SOMATOSTATIN RECEPTOR RADIOLIGAND WITH INCREASED UPTAKE

Abstract: A radioligand comprising a peptide capable of binding to a receptor wherein the peptide is coupled to at least one chelating agent, which chelating agent is not coordinated to a metal ion under physiological conditions and a composition comprising said radioligand as a diagnostic or pharmaceutical and a kit for the detection of receptors.

Description: SOMATOSTATIN RECEPTOR RADIOLIGAND WITH INCREASED UPTAKE The invention relates to a radioligand, its use as a pharmaceutical (therapeutic or diagnostic) and a method for the detection of peptide receptors in cell material. Radiolabelled compounds are being used in modern medicine for both diagnostic and therapeutic purposes. In the case of radionuclidetherapy, the radioactive compound is used to treat, for instance, tumours or other groups of malignancies or unwanted cells. In diagnostic methods radioactive compounds are being used to visualise certain parts of the body or specific tissues, for instance bones, or again, a tumour. One of the disadvantages of radiolabelled compounds is the radiotoxicity of these compounds for normal tissue. The selective interaction of radioactive compounds is expressed in the target/non-target ratio of these compounds. In case of a high target/non-target ratio, the radiotoxicity of the radioactive compounds can increase to an undesirable high level, too high for normal and healthy tissue Minimisation of radiotoxicity and/or exposure of tissue to radiation is therefore an ongoing incentive for research in this area. Minimisation can, in general, be accomplished by using smaller doses of radioactive compounds and/or by using more effective radioactive compounds. Effectiveness of a radioactive compound used for these purposes regards two aspects. One aspect is the characteristics of the radioactive compound in relation to its purpose (diagnosis or therapy) . Half-life and emitted energy are the main features. The other aspect is concerned with the characteristics of the radioactive compound in relation to the ability to express its activities at a specific location, for instance a tumour or a specific cell-type. A disadvantage related to the second aspect of the use of radiolabelled compounds is that the radiolabelled compound will spread to a certain extent throughout the entire body or material causing a lower target/non-target ratio. A low target/non-target ratio (e.g. tumour/non-tumour ratio) may result in a smaller therapeutic window. It is a significant advantage if the uptake of radiolabelled compounds by the targeted tissue, whether a tumour or otherwise, for diagnostic or therapeutic purposes is increased and the target/non-target ratio and/or therapeutic window is enhanced. The radiolabelled compounds which are used for the diagnostic and therapeutic purposes generally comprises a ligand which contains a radiolabel. The radiolabel is usually a radionuclide specifically selected for the purpose. In case of diagnosis, in general radionuclides with relative low radiotoxicity can be used, the most important criterion is the detection of the nuclide. This can be accomplished with radiolabels with a lower energy over a larger distance such as γ-emitter or low energy β- emitters. For radiotherapy nuclides are needed for which an important criterion is the ability to express anti- proliferative activities in a tumour, e.g. attack the DNA of a tumourcell. In general this requires radiolabels which emit particles with higher energy over a relative small distance. Particles which have such high Linear Energy Transfer are α- emitters or high energy β-emitters. The radioligand in general consists of a part which associates with parts of tissue or cell material by, for instance, binding to a substance associated with a cell surface such as a receptor. By carefully selecting the characteristics of the binding part, selective labelling of proteins, receptors, tissue etc. is achieved. The radiolabel coupled to the binding part subsequently provides the detectability or the therapeutic effect of the radioligand. The radiolabel can be detected using conventional techniques. One of the techniques which uses this concept is peptide receptor scintigraphy. Peptide receptor scintigraphy is a technique in which a receptor for a peptide is detected by contacting the receptor with a radiolabelled peptide or analogue of the peptide, which radiolabelled peptide or its analogue is capable of binding to the receptor. The labelled peptide is subsequently detected by scintigraphy. Peptide receptor scintigraphy with radiolabelled peptides or analogues is a sensitive and specific technique to show in vivo and in vitro the presence and abundance of peptide receptors in cell material. Mammalian tissues containing (peptide) receptors can be visualised or treated using this technique. For instance, many endocrine tumours express somatostatin (SS) receptors (SSR) (Reubi et al. 1992) . The presence of a high density of SSR on these tumours has been the basis for the successful development of the technique of SSR scintigraphy. In this method an SS-analogue carrying a γ-emitting radiolabel is injected. The SS-analogues will subsequently bind to the SSRs. In this way a radiolabel can be targeted to tissue having SSRs. Because of the presence of the radiolabel the tissue can be visualised using a γ-camera (Krenning et al. 1993) . By this technique the SSR-positive tumours and their metastases can be localised. One of the known SS-analogues is octreotide (OCT, Formula 1) . I I D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr (ol) Formula 1: Octreotide ® (OCT) . Radioiodinated OCT derivatives are in general attractive radioligands for use in nuclear medicine. The short retention time of radioactivity following the internalisation of radioiodinated OCT derivatives by such tumours is a serious drawback in this respect. It has been found (Breeman et al. 1998) that the retention time of radioactivity is increased in tumours by administration of radioiodinated OCT analogues derivatised with a DTPA (Diethylene TriaminePentaacetic Acid) group. When comparing t 125 I-D-Tyr 1 ]OCT [DTPA 0 , 125 I-D-Tyr 1 ]OCT [ 125 I-Tyr 3 ]OCT and [DTPA 0 125 I-Tyr 3 ]OCT, the last one was found to have the greatest retention time in OCT receptor positive tissue. Unfortunately, the kidney to tumour ratio was also very high, which seriously hinders the potential application of [DTPA 0 , 125 ι-Tyr 3 ]OCT in peptide receptor radionuclide therapy of OCT expressing tumours. An important disadvantage of the currently known radiolabelled chelated peptides is, as addressed earlier, that the increased uptake in the target-organ or -tissue, is combined with a corresponding uptake in the kidneys. The maximum level of radiolabelled compounds in the kidneys determine the therapeutic window wherein the compounds can be applied. A high kidney-uptake therefor limits the window wherein these peptides can be used. Surprisingly, we have now found a group of compounds which, when coupled to an SS or -analogue, result in a radioligand with an increased internalisation rate. The internalisation rate is the relative amount of the radioligand which is incorporated in the cell instead of remaining bound to the receptor on the cell membrane. For instance in nuclear therapy, a radioligand with an increased internalisation rate will transport the radioactive compound closer to the nucleus of the cell (increasing the target/non- target ratio) and hence be more effective in its anti- proliferative effects. The coupling of such a compound to an SS-analogue does not prevent the internalisation of OCT after binding to SSR. The OCT analogues retain an intact high affinity binding characteristics to the somatostatin receptor. The invention accordingly comprises a peptide capable of binding to a receptor wherein the peptide is coupled to at least one chelating agent, which chelating agent is not coordinated to a metal ion under physiological conditions. An important advantage of the present invention is that the radioligand according to the invention not only has an increased uptake in the receptor positive tissue but also expresses a lower uptake in the kidney. This results in an increased tumour/kidney ratio and hence in a larger window for the application of these peptides. The in vivo uptake of radioactivity in somatostatin receptor positive tissues at several time points after the injection of the radioligand also depends on its rate of metabolism, locally as well as in the kidneys and liver which are major clearance sites for the clearance of OCT derivatives. The radioligand according to the invention therefore has an increased uptake and an improved tumour/kidney ratio. Without being bound by theory, the chelating agent bond to the ligand according to the invention is thought to interfere with the degradation of the OCT analogues by peptidases and to induce the accumulation of the radioligand or its metabolic products in tissue or cellmaterial. A preffered chelating agent according to the invention is DOTA (Tetraazacyclododecane tetraacetic acid ). Chelating agents in general are organic compounds with the capability of capturing (ir)reversibly metal ions. Usually these compounds have coordinating atoms or groups in their structure such as N, O, S, P, acid groups (COO ~ ) , ester groups (COOR) and the like. In order to bind the positive metal ions, these coordinating atoms or groups carry negative charges (COO-)or are free-electron donors (N|). Chelating agents are known in many varieties such as crown ether, crown thioethers, EDTA (Ethylene diaminetetraacetic acid) and many others. For the purpose of the present invention a chelating agent which is coordinated or bound to a metal ion is considered 'full', whereas a chelating agent which is not bound to a metal ion is called 'empty'. For the purpose of the invention a 'empty* ligand means that a charge remains on the chelating agent. The receptor mediated uptake of the radioligands is favoured by the presence of the 'empty' chelating agent. The empty chelating agent may be able to influence the charge distribution of the α-amino acid to which the chelating agent is bound. The charge present at the α-amino acid can be neutralised, delocalised or dissipated by the chelating agent. Accordingly, another aspect of the invention relates to a radioligand comprising a peptide capable of binding to a receptor wherein the peptide is coupled to a compound which can neutralise, delocalise or dissipate positive or negative charges in the peptide. In a different embodiment of the invention the peptide can also be coupled to a succinimide-containing group or the like. The succinimide group is an example of a charge dissipating group. In another embodiment of the invention a spacer is positioned between the peptide and the ligand. The spacer itself can also attribute to the charge dissipating, delocalising or neutralising effect. As a spacer any compound known in the art will suffice. In another embodiment of the invention, a toxin is coupled to the peptide. The toxin can then be transported to the receptor. In this way the toxin can be selectively delivered. Possible toxins are small toxins, such as doxorubicine, vincrystine, vinblastine, adriamycine and the like. A preferred embodiment of the invention is one wherein the receptor is a peptide binding receptor, preferably a tumour associated receptor. In principle any receptor will suffice. The requirement for the receptor is mostly based on the presence of the receptor in the targeted organ or tissue and that the receptor can be sufficiently labelled to allow for the detection or treatment of the tumour. Without being bound by theory, the difference in behaviour can be thought to arise from a difference in affinity for metals. DTPA has a very high affinity for a widespread range of metal ions, which it will bind with a high rate and a high yield. DOTA is a preferred chelating agent because of the different affinity for metal ions. DOTA expresses more selective binding characteristics and only under enforced conditions, such as increased temperatures, is the ligand coordinating towards metal ions. It is therefore likely that after administration originally empty DTPA becomes full by coordination or binding to metal ions present in the tissue or body such as for example Ca , Mg 2+ and the like. The peptide according to the invention can be any peptide capable of binding to its receptor. With a radioligand according to he invention the receptor can be selectively labelled. The peptide having affinity for a receptor is preferably a peptide receptor in a tumour, more preferably a somatostatin receptor. The peptide according to the invention can also comprise peptides such as adrenocorticotrope hormone (ACTH) , Molecular recognition units (MRU) , Gonadotropine releasing (GnRH) , Bombesine (gastro-releasing hormone) , cholesystokinine (Substance-P) and the like and analogues thereof. According to the invention, the radioligand has not only an enhanced internalisation and/or binding rate with somatostatin receptors but also in other receptors, for instance those for the peptides mentioned above. A preferred embodiment of the invention is therefor one wherein the peptide contains between about 6 and about 40 aminoacids. The lower limit is determined by the minimal desired selectivity of the peptide for the receptor. A more preferred embodiment of the invention is one wherein the peptide is somatostatin or a somatostatin analogue, preferably wherein the somatostatin analogue is octreotide or analogues thereof, preferably tyrosine-octreotide, more preferably 3-tyrosine-octreotide. To impart detectability or a therapeutic effect of the radioligand, a radiolabel is coupled to the peptide. The replacement of Phe by Tyr in OCT allows the radio-iodination of the phenolic group of the molecule and results in the 125 I-labelled radioligand [DOTA°- 125 I-Tyr 3 ]OCT. Other radiolabels are also suitable for imparting radiodetectability or therapeutic effects. A preferred embodiment of the invention therefore is a radioligand wherein the radiolabel is selected from 123 I, 125 I, 211 At. Chelating agents can also be coupled to other positions at the peptide. These chelating agents are coupled independently from the substituent at the α-position and thus provide alternate positions for the incorporation of other radiolabels than iodine or the like, such as β-emitters (Yttrium-90) or Auger-electron emitting isotopes, which make it possible, depending on the specific characteristics of the radiolabel, to create radiolabelled radioligands with an increased uptake, which are applicable in radiotherapy. Thus another embodiment of the invention is a radioligand wherein two or more chelating agents are coupled to the peptide. One of the chelating agents is empty and coupled to the α-position, the other is coupled at any other position of the peptide and can contain a radiolabel. A preferred embodiment of the invention is therefor a radioligand wherein two or more chelating agents are coupled to the peptide wherein one of the chelating agents contains a radionuclide. In a preferred embodiment of the invention the radioligand encompasses a radiolabel suitable for diagnostic or therapeutic purposes. The invention accordingly encompasses compositions which are suitable as a pharmaceutical and/or a diagnostic. By using compounds with an increased internalisation rate according to the invention the detection of somatostatin receptors and the like can be achieved with a higher signal to noise ratio. An aspect of the invention therefor comprises an method for the detection of somatostatin receptors in cell material by contacting said cell material or tissue with a composition comprising the radioligand according to the invention. An embodiment of the invention comprises also a kit for the detection of somatostatin receptor positive material in vivo or in vitro . The invention is further illustrated by the examples without limiting the scope of the invention. Materials and methods Abbreviations: DMEM, Dulbecco's Minimal Essential Medium; FCS, foetal calf serum; MEM, Minimal Essential Medium. Compounds: [Tyr 3 ]OCT and [DTPA 0 ,Tyr 3 ]OCT were synthesised according to the solid phase method using Fmoc-Threoninol attached to Rink acid resin (Schmidt et al. 1997) . The corresponding DTPA-derivatives were synthesised using tributyl-DTPA as the acylating agent by solid phase method (Srinavasan et al. 1997) . [DOTA 0 ,Tyr 3 ]OCT was synthesised by an analogous route (Desphande et al., J. Nucl. Med. 31, 1990, 473-479; Otte et al. Eur. Journ. Nucl. Med. 1997, 24, 792- 795) . 1251-labelling of the SS-analogues was performed as described (Bakker et al. 1990). OCT (octreotide ® ) was obtained from Sandoz (Basel, Switzerland, Pertussis toxin (PT) and phenyl arsine oxide (PAO) were purchased form Sigma (St. Louis, USA) . Cell culture: AtT20 mouse pituitary tumour cell were cultured in DMEM with 10% foetal calf serum as described (Hofland et al. 1995) . Human insulinoma cell were dissociated with collagenase and cultured in MEM with 10% FCS as described (Lamberts et al. 1990). Internalisation studies: The cells were washed twice with internalisation medium (DMEM supplemented with HEPES (30 mM) , L-glutamine (2 mM) , sodium pyruvate (1 mM) , penicillin (10 5 U/L) , fungizone (0.5 mg/L) and 0.2% bovine serum albumin( Fraction V, Sigma Chemical Co., St. Louis and allowed to adjust to the medium for 1 h at 37 °C. Approximately 200.00 cpm radioligand (0.1 nM final concentration) were added to the medium and the cells were incubated at 37 °C for a period up to 4 h in quadruplicate without or with excess unlabelled OCT (lOOnM) to determine non-specific internalisation. Treatment of the cells with low pH was used to distinguish between surface bound (acid-releasable ) and internalised (acid resistant) radioligand. Controls for the internalisation experiments have been described in detail in (Hofland et al. 1995) . SSR binding studies on membrane homogenates of AtT20 cells were carried out as described in detail previously in (Hofland et al. 1995) . Animal studies: The in vivo studies of tissue distribution of radioactivity after the injection of 2 MBq (0.5 μg) of the radioiodinated compounds were carried out in male Wistar rats as described in detail previously (de Jong et al. 1997) . Rats (n=3 per treatment group) were sacrificed at several time points after the injection of the radioisotopes and radioactivity in the pituitary, pancreas and adrenals was measured in a γ-counter. Animals were kept, treated, and cared for in accordance with the guidelines approved by the European Community on November 24, 1986. Analysis of Data: Statistical analysis of data was performed using one way analysis of variance (ANOVA) , multiple comparisons were made by the Newman-Keuls test. Data are expressed as mean ± SE. Results Saturation experiments revealed that [ 125 I-Tyr 3 ]OCT, [DTPA 0 , 125 1-Tyr 3 ]OCT and [DOTA 0 , 125 1-Tyr 3 ]OCT bound with comparable high affinity (Kd-values of 0.2, 0.2,and 0.3 nM, respectively) to membrane preparations of AtT20 cells. The three radioligands were internalised by AtT20 cells in a time-dependent manner (Figure 1) . In comparison with [ 125 I-Tyr 3 ]OCT and [DTPA 0 , 125 1-Tyr 3 ]OCT, [DOTA°, 125 I- Tyr 3 ]OCT was internalised in a significantly higher amount (approximately 5-fold higher after 4h of incubation, p<0.01 at all time points studied) . Internalised radioactivity dissociated rapidly from the cells to 62 ' , 24 and 40% of radioactivity t=0 min, after 4 h. In agreement with the high internalisation rate of [DOTA 0 , 125 1-Tyr 3 ]OCT, human insulinoma cells also internalised [DOTA 0 , 125 1-Tyr 3 ]OCT in a significant (p<0.01) higher amount (6.7-fold) in comparison with [DTPA°, 125 I- Tyr 3 ]OCT (Table 1) . PT or PAO (an inhibitor of the process of receptor mediated endocytosis) (Gibson et al. 1989, Nouel et al. 1997) significantly reduced the amount of internalisation of the three radioligands to the same extent, demonstrating that all three compounds are internalised by a receptor mediated process (Figure 2) . Consonant with the high amount of internalisation of [DOTA 0 , 125 I-Tyr 3 ]OCT by AtT20 and human insulinoma cells a considerable higher uptake of this radioligand was found in SSR-positive organs in vivo in rats. Figure 3 shows that uptake, 4 h post-injection, of [DOTA 0 , 125 1-Tyr 3 ]OCT was significantly higher (p<0.01) in comparison, with that of [ 125 I-Tyr 3 ]OCT and [DTPA 0 , 125 I-Tyr 3 ]OCT in the pituitary (10- fold) , pancreas (5-fold) and adrenals (8-fold) . Also inline with the in vitro studies is the rapid dissociation of radioactivity from these organs. Table 1. Internalisation of [DTPA 0 , 125 I-Tyr 3 ]OCT and by [DOTA 0 , 1 5 I-Tyr 3 ]OCT a primary culture of human insulinoma cells. radioligand amount internalised (% dose specific ± SE) [ DTPA 0 , 125 1 -Tyr 3 ] OCT 0.09 ± 0.00 [ DOTA 0 , 125 I-Tyr 3 ] OCT 0.60 ± 0.04 a a - p<0.01 vs [DTPA 0 , 125 1-Tyr 3 ]OCT. Incubation time: 4h; n=4 wells per treatment group; 10 cells per well. Value in bracket represents the fold-difference with [DTPA°, 125 I- Tyr 3 ] [ 125 I-Tyr 3 ]OCT. Description of the Figures: Figure 1: Time dependent internalisation of [ 125 I-Tyr 3 ]OCT (Δ) , [DTPA°, 125 I-Tyr 3 ] OCT (O) , and [DOTA 0 , 125 1-Tyr 3 ]OCT (D) by mouse AtT20 pituitary tumour cells. Figure 2: Effect of pertussis toxin (PT) and phenyl arsine oxide (PAO) on the internalisation of [ 125 I-Tyr 3 ]OCT, [DTPA 0 , 125 1-Tyr 3 ]OCT, and [DOTA 0 , 125 I-Tyr 3 ]OCT by mouse AtT20 pituitary tumour cells. PAO (lOμM) was added simultaneously with the radioligand, while the cells were pre-treated for 24 h with pertussis toxin (100 μg/L) prior to the internalisation experiment. p<0.01 vs. control (C) . Figure 3: Uptake of radioactivity in pituitary, pancreas and adrenals in rats after the injection of 2 MBq (0.5 μg) [ 125 I- Tyr 3 ]OCT (D) , [DTPA 0 , 125 1-Tyr 3 ]OCT (O) or [DOTA°, 125 I- Tyr 3 ]OCT (Δ) . Values are expressed in % injected dose (%ID) of radioactivity per gram tissue. Uptake of radioactivity in these organs could be displaced by more than 90 % by co- injection with 0.5 mg unlabelled octreotide®, demonstrating that the uptake represented specific binding to SSR. REFERENCES Reubi JC, Laissue J, Krenning E, Lamberts SWJ. 1992. Somastatin receptors in human cancer: incidence characteristics functional correlates and clinical implications. J. Steroid Biochem. Mol. Biol. 43: 27-35. Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WAP, Kooij PPM, Oei HY, van Hagen M, Postema PTE, de Jong M, Reubi JC, Visser TJ, Reijs AEM, Hofland LJ, Koper JW, Lamberts SWJ. 1993. Somastatin receptor scintigraphy with 1:11 In-DTPA-D- Phe 1 ]- and I-Tyr -octreotide: The Rotterdam experience with more than 1000 patients. Eur. J. Nucl. Med. 20: 716-731. Breeman WAP, de Jong M, Bernard B, Hofland LJ, Srinavasan A, van der Pluijm M, Bakker WH, Visser TJ, Krenning EP. 1998.Tissue distribution and metabolism of radioiodinated DTPA 0 , D-Tyr 1 and Tyr 3 derivatives of octreotide in rats. Anticancer research 18: 83-90. Schmidt MA, Wilhelm RR, Srinavasan A. 1997. Synthesis of peptide alcohols using Rink acid resin. American Peptide symposium, Nashville Tennessee, P159. Srinavasan A, Schmidt MA. 1997.Tri-t-butyl-DTPA: a versatile synthon for the synthesis of DTPA containing peptides. American Peptide Symposium Nashville Tennessee, P110. Bakker WH, Krenning EP, Breeman WAP, Koper JW, Kooij PPM, Reubi JC, Klijn JG, Visser TJ, Docter R, Lamberts SWJ. 1990. Receptor scintigraphy with a radioiodinated somastatin analogue: radiolabelling, purification, biologic activity, and in vivo application in animals. J. Nucl. Med. 31: 1501- 1509. Hofland LJ, van Koetsveld PM, Waaijers M, Zuyderwijk J, Breeman WAP, Lamberts SWJ. 1995. Internalisation of the radioiodinated somatostatin analogue [ 125 I-Tyr 3 ] octreotide by mouse and human pituitary tumour cells: increase by unlabelled octreotide. Endocrinology 136: 3698-3706. Lamberts SWJ, Hofland LJ, Reubi JC, Bruining HA, Bakker WA, Krenning EP. 1990. Parallel in vivo and in vitro detection of functional somatostatin receptors in human endocrine pancreatic tumours: consequences with regard to diagnosis, localisation and therapy. J. Endocrin. Metab. 71: 566-574. de Jong M. , Bakker WH, Krenning EP, Breeman WAP, van der Pluijm ME, Bernard BF, Visser TJ, Jermann E, Behe M, Powell P, Macke HR. 1997. Yttrium-90 and indium-Ill labelling, receptor binding and biodistribution of [DOTA 0 , D-Phe 1 , Tyr 3 ]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur. J. Nucl. Med. 24: 368-371. Gibson AE, Noel RJ, Herlihy JT, Ward, WF. 1989. Phenylarsine oxide inhibition of endocytosis: effects on asialofetuin internalisation. Am. J. Physiol. 257 :C182-C184. Nouel D, Gaudriault G, Houle M, Reisine T, Vincent J-P, Mazella J, Beaudet A. 1997. Differential internalisation of somatostatin in COS-7 cell transfected with sstl and sst2 receptor subtypes: a confocal microscopic study using novel fluorescent somatostatin derivatives. Endocrinology 138:296- 306.

Claims: CLAIMS I. A radioligand comprising a peptide capable of binding to a receptor wherein the peptide is coupled to at least one chelating agent, which chelating agent is not coordinated to a metal ion under physiological conditions. 2. A radioligand comprising a peptide capable of binding to a receptor wherein the peptide is coupled to a compound which can neutralise, delocalise or dissipate positive or negative charges in the peptide. 3. Radioligand according to claim 1 wherein the chelating agent is coupled at the α-position of the peptide. 4. Radioligand according to claim 2 wherein the compound is coupled at the α-position of the peptide. 5. Radioligand according to claim 1-4, wherein a spacer is positioned between the chelating agent and the peptide. 6. Radioligand according to claim 1-5, wherein the receptor is a peptide binding receptor, preferably a receptor associated with a tumour. 7. Radioligand according to claim 1-6, wherein the peptide is based on somatostatin, ACTH, MRU, GnRH, cyclic peptides and the like and analogues thereof. 8. Radioligand according to claim 1-7, wherein the peptide contains between about 6 and about 40 aminoacids. 9. Radioligand according to claim 1-8, wherein the peptide is somatostatin or a somatostatin analogue. 10. Radioligand according to claim 1-9, wherein the somatostatin analogue is octreotide or analogues thereof, preferably tyrosine-octreotide, more 3-tyrosine-octreotide. II. Radioligand according to claim 1, wherein the chelating agent is DOTA. 12. Radioligand according to claim 2, wherein the peptide- coupled-compound contains succinimide-containing groups. 13. Radioligand according to claim 1, wherein two or more chelating agents are coupled to the peptide. 14. Radioligand according to claim 13 , wherein one of the chelating agents contains a radionuclide. 15. Radioligand according to claim 2, wherein the charge- influencing compound coupled to the peptide is a chelating agent. 16. Radioligand according to claim 1 or 2, wherein a radiolabel is attached to the radioligand. 17. Radioligand according to claim 15, wherein the radiolabel is selected from 123 I, 125 I, 131 I, 211 At. 18. A composition comprising a radioligand according to claim 1-17. 19. Composition according to 18 as a pharmaceutical. 20. Composition according to 19 as a diagnostic. 21. Method for the detection of somatostatin receptors in cell material by contacting said cell material with a composition according to claim 18. 22. Kit comprising a composition according to claim 20, and means for the detection of somatostatin receptor-positive cell material in vivo or in vitro.

Inventors: BREEMAN WOUT A, DE JONG MARION, KRENNING ERIC PAUL, SRINIVASAN ANANTHACHARI, VISSER THEOFILUS JOHANNES, DE JONG, MARION
Applicants: BREEMAN WOUT A, JONG MARTINUS THEODORUS MARIA, KRENNING ERIC PAUL, MALLINCKRODT INC, SRINIVASAN ANANTHACHARI, VISSER THEOFILUS JOHANNES, BREEMAN, WOUT, A., DE JONG, MARTINUS, THEODORUS, MARIA, KRENNING, ERIC, PAUL, MALLINCKRODT INC., SRINIVASAN, ANANTHACHARI, VISSER, THEOFILUS, JOHANNES
Application year: 1999
Main classification: A61K51
IPC codes: A61K47, A61K51, A61P35, C07K7, C07K14, G01N33