Ty -OCT negative

¹²⁵ l-Tyr ¹¹ -SST-14 1.0 0.5 154>1000>1000>1000>1000> 1000 hSSTR2 '-DOTA-Lanreotid 7 3.8 1.1 ND 0.7 0.2 ND> 1000

¹¹¹ ln-DOTA lanotide 4.3 0.5 1.3 0.2 0.35 0.4 1.6> 500

¹¹¹ ln-OCT / ^{1 3} Tyr ³ -OCT 1.5 1 ND ND ND 1 ND> 1000

¹²⁵ l-Tyr ¹ -SST-14 0.3 1.0 0.3 1.1 0.13 0.3 1.4> 1000 hSSTR3

^11l ln-DOTA-Lanreotide 5.1 1.2 6.3 19 100 1.2 3.3 1

¹¹¹ ln-OCT / ¹²³ Tyr ⁱ -OCT 32 10 ND ND ND 10 ND 10 ²⁵ l-Tyr ¹¹ -SST-14 0.8 1.2 15 15 73 20 28 7 hSSTR4

^11l ln-DOTA-Lanreotide 3.8 1.4 3.7 ND>500> 1000 ND ND

^{111 In} -OCT / ¹²³ Tyr ³ -OCT negative

¹²⁵ l-Tyr ¹ -SST-14 0.7 1.8 2.5 ND>500>500>1000> 1000 hSSTRδ

'"In-DOTA-Lanreotide 10 1 1 ND ND ND ND neg

¹¹¹ ln-OCT / ¹²³ Tyr ³ -OCT 1.1 1 ND ND ND 5 ND neg

^{1 5} l-Tyr ¹¹ -SST-14 1.0 0.9 0.45 21 260 1.5 5.4> 1000

Example 6: Somatostatin receptor subtype 3 expressing tumors

Gastric cancer, colon and rectal cancer; Skin cancer; Breast cancer; Pancreas, thyroid tumors, lymphomas, lung cancer, various neuroendocrine tumors such as carcinoids, gastrinomas, pheochromocytomas; Prostate cancer, glandular cancer, and the daughter tumors of these tumors.

Example 7: Biodistribution of the ⁹⁰ Y-labeled peptide in animal experiments

Biodistribution of the ⁹⁰ Y-labeled peptide of the invention was examined in rats. The radiolabeled peptide Sprague Dawley rats (180-220 g, 4 MBq, 160 pmol) were administered intravenously into the tail vein. The rats were sacrificed after 1, 24 and 48 hours and the organs removed. The following distribution of radioactivity was found:

1 hour p.i. 24 hours p.i. 48 hours p.i.

Tissue% ini dose / g (n = 4)% ini dose / q (n = 3)% ini dose / α (n = 3)

Blood 0.24 ± 0.04 0.01 ± 0.004 0.006 ± 0.001

Heart 0.10 +0.05 0.006 ± 0.001 0.004 ± 0.001

Lungs 0.28 ± 0.10 0.05 ± 0.01 0.03 ± 0.006

Liver 0.16 ± 0.02 0.21 ± 0.03 0.13 ± 0.005

Spleen 0.12 ± 0.04 0.06 ± 0.01 0.05 ± 0.008

Kidney 2.41 ± 0.64 2.10 ± 0.50 1, 81 ± 0.45

Pancreas 1, 12 ± 0.27 0.55 ± 0.24 0.35 ± 0.13

Adrenal gland 4.30 ± 0.61 2.14 ± 0.83 2.02 ± 0.92

Pituitary 1.69 ± 0.88 1.34 ± 0.50 1.02 ± 0.30

Muscle 0.03 ± 0.02 0.003 ± 0.001 0.003 ± 0.001

Spine acid 0.10 ± 0.04 0.02 ± 0.005 0.02 ± 0.003

Sternum 0.16 +/- 0.06 0.01 +/- 0.001 0.01 +/- 0.006

This distribution shows that organs known to express somatostatin receptors have a significantly higher uptake. The relatively low absorption in the spleen and liver (non-target organs) is also striking. The uptake of the substance in the skeletal system is still very low 48 hours after application, which indicates the high in vivo stability of the ⁹⁰ Y-labeled peptide of the invention. Example 8: Biodistribution and dosimetry of the ^UI In-labeled peptide in humans

The biodistribution and dosimetry of ^ιn In-labeled peptide of the invention was compared with the biodistribution and dosimetry of ^{1 I 1} In-DTPA (D) Phe ¹ octreotide. Approx. 3 mCi of one or the other substance was administered intravenously at intervals of approx. 6-8 weeks. Following the application, blood samples, urine samples and stool samples were examined for their radioactivity at different times. The gamma radiation was recorded using a gamma camera, the measuring points being applied up to 144 hours after application. The gamma camera images included whole-body images in anterior and posterior projection, as well as single-photon emission tomography (SPET) for precise tumor localization and size estimation. The relative uptake into individual organs and tumors or metastases was determined by creating regions of interest. Dosimetric data were extrapolated using the MIRD program.

The results of the comparison between ^m In-DTPA octreotide and ^nι In-DOTA lanreotide are shown in the drawing in FIG. 1 A to FIG. 1D represented graphically.

From FIG. 1A it can be seen that the substance of the invention is excreted from the body somewhat more slowly than ¹¹¹ In-DTPA- (D) Phe ¹ octreotide. The uptake of the peptide of the invention in the tumor is significantly higher in direct comparison (see FIG. 1B). It is also important that, compared to ^III In-DTPA- (D) Phe'-octreotide, the peptide of the invention a priori shows a significantly lower uptake in the spleen (FIG. IC) and kidneys (FIG. 1D). This biodistribution forms the basis for effective radiotherapy with the ⁹⁰ Y-labeled peptide of the invention, since these organs are critical to radiation exposure. literature

1) M.-S., Jiang, E.G. Corley, H.N. Wagner Jr. and M.-F. Tsan. Localization of abscess with an iodinated synthetic chemotactic peptide. Nucl. Med., XXI (3), pp 110-113 (1982).

2) E.P. Krenning, W.H. Bakker, W.A.P. Brevmann et al .. Localization of endocrine related tumors with radioiodinated analogue of somatostatin. Lancet 1989 (1) pp242-244.

3) E.P. Krenning, W.H. Bakker, P.P.M. Kooij, et al. Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with lodine-123-Tyr-3-octreotide. J. Nucl. Med., 33, pp 652-658 (1992).

4) Virgolini I., Raderer M., Kurtaran A., et al. Vasoactive intestional peptide receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors. New Eng. J. Med., 331, pp1116-1121 (1994).

Claims

Claims:

1 carrier substance for a metal compound for the diagnosis and / or destruction of tumor tissue or other target cells, which substance selectively binds to the somatostatin-binding surface receptors of the affected cells, a macrocyclic chelating agent being bound to a somatostatin 14 agonist, characterized in that as Somatostatin 14 agonist is an octapeptide of the general formula (I)

(D) ßNal-Cys-Tyr- (D) Trp-Lys-Val-Cys-Thr-NH ₂ (I)

is bound to the macrocyclic chelating agent via its C or N termmus

2 carrier substance according to claim 1, characterized in that as the chelating compound 1,4,

7.10 tetraazacyclododecane tetraacetic acid or the compound 1,4,8,11 teraazacyclotetradecane, 4 ',

8 ', 11' tetraacetic acid (TETA) is used

3 carrier substance according to claim 1 or 2, characterized in that the metal compound is a radionuclide

4 carrier substance according to claim 3, characterized in that for diagnosis as radionuclide ^m In or ⁶⁷ Ga is bound to the chelating agent

5 carrier substance according to claim 3, characterized in that for the destruction of tumor tissue as radionuclide ⁹⁰ Y or rare earths such as Sm, Ho, or ^I65 Dy are bound to the chelating agent

6 carrier substance according to claim 3, characterized in that for diagnosis by means of positron emission tomography a corresponding nuclide such as Ga, Y is bound to the chelating agent

7 carrier substance according to claim 1 or 2, characterized in that the metal compound is a heavy metal atom or a metal ion of atomic number 20-32, 42- 44, 45 and 57 to 83 for medical imaging for diagnostic purposes 8 carrier substance according to claim 1, 2 or 7 , characterized in that the

Metal compound a paramagnetic metal or a metal ion of atomic number 21- 29, 42, 44 or 57-71, in particular Gd ³⁺ , Mn ²⁺ or Dy ³⁺ for the nuclear magnetic resonance image ^display .

9. carrier substance according to claim 1 or 2, characterized in that the metal compound is a pharmaceutically acceptable alkali, alkaline earth or transition metal or a metal ion, in particular Na ⁺ , K ⁺ , Ca ²⁺ , Fe ^{2+ 3+} , Zn ²⁺ and Mn ^{2+ is} for therapeutic purposes.

10. Use of the carrier substance coupled to a metal compound according to one of claims 1 to 9 in a method for producing an agent for diagnosis such as therapy of target cells, such as tumor cells, or leukocyte accumulations, the somatostatin receptor subtypes SSTR2, SSTR3, SSTR4 or Express SSTR5.

11. Use of the carrier substance coupled with a radionuclide according to one of claims 3 and 5 in the manufacture of an agent for the treatment of target cells in the form of a mixture of radionuclides, such as the ⁹⁰ Y-labeled and the ¹⁶¹ Tb-labeled peptide.

12. Use of the carrier substance coupled with a radionuclide according to one of claims 3 to 6 in the manufacture of an agent for diagnosis and therapy in the form of a mixture of radioisotopes, such as ⁸⁶ Y-labeled peptide and ⁹⁰ Y-labeled peptide, or radionuclides, such as ^{ι n} In-labeled peptide and ⁹⁰ Y-labeled peptide, for simultaneous diagnosis and radiotherapy.

13. Use of the carrier substance coupled with a radionuclide for evaluating somatostatin receptor-positive tumor diseases or endocrinological diseases by repeated use of the labeled peptide for the accompanying control of the therapy.

14. A process for the preparation of a compound according to claim 1, characterized in that a peptide compound of the formula (i) or a derivative thereof is reacted with a macrocyclic chelating agent or a derivative thereof to obtain a chelate-peptide compound, and optionally to form a metal chelate complex therefrom.