JP2001515494A - Radiolabeled somatostatin receptor ligands for diagnosis and therapy - Google Patents

Abstract

(57) Abstract The present invention relates to a carrier substance for a radionuclide used in diagnosis and / or radiotherapy of a somatostatin receptor-positive tumor or target cell. A conjugate comprising a somatostatin-14 agonist, lanreotide, and a metal radionuclide and a macrocyclic chelator that forms a stable chelate under various physiological conditions.

Description

DETAILED DESCRIPTION OF THE INVENTION      Radiolabeled somatostatin receptor ligands for diagnosis and therapy   The present invention provides for selective binding of somatostatin-binding surface receptors on diseased cells. Support for various metal compounds for the diagnosis and / or destruction of tumor tissue With respect to body substances, the somatostatin-14 agonist has a macrocyclic chelator Are combined.   Enhanced expression of peptide receptors on a wide variety of tumor cells is a nuclear medicine Molecular basis for the use of radiolabeled peptides in the context of localization diagnostics Eggplant One of the first molecular species of this type, radioiodinated N-formyl-Nle-L eu-Phe-Nle-Tyr-Lys (1) binds to binding to chemotactic receptors on neutrophil blood cells It was developed for the location of abscesses. Then, (D) Phe-Cys-Phe- (D) Trp--Lys-T hr-Cys-Thr (o1) ｛Tyr^Three-Octreotide: 2)｝ and¹¹¹In-DTPA- (D) Phe-Cys-Phe- ( D) Trp-Lys-Thr-Cys-Thr (o1) ｛(DTPA)-(D) Phe¹-Octreotide: 3) Peptides have been used to locate malignant diseases such as neuroendocrine tumors, breast cancer and lymphomas. Used for   Radioactive iodine-labeled naturally occurring peptide developed in Vienna Of scintigraphy using VIP, a {vasoactive intestinal polypeptide: 4)} Technology offers another method for the display of various tumors. This radioligand (Ie^{one two Three}I-VIP) only binds with high affinity to neuroendocrine tumors No, not least,¹¹¹In-DTPA- (D) Phe¹-Not visible with octreotide It also binds to many adenocarcinomas. Of note, however, are carcinoids and insulin. A series of early tumors like linoma^{one two Three}Not only by I-VIP¹¹¹In-DTPA- (D) Phe¹-It is also indicated by octreotide. In this case, wee Phenomena of interest in VIP, namely VIP and octreotide / somatostatin Was observed to be cross-competitive for binding to tumor cell membranes.   To date, five different human-somatostatin receptors (hSSTR1-5) and different Only two VIP receptors have been identified and cloned. form With the use of transfektiert peptide receptors, somatostati SSTR 3 subtype among tumor receptors is the most spread to somatostatin in tumor tissue Binding site. And that VIP binds to SSTR 3; And that there is a cross-competition of binding of somatostatin and VIP to early tumor cells. It was also shown.   Binding of peptide to tumor receptor is used to diagnose tumor localization (Lokalisationsdiagnose) It can be used not only for the diagnosis but also for the diagnosis of the dislocation. That is, the diagnostic eye Commonly used¹¹¹In-DTPA- (D) Phe¹-Octreotide is already aggressive radiation therapy High doses were also used as receptor ligands for the method.   From European patent EP 0714911 A2, with the octapeptide of octreotide Macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N, N ', N ", N'"-4acetic acid ( Conjugates with DOTA) produce radionuclides, which are used in vivo to treat various tumors. Can be complexed so that it can be used for This patent is Limited to therapeutic use of the aforementioned substances. Octreotide was found in the meantime Binds with high affinity only to some of the identified somatostatin-14 subtype receptors. In vivo¹¹¹In-DTPA- (D) Phe¹-Octreotide is found in kidney, liver and spleen Are also taken up, which leads to an unnecessarily high radiation load on these organs.   The present invention relates to the discovery of the broadest possible somatostatin-14 subtype (hSSTR 2-5). The radiation load on healthy body tissue is low, Such as those described in the introductory text that have good biodistribution It is an object of the present invention to obtain a carrier molecule. Its effect on tumor tissue High dose and relatively low radiation load on healthy tissues, especially spleen and kidney .   The same is true when heavy metal atoms or paramagnetic metals are used instead of radionuclides. This is also true.   The present invention solves this problem by using a somatostatin-14 agonist represented by the following general formula: Octapeptides are linked to their macrocyclic chelators via their C-terminus or N-terminus The problem is solved by being combined (Example 1). This octapeptide is called Is known under the designation `` Tide '', but in the binding with the macrocyclic chelating agent unknown. The peptides of the present invention are radionuclide-free in metal-free buffers. It can be labeled at elevated temperatures with salts (Examples 2 to 4). This high labeling efficiency constitutes the starting platform for the preparation of a dispensing kit. The present invention Peptides under various physiological conditions¹¹¹In,⁹⁰Y or^67/68Ga and stable chelate To form For example, the chelate can be found in human serum or in diethylenetriamine. It is stable in the presence of a 10,000-fold excess of pentaacetic acid (DTPA). Pep of the present invention Pide is a rare earth (¹⁶¹Tb,¹⁵³Sm) form stable chelates.   European Patent EP 0 714911 A2⁹⁰Y or¹⁶¹In Tb-labeled form and α- DOT labeled with particles, β-particles or radionuclides emitting Auger electrons A covers the use of octreotide. In particular, release through isomer transitions Radionuclide (^99mTc), the radionuclide that captured the electron (ie,⁶⁷Ga,¹¹¹I n) or a radionuclide that emits a positron (⁶⁸Ga) is not mentioned (Example 8). Departure The light peptide is in each case¹¹¹In or^67/68Can be stably labeled with Ga And therefore not only for treatment, but also for radiodiagnostics (SPECT and PET) Also suitable for use as).   The octapeptide according to the invention has a broad somatostatin receptor discrimination profile. I do. Specifically, this low nanomolar K_dRadiolabeled pepti with value Also binds to SSTR2, SSTR3, SSTR4 and SSTR5 (Example 5). The radioactive label Ligands identified were on PC3 and DU145 prostate cancer cells, PANC1 and HT29 adenocarcinoma cells, A431 High binding affinity for skin cells, ZR75-1 and T47D breast cancer cells and 518A2 melanoma cells Show. In addition, this peptide is useful for breast cancer, melanoma, adenocarcinoma, lymphoma, hepatocellular tumor, Binds to a range of early tumors, such as in thyroid tumors and various neuroendocrine tumors You. The most important somatostatin receptor expressed in the tumor is SSTR3 Which is a target-R for the peptides of the invention ( Example 6). In experiments, the binding behavior of this octapeptide and the macrocyclic chelator Slightly different from that of the octapeptide bound to This indicates that the bound state of this octapeptide was It should be attributed to the different lipophilicity in the state of association.   ⁹⁰Sprague Dawley rats (180-220 g, 4 MBq, 160 pmol) of peptide labeled with Y The biodistribution in) is due to the rapid elimination of this substance from the blood and the SS in a physiological manner. It showed high absorption and retention in TR expressing tissues (such as pancreas). In contrast Therefore, absorption in organs that express no or only minimal SSTRs is usually It was distinguished by a very slight absorption of Noh. That is, for example, calculations on bones It gives only about 0.01% blot per gram of injection even 48 hours after injection. None (Example 7).   In place of the radionuclides listed above, atomic numbers 20 to 32, 42 to 44, 45 and 57 -83 heavy metal atoms or metal ions may also be used for medical imaging diagnosis. it can. For magnetic resonance imaging, the atomic numbers 21 to 29, 42, 44 or 57 to 71 Paramagnetic metals or metal ions, especially Gd³⁺, Mn²⁺Or Dy³⁺Can be used . Further, for dispensing purposes, alkali metals, alkaline earth metals or transition metals, or Or these metal ions, especially Na⁺, K⁺, Ca²⁺, Fe^{2 + / 3 +}, Zn²⁺And Mn²⁺use Can be used.   As a chelating agent, 1,4,7,10-tetraazacyclododecane-N, N ', N ", NH'"-4 Acetic acid (DOTA) was advantageously used. Obtained from Lanreotide and DOTA The conjugate is relatively lipophilic and similar to other somatostatin 14 in humans Shows slower elimination from the blood and higher intratumoral retention than the body. D Based on the hydrophilicity of OTA, the lipophilicity of the octapeptide used decreases. Thus, on the one hand, good contrast of these tumors is maintained and In unaffected organs, i.e., non-target spleen and kidneys. A relatively low absorption of the substance is achieved. In humans the invention¹¹¹In-labeled Peptide directly¹¹¹In-DTPA- (D) Phe¹-Compared to octreotide. Pep of the present invention After intravenous application of Pide (3mCi, 6nmol)¹¹¹In-DTPA- (D) Phe¹-Octreotide Higher intratumoral uptake, lower renal retention, and reduced Absorption was found (Example 8).   Advantageously, as a radionuclide for diagnosis¹¹¹In or^67/68Ga is that sharp A radionuclide that is suitable for diagnosis. The body has the advantage of emitting gamma rays with a relatively low radiation load. As a radionuclide for destruction of tumor tissue⁹⁰Y is bound to the chelator Which emits beta radiation which leads to the destruction of tumor cells in a known manner. The action of the radionuclide, based on the specific binding of this octapeptide, It remains essentially restricted to the diseased cells (Example 8).⁹⁰Y reaches its radiation Distance (β^-Line, 2.3 MeV), is well suited for the treatment of relatively large tumors However, relatively small tumors can also be bound to the peptides of the invention. To¹⁶¹Tb (β^-Line, 0.5 and 0.6 MeV) or¹⁵³Sm (β^-Line, such as 0.7 and 0.8MeV) It can be better treated by other β-radionuclides. For this reason, Tumor patients (the tumors express SSTR 2 to 5, especially SSTR 3) are treated according to the invention. One can consider treating with a mixture of peptides (⁹⁰Labeled with Y And¹⁶¹Radiation for radiotherapy, such as a peptide of the invention labeled with Tb Sexual nuclide "cocktail"). In addition, "cocktails" of various radioisotopes (⁸⁶In Y With labeled peptides⁹⁰Like Y-labeled peptide) or various radioactive Nuclide "cocktail" (¹¹¹In-labeled peptide⁹⁰With a peptide labeled with Y ) Can be made for simultaneous diagnosis and radiation therapy.   Somatostatin receptor-positive tumor disease or endocrine for treatment-related adjustments Repeated use of this radiolabeled peptide for the evaluation of biological diseases Can be.Example Example 1: Chemical synthesis of peptideEllipsis : DOTA: 1,4,7,10-tetraazacyclododecane-N, N ', N', N'-4 acetic acid BOC: tert-butyloxycarbonyl   80 mg DOTA, 74 mg N-hydroxysuccinimide and 80 mg [ε-Boc-lys^Five]-Lanreotide in 15 ml of H_TwoO and 30 ml of N, N-dimethylform Dissolve in amide. 100 mg of N, N'-di-cyclohexylcarbodiimide Add to this and stir the resulting solution at room temperature for 16 hours. So The product of [α-DOTA- (D) -βNaI¹, Ε-Boc-Lys^Five]-Lanreotide is separated to silica gel 60 columns, methylene chloride / methanol / 50% acetic acid (9/1 / 0.1 Purify using 25-7 / 3/1) as solvent. Protected by that Boc The [α-DO] group was prepared using 4 ml of methylene chloride and 2 ml of trifluoroacetic acid. TA- (D) -βNaI¹, Ε-Boc-Lys^Five] -Lanereotide product (in a mixed chamber) 30 minutes). The resulting product [α-DOTA- (D) -βNaI¹, Ε-Boc-Lys^Five]-Lan Leo The tide was precipitated using ether and was run on a C18 reverse phase HPLC column. Water / acetonitrile 1 / 0.1% trifluoroacetic acid solvent mixture Purify. The use of a second H 2 with the use of a solvent mixture of water / acetonitrile / 1% acetic acid Subsequent PLC purification steps give the pure product of the invention as the acetate. FAB-MNH +: 1482                            Conjugation at the N-terminus                           Conjugation at the C-terminus Example 2: of this peptide¹¹¹Radiolabeling with In   The peptide of the present invention was added to a 0.2 mol / l ammonium acetate buffer solution (pH 7, metal Containing no) and in 0.05 mol / l HCl¹¹¹InCl_Three(Carrier And Me⁺⁺Incubate with <0.1 μg / mCi, <1 μg / ml). 0.5mCi¹¹¹ An In / 1 nmol DOTA-lanreotide ratio was made and the reaction mixture was Boil at 100 ° C. for 30 minutes. One part for thin layer chromatography Therefore, its purity is tested. Typically, the radiochemical purity of this product is > 99%. If lower, the product is analyzed by reverse phase LC or HPLC. And refine it. The radioligand was added to 0.075 mol / l NaCl, 0.05 mol / l l NH_FourOAc, 0.2 mol / l ascorbic acid and 0.01% human serum albumin Take up in a solution of min and sterilize by filtration through a 0.2 μm membrane. Example 3: Peptide⁹⁰Radioactive labeling with Y   Proceed as in Example 2, except¹¹¹InCl_ThreeInstead of⁹⁰YCl_Three(1mCi: 1 nmol   DOTA-lanreotide). Example 4: Peptide^67/68Radiolabeling with Ga   For radiolabeling of the peptide of the present invention¹¹¹InCl_ThreeInstead of^67/68GaCl_ThreeFor I have. Example 5:¹¹¹In /⁹⁰In vitro binding of Y-labeled peptides.   The labeled and unlabeled substances of the present invention were tested in saturation and competition experiments. Their binding to tumor cells dispersed in vitro (early tumors, viable cells) and soma Tested for their binding to the tostatin receptor subtypes SSTR 1 through SSTR 5 . To this end, the receptors of each subtype were converted to COS-7 cells using cDNA probes. Was expressed on For comparative studies, other somatostatin receptor agonists Was performed using As a radioligand in comparative tests¹²⁵I-Tyr¹¹-Somato Statin-14 was used. Of the present invention¹¹¹In-labeled peptide⁹⁰Marked with Y No essential differences were found in the binding behavior between the peptide and the peptide. However, the data below shows that the peptide of the invention¹¹¹In-DTPA- (D) Phe¹-Ok There is an essential difference in binding to SSTR 3 and SSTR 4 with threotide It clearly shows thatExample 6: Tumor expressing somatostatin receptor subtype 3   Gastric cancer, colorectal and rectal cancer, skin cancer, breast cancer, pancreas, thyroid tumor, lymphoma, lung cancer , Disseminated neuroendocrine tumors such as various carcinomas, gastric cancer, pheochromocytoma, prostate cancer , Adenocarcinoma, and daughter tumors of these tumors. Example 7: In animal experiments⁹⁰Biodistribution of peptide labeled with Y   In rats.⁹⁰The biodistribution of the Y-labeled peptide was tested. That This radioactively labeled peptide was used for Sprague Dowley rats (180-220 g, 4 MBq, 160 pmol) was applied intravenously into its tail vein. These rats were 1, 24 and After 48 hours, each organ was removed by sacrifice. The following distribution of radioactivity was found :   As is known, each distribution of somatostatin receptor-expressing organs is essentially It shows that it has high absorbency. Spleen and liver (not target organ) The relatively slight absorption of the catalyst is also noticeable. 48 hours after injection of this substance in the skeletal system The blotting after a short time is still very low,⁹⁰Peptides of the invention labeled with Y This suggests a high in vivo stability of the tide. Example 8: In human¹¹¹In-labeled biodistribution and dosimetry   ¹¹¹Biodistribution and dosimetry of the peptide of the present invention labeled with In¹¹¹In-DTPA- (D ) Phe¹-Compared with octreotide biodistribution and dosimetry. In this case, about 6-8 Approximately 3 mCi of one or the other substance was applied intravenously at weekly intervals. This administration Blood, urine and stool samples at different times Was examined. Gamma rays are captured using a gamma camera, and each measurement point is applied. It was kept in contact until 144 hours later. Gamma camera imaging forward projection -Body imaging and more accurate tumor location and size evaluation in front and rear projection Single photon emission tomography (SPET) was included for titer. Individual Relative imaging of organs, tumors and dislocations is determined by aiming at the "target area" Was.   Dosimetry data was computed using the MIRD program.   ¹¹¹In-DTPA-octreotide and¹¹¹The result of the comparison between In-DOTA-lanreotide is This is shown graphically in FIGS. 1A-1D of the accompanying drawings.   From FIG. 1A, the substance of the present invention¹¹¹In-DTPA- (D) Phe¹-Compared to octreotide It can be seen that they are eliminated from the body slightly more slowly. The pepti of the present invention Absorption of the drug into the tumor is essentially higher in direct comparison (see FIG. 1B). Also¹¹¹ In-DTPA- (D) Phe¹-The peptide of the present invention is a priori essential compared to octreotide It is also important to show extremely low intrasplenic (Fig. 1C) and intrarenal (Fig. 1D) absorption. You. This biodistribution is⁹⁰Effective radiation therapy with Y-labeled peptide This organ is based on the fact that this organ Because it is easy to be done.

[Procedure for Amendment] Article 184-4, Paragraph 4 of the Patent Act [Date of Submission] June 18, 1999 (June 18, 1999) [Details of Amendment] New Claims 1. Selectively binds to somatostatin-binding surface receptors on diseased cells, for diagnostic and / or metal compounds for destruction of tumor tissue or other target cells, wherein the macrocycle binds to a somatostatin-14 agonist In a carrier substance to which a chelating agent is bound, a somatostatin-14 agonist represented by the following general formula (I) Wherein said octapeptide is linked to said macrocyclic chelator via its C-terminus or N-terminus. 2. As a chelating agent, compound 1,4,7,10-tetraazacyclododecanetetraacetic acid or compound 1,4,8,11-tetraazacyclotetradecane-1 ′, 4 ′, 8 ′, 11′-tetraacetic acid (TETA A carrier substance according to claim 1, characterized in that: 3. 3. The carrier substance to which the macrocyclic chelating agent according to claim 1 or 2 is bound, wherein the metal compound is a radionuclide. 4. 4. A carrier substance bound with a macrocyclic chelator according to claim 3, wherein ¹¹¹ In or ⁶⁷ Ga is bound as a radionuclide to the chelator for diagnosis. 5. Macrocyclic chelate according to claim 3, characterized in that ⁹⁰ Y or a rare earth such as ¹⁵³ Sm, ¹⁶⁶ Ho or ¹⁶⁵ Dy is bound to the chelating agent as radionuclide to destroy the tumor tissue. The carrier substance to which the agent is bound. 6. A macrocyclic chelator according to claim 3, wherein the corresponding nuclide such as ⁶⁸ Ga, ⁸⁶ Y is bound to the chelator for diagnosis by positron emission tomography. Carrier material. 7. 3. The giant according to claim 1, wherein the metal compound is a heavy metal atom or a metal ion having an atomic number of 20 to 32, 42 to 44, 45 and 57 to 83 for medical imaging for diagnostic purposes. A carrier substance to which a ring chelator is attached. 8. The metal compound is a paramagnetic metal or a metal ion having an atomic number of 21 to 29, 42, 44 or 57 to 71 for nuclear magnetic resonance imaging, particularly Gd ³⁺ , Mn ²⁺ or Dy ^3+. A carrier substance to which a macrocyclic chelator according to claims 1, 2 or 7 is bound. 9. Metal compounds for therapeutic purposes, pharmaceutically acceptable alkali metals, alkaline earth metals or transition metals or metal ions, especially Na ⁺ , K ⁺ , Ca ²⁺ , Fe ^{2 + / 3 +} , Zn ²⁺ and A carrier substance to which a macrocyclic chelator according to claims 1 or 2 is bound, characterized in that it is Mn ²⁺ . 10. A carrier substance according to one of claims 1 to 9 conjugated to a metal compound and a method for the preparation of a diagnostic agent, and a target cell such as a tumor cell, or a somatostatin receptor subtype SSTR2, SSTR3, SSTR4 or SSTR5. Methods for treating expressed leukocyte aggregates. 11. ^A carrier substance according to one of claims 3 and 5, which is bound to a radionuclide, in the form of a mixture of radionuclides, such as a peptide labeled with ⁹⁰ Y and a peptide labeled with ¹⁶¹ Tb, A method used in the manufacture of a medicament for processing. 12. ^In the form of a radioisotope, such as a peptide labeled with ⁹⁰ Y and a peptide labeled with ⁹⁰ Y, or a mixture of radionuclides, such as a peptide labeled with ¹¹¹ In and a peptide labeled with ⁹⁰ Y Use of a carrier material according to one of claims 3 to 6 in combination with a radionuclide in the manufacture of a diagnostic and therapeutic agent for simultaneous diagnosis and radiation therapy. 13. A method of using a carrier substance labeled with a radionuclide for the evaluation of concomitant therapeutic adjustment of a somatostatin-positive tumor disease or endocrine disease by repeated use of a labeled peptide. 14． In preparing a compound according to claim 1, a peptide compound according to 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 a metal A method comprising forming a chelate complex salt.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07K 14/655 A61K 49/02 C 43/00 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, H, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW

Claims (1)

[Claims] 1. Selectively binds to somatostatin-binding surface receptors on diseased cells, for diagnostic and / or metal compounds for destruction of tumor tissue or other target cells, wherein the macrocycle binds to a somatostatin-14 agonist In a carrier substance to which a chelating agent is bound, a somatostatin-14 agonist represented by the following general formula (I) Wherein said octapeptide is linked to said macrocyclic chelator via its C-terminus or N-terminus. 2. As a chelating agent, compound 1,4,7,10-tetraazacyclododecanetetraacetic acid or compound 1,4,8,11-tetraazacyclotetradecane-1 ′, 4 ′, 8 ′, 11′-tetraacetic acid (TETA A carrier substance according to claim 1, characterized in that: 3. 3. The carrier material according to claim 1, wherein the metal compound is a radionuclide. 4. 4. The carrier substance according to claim 3, wherein ¹¹¹ In or ⁶⁷ Ga is bound to the chelating agent as a radionuclide for diagnosis. 5. Carrier material according to claim 3, characterized in that ⁹⁰ Y or a rare earth such as ¹⁵³ Sm, ¹⁶⁶ Ho or ¹⁶⁵ Dy is bound to the chelating agent as radionuclide for destroying tumor tissue. 6. 4. The carrier material according to claim 3, wherein the corresponding nuclide such as ⁶⁸ Ga, ⁸⁶ Y is bound to the chelating agent for diagnosis by positron emission tomography. 7. 3. The carrier according to claim 1, wherein the metal compound is a heavy metal atom or a metal ion having an atomic number of 20 to 32, 42 to 44, 45 and 57 to 83 for medical imaging for diagnostic purposes. material. 8. The metal compound is a paramagnetic metal or a metal ion having an atomic number of 21 to 29, 42, 44 or 57 to 71 for nuclear magnetic resonance imaging, particularly Gd ³⁺ , Mn ²⁺ or Dy ^3+. A carrier material according to claim 1, 2 or 7. 9. Metal compounds for therapeutic purposes, pharmaceutically acceptable alkali metals, alkaline earth metals or transition metals or metal ions, especially Na ⁺ , K ⁺ , Ca ²⁺ , Fe ^{2 + / 3 +} , Zn ²⁺ and A carrier substance according to claim 1 or 2, characterized in that it is Mn2 ⁺ . 10. A carrier substance according to one of claims 1 to 9 combined with a metal compound and a method for the preparation of a diagnostic agent, and a target cell such as a tumor cell, or a somatostatin receptor subtype SSTR2, SSTR3, SSTR4 or SSTR5. Methods for treating expressed leukocyte aggregates. 11. ^A carrier substance according to one of claims 3 and 5, which is bound to a radionuclide, in the form of a mixture of radionuclides, such as a peptide labeled with ⁹⁰ Y and a peptide labeled with ¹⁶¹ Tb, A method used in the manufacture of a medicament for processing. 12. ^In the form of a radioisotope, such as a peptide labeled with ⁹⁰ Y and a peptide labeled with ⁹⁰ Y, or a mixture of radionuclides, such as a peptide labeled with ¹¹¹ In and a peptide labeled with ⁹⁰ Y Use of a carrier material according to one of claims 3 to 6 in combination with a radionuclide in the manufacture of a diagnostic and therapeutic agent for simultaneous diagnosis and radiation therapy. 13. A method of using a carrier substance labeled with a radionuclide for the evaluation of concomitant therapeutic adjustment of a somatostatin-positive tumor disease or endocrine disease by repeated use of a labeled peptide. 14． In preparing a compound according to claim 1, a peptide compound according to 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 a metal A method comprising forming a chelate complex salt.