CONJUGATES OF METAL COMPLEXES AND OLIGONUCLEOTIDES, WHICH SPECIFICALLY BOND TO SPECIFIC TARGET STRUCTURES, AGENTS CONTAINING THESE CONJUGATES, THEIR USE IN NMR DIAGNOSIS AS WELL AS PROCESS FOR THEIR PRODUCTION

Abstract: This invention relates to chemically modified oligonucleotide conjugates that contain a complexing agent or complex that is bound by a connecting component to the oligonucleotides. In this case, the oligonucleotides are modified in a way that prevents or at least significantly inhibits the degradation by naturally occurring nucleases. The oligonucleotide radical can bond specifically and with high bonding affinity to target structures and can thus produce a specific therapeutic or diagnostic effect by the bound complexing agent or complex.

Description: Conjugates of Metal Complexes and Oligonucleotides. Which Specifically Bond to Specific Target Structures. Agents Containing these Conjugates. Their Use in NMR Diagnosis as well as Process for their Production This invention relates to the object characterized in the claims, i.e., oligonucleotide conjugates, which exhibit a complexing agent or a complex. These conju¬ gates are used in the field of NMR diagnosis. The imaging diagnosis has achieved great progress in the past decades and is continuously further developing. It is now possible to make visible the vascular system, most organs and many tissues in the living body without major intervention. Diseases are diagnosed in many cases, because they lead to clear changes of shape, size and position of anatomical structures in the body. Such anatomical data from the inside of the body can be obtained by x-ray technology, ultrasonic diagnosis and magnetic resonance tomography. The efficiency of each of the mentioned technologies can be improved by the use of pharmaceutical agents for enhancement of the natural con¬ trasts of the tissues and body fluids in the resulting picture. The pharmaceutical agents in question are introduced in body cavities or injected in blood vessels, with the purpose of changing the contrast of the cavities or vessels. In addition, they are spread through the bloodstream in the organism and can change the visibility of organs and tissues. In exceptional cases, such sub¬ stances are bound to certain structures in the body and/or actively transported and/or excreted from the latter. In this way, functions can also be made visible in individual cases and used to diagnose diseases. A general problem is the diagnosis and localization of pathological changes at a time at which no clear changes of shape, structure and circulation of the organs and tissues in question are available. Such a diagnosis and follow-up is of decisive importance, e.g., in the case of tumor diseases, including the search for metasta- ses, the assessment of an undersupply of tissues with oxygen and in the case of certain infections as well as metabolic diseases. The now available imaging diagnostic methods are essentially dependent on the availability of pharmaceuti¬ cal preparations which accumulate at sites of otherwise undetectable pathological changes. The contrast media found commercially at this time are quite predominantly so-called nonspecific prepara¬ tions. They spread passively into those spaces into which they are introduced, e.g., by injection. In the past, many substances and -substance classes have been identified that can detect or can be expected to have a specificity with respect to their distribution in the living organism. Examples in this respect are, in addition to the antibodies, lectins, all types of recep¬ tor-bound substances, cells, membranes and membrane com¬ ponents, nucleic acids, natural metabolites and their derivatives, as well as countless pharmaceutical sub¬ stances. Peptides have been and are also studied with special care. EP-A-0 285 057 describes nucleotide-complexing agent conjugates, which are not suitable for use as in vivo diagnostic agents, i.a., because of the in vivo instabil¬ ity of the nucleotides used, and also hardly meet the other requirements of compatibility and pharmacokinetics. Many US patents, such as, for example, US Patent No. 4,707,440, deal with modified polymers, which contain a detectable chemical group. The polymers can be polynuc- leotides and oligonucleotides, but they are neither sta¬ bilized against a degradation by naturally occurring nuc¬ leases nor selected by a special process, so that they bond specifically with high bonding affinity to target structures. Special embodiments of these detectable molecules are named in US Patents No. 4,843,122 and 4,943,523. An individual nucleotide, modified in this way, is claimed in US Patent No. 4,952,685. The use of these agents in imaging processes is disclosed in US Patent No. 4,849,208. The object of this invention is the provision of specifically bonding diagnostic agents for the detection of target structures, by which, for example, the visuali¬ zation of organs, tissues and their pathological changes in vitro and in vivo is made possible. It has now been found that this object is achieved by oligonucleotide conjugates, which in addition to an oligonucleotide radical exhibit a complexing agent, bound by a direct bond or a connecting component, and whose oligonucleotiide radical is modified so that the degrada¬ tion by naturally occurring nucleases -is prevented or at least significantly inhibited. Object of this invention are: 1. Oligonucleotide conjugates consisting of an oligonucleotide radical N and n substituents (B-K) , in which B stands for a direct bond or a connecting com¬ ponent to the oligonucleotide radical, and K means a complexing agent or complex of elements of atomic numbers 21-29, 42, 44 or 58-70, characterized in that oligonuc¬ leotide radical N exhibits a modification, which prevents or at least significantly inhibits the degradation by naturally occurring nucleases. 2. In preferred form, the oligonucleotide conju¬ gates of this invention exhibit the general formula N-(B-K) n (I) in which N is an oligonucleotide, which bonds specifically with high bonding affinity to other target structures and exhibits modifications that significantly reduce the degradation by naturally occurring nucleases, B is a chemical bond or a connecting component, which produces the connection between N and K, and K is a complexing ligand, which exhibits at least one element of the atomic numbers mentioned in point 1 and n is a number between 1 and 30. 3. Compound according to point 1 or 2, in which N is an oligonucleotide with 5 to 200 nucleotides, wherein a) the 2'-position of the sugar unit, independently of one another, is occupied by the following groups: a group -OR, in which R means an alkyl radical with 1 to 20 carbon atoms, which optionally contains up to 2 hydroxyl groups and which optionally is interrupted by 1-5 oxygen atoms, a hydrogen atom, a hydroxyl group, a fluorine atom, an amine radical, an amino group and hydroxyl groups present in 3'- and 5' -positions optionally are etherified with radical R and/or b) the phosphodiesters, being used as the internuc- leotide bond, independently of one another, are replaced by phosphorothioates, phosphorodithioates or alkylphos- phonates, especially preferably methyl phosphonate, and/or c) the terminal radicals in 3 ' - and 5' -positions are linked by an internucleotide bond as described in b) and/or d) it optionally contains an internucleotide bond as described in b) , which links 3'3'- or 5' -5' -position, and/or e) it optionally contains a phosphodiester bond as described under b) , which connects, esterlike, two thymi- dines by a C 2 -C 10 hydroxyalkyl radical respectively in 3-position or connects an analogously substituted thy¬ midine radical, esterlike, with a hydroxyl group in 2'- or 3'- or 5'-position and/or f) optionally modified internucleotide bonds are contained preferably on the ends of the polynucleotide, especially preferably on thymidines . 4. Compound according to point 3, wherein oligonuc- leotide N comprises 10 to 100 nucleotides. 5. Compound according to one of points 1 to 4, wherein N is an oligonucleotide, which bonds specifically with high bonding affinity to other target structures and which can be obtained in that a mixture of oligonucleo- tides containing random sequences is brought together with the target structure, and certain oligonucleotides exhibit an increased affinity to the target structure relative to the mixture of the oligonucleotides, the lat¬ ter are separated from the remainder of the oligonucleo- tide mixture, then the oligonucleotides with increased affinity to the target structure are amplified to obtain a mixture of oligonucleotides that exhibits an increased portion of oligonucleotides that bond -on the target structures. 6. Compound according to one of points 1 to 5, wherein N is an oligonucleotide, which specifically bonds with high bonding affinity to other target structures, and which can be obtained in that a) first, a DNA strand is produced by chemical synthesis, so that on the 3' -end, this DNA strand exhibits a defined sequence, which is complementary to a promoter for an RNA-polymerase and at the same time com¬ plementary to a primer of the polymerase chain reaction (PCR) , and so that this DNA strand exhibits a defined DNA sequence on the 5' -end, which is complementary to a pri¬ mer sequence for the polymerase chain reaction, and the sequence between the defined sequences contains a random sequence, and in that b) this DNA strand is transcribed in an RNA strand with the help of an RNA-polymerase, and nucleotides are offered to the polymerase, which are modified in the 2' -position of the ribose unit, and in that c) the RNA oligonucleotides, produced in this way, are brought together with the target structure on which the oligonucleotide specifically is to bond, and in that d) those oligonucleotides that have bound on the target structure are separated first together with the target structure from the nonbinding oligonucleotides and then the bound oligonucleotides are separated again from the target structure, and in that e) these target-structure-specific RNA oligonucleo- tides are transcribed with the help of reverse transcrip¬ tase in a complementary DNA strand, and in that f) these DNA strands are amplified using the defined primer sequences with the polymerase chain reac¬ tion, and in that g) the DNA oligonucleotides amplified in this man¬ ner are then transcribed again with the help of the RNA- polymerase and with modified nucleotides in RNA-oligonuc- leotides, and in that h) above-mentioned selection steps c) to g) option- ally are repeated often until the oligonucleotides, which are characterized by a high bonding affinity to the tar¬ get structure, are sufficiently selected, and then the sequences of the thus obtained oligonucleotides option¬ ally can be determined. 7. Compound according to point 6, wherein the tar¬ get structure is selected from macromolecules, tissue structures of higher organisms, such as animals or humans, organs or parts of organs of an animal or human, cells, tumor cells or tumors. 8. Compound according to one of points 1 to 7, wherein connecting component (s) B is (are) bound a) to the 4'-end of oligonucleotide radical N reduced in 4'-position by the CH--0H group and/or b) to the 3' -end of oligonucleotide radical N reduced in 3'-position by a hydrogen atom and/or c) to the phosphodiester bridge (s), reduced by the OH group (s) , between two nucleotides in each case and/or d) to 1 to 30 nucleobase(s) , which is (are) reduced by a hydrogen atom respectively in 5-, 8-position(s) and/or the amino group(s) in 2-, 4- and 6-position(s) . 9. Compound according to point 8a) or 8b), wherein B has general formula X-Y-Z 1 , which is connected on the X side with the complexing agent or complex and on the Z side with the oligonucleotide, in which X stands for a direct bond, an -NH or -S group, Y stands for a straight-chain or branched-chain, saturated or unsaturated Ci-Cj o alkylene chain, which optionally contains 1-2 cyclohexylene, 1-5 imino, 1-3 phenylene, 1-3 phenylenimino, 1-3 phenylenoxy, 1-3 hydroxyphenylene, 1-5 amido, 1-2 hydrazido, 1-5 carbonyl, 1-5 ethylenoxy, a ureido, a thioureido, 1-2 carboxyalkyl- imino, 1-2 ester groups, 1-3 groups of Ar, in which Ar stands for a saturated or unsaturated 5- or 6-ring, which optionally contains 1-2 heteroatoms selected from nitro¬ gen, oxygen and sulfur and/or 1-2 carbonyl groups; 1-10 oxygen, 1-5 nitrogen and/or 1-5 sulfur atoms, and/or optionally is substituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thioxo, 1-3 carboxy, 1-5 carboxy-C 1 -C 4 -alkyl, 1-5 ester, 1-3 amino, 1-3 hydroxy-C 1 -C 4 -alkyl, 1-3 C^-C-- alkoxy groups, and Z 1 stands for -C0NH-CH 2 -4' , -NH-CO-4', -O-P(O)R^NH- CH 2 -4', -0-P(0)R 1 -0-CH 2 -4' , -O-P(S)R^O-S' or -O-P(O)R' -O- 3', in which 4' or 3' indicates the linkage to the termi¬ nal sugar unit(s) and R 1 stands for O", S", a C 1 -C 4 alkyl or NR 2 R 3 group, with R 2 and R 3 meaning hydrogen and C.-C 4 alkyl radicals. As cyclic structures Ar, especially cyclic saturated or unsaturated alkylenes with 3 to 6, especially 5 or 6 C atoms, which optionally can contain heteroatoms, such as N, S or O, are suitable. For example, cyclopentylene, pyrrolylene, furanylene, thiophenylene, imidazolylene, oxazolylidene, thiazolylene, pyrazolylene, pyrrolidylene, pyridylene, pyrimidylene, maleinimidylene and phthal- imidylene groups are considered. 10. Compound according to point 8c), wherein B has general formula X-Y-Z 2 , in which Z 2 , in the bridge linking two adjacent sugar units, 0 S •P-0-5' and/or •P-0-5' 3' 3' stands for the group -NR 2 ' , -0- or -S-, and X, Y and R 2 have the meaning indicated in point 9. As radicals Y of connecting component Z x -Y-X or Z 2 -Y-X, there can be mentioned as examples the radicals - (CH 2 ) 6 -NH-CS-NH-C 6 H 4 -CH(CH 2 C0 2 H) -CH 2 -C0-NH-CH 2 -CH(OH) -CH 2 - , - (CH 2 ) 6 -NH-CS-NH-C 6 H 4 -CH 2 -, - (CH 2 ) 6 -NH-CO-CH 2 -, -(CH 2 ) 6 -NH-CO-CH 2 -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 6 -, - (CH 2 ) 6 -S- (CH 2 ) 2 - , -(CH 2 ) 6 -S-(CH 2 ) 6 -, -(CH 2 ) 2 -NH-CO-, - (CH 2 ) 6 -NH-C0-, - (CH 2 ) S -S- (CH 2 ) -NH-CO, -(CH 2 ) s -S-(CH 2 ) 6 -NH-CO-, - (CH 2 ) t -S-CH-CH 2 -CO-;N- (CH 2 ) s -NH-NH-CO-CH 2 -0-C 6 H 4 -CH 2 -, - (CH 2 ) 6 -S-CH-CH 2 -CO;N- (CH 2 ) 2 -0- (CH 2 ) 2 -NH-C0-CH 2 -, o^" "^ - (CH 2 ) 6 -S-CH-CH 2 -CC^_N- (CH 2 ) 2 -CO-ΝH- (CH 2 ) 3 -, - (CH 2 ) 6 -S-CH-CH 2 -CO^N- (CH 2 ) 2 -CO-NH- (CH 2 ) 4 -, ^CO""" ^ - (CH 2 ) 6 -S- (CH 2 ) ) 6 - 11. Compound according to point 8d) , wherein B has general formula X-Y-Z 3 , in which Z 3 stands for an -NH group or a direct bond to the nucleobase and X and Y have the meaning indicated in point 9. As radicals Y of connecting component Z 3 -Y-X, there can be mentioned as examples the radicals -CH 2 -CO-NH-CH 2 - CH(OH) -CH 2 -, -NH-CO-CH 2 -CO-NH-CH 2 -CH(OH) -CH 2 - , -CO-NH-CH 2 -CH 2 -NH-, -CH 2 -S-CH 2 -CH 2 -NH- , -CH 2 -S-CH 2 -CH 2 - , - (CH 2 ) -S-CH 2 -CH 2 -NH- , -CO-CH 2 -S-CH 2 -CH 2 -NH-, -CO-CH 2 -S- (CH 2 ) 6 -NH-, -CH=CH-CO-NH-CH 2 -CH 2 -NH-, -CH=CH-CH 2 -NH-, -CsC-CH 2 -NH- or -CO-CH 2 -CH 2 -NH-CH 2 -CH 2 -NH- . As bonding sites in the case of the purine bases, especially 8-position is suitable, and in the case of the pyrimidine bases, 5-position is suitable. Purely for¬ mally, in this case, a hydrogen atom of the respective base is substituted by radical B-K. But a linkage can also take place by amino groups optionally contained in 2-, 4- or 6-position, thus, e.g., by the 2-amino group in guanine, by the 6-amino group in adenine or by the 4-amino group in cytosine. In this case, a hydrogen atom of the respective amino group is respectively substituted by radical B-K. 12. Compound according to one of the preceding points, wherein the metal complex contains gadolinium, manganese or iron as an imaging element. 13. Process for detecting a target structure, wherein one or more of the compounds according to one of the preceding points are brought together with the sample to be studied in vivo or in vitro and based on the sig¬ nal, it is detected whether the target structure, on which oligonucleotide N bonds specifically and with high bonding affinity, is present in the sample. 14. Process for noninvasive diagnosis of diseases, wherein one or more of the compounds according to one of points 1 to 12 is brought together with the target struc¬ ture to be studied in vivo and based on the signal, it is detected whether the target structure, on which oligonuc¬ leotide N specifically bonds, is present in the organism to be studied. The number of imaging substituents B-K linked with the oligonucleotide radical is, on the one hand, limited by the value of the oligonucleotide, but is never greater than 30. According to the invention, 1 to 20 substitu- ents B-K are preferred. The value of oligonucleotide radical N is in prin¬ ciple not limited. For this invention, oligonucleotides with 5 to 200 nucleotides are practicable, especially preferred are oligonucleotides with 10 to 100 nucleo¬ tides. Oligonucleotides usable according to the invention are stabilized against degradation by nucleases occurring in vivo. Unmodified oligonucleotides or polynucleotides are cleaved in vivo by endonucleases and exonucleases. The degradation reaction in the RNA series begins with an activation of the 2'-hydroxy group. Other catabolic enzymes are, e.g., ribozymes, which cleave the phosphodi- ester bond of RNS (see Science 261, 709 (1993) ) . The in vivo stability of RΝS derivatives can be increased by partial or complete substitution of the 2'-hydroxyl group by other substituents. Such substituents are, e.g., alkoxy groups, especially the methoxy group (see, e.g., Chem. Pharm. Bull. 13_, 1273 (1965), Biochemistry 10. 2581, (1971)), a hydrogen atom, a fluorine atom (see, e.g., Can. J. Chem. £6., 1131 (1968)) or an amino group (see, e.g., J. Org. Chem. 2., 714 (1977)) . Several of these substituents, as well as others, can also be intro¬ duced at the 2' -position using the methods disclosed in U.S. application Ser. o. 08/264,029, filed June 22, 1994. Other possibilities for stabilizing the internuc¬ leotide bond are the replacement of one or two oxygen atoms in the phosphodiester bridge while forming phos- phorothioates (Trends Biochem. Sci. ϋ, ~~ (1989)) or phosphorodithioates (J. Chem. Soc, Chem. Commun. 591 (1983) and Nucleic Acids Res. 12/ 9095 (1984)) and the use of alkylphosphonates instead of phosphodiesters (Ann. Rep. N. Y. Acad. Sci. 5H, 220 (1988)). The stabilization can be achieved in that the hydroxyl groups in 2'-position of the ribose units, inde¬ pendently of one another, are modified. Such a modifica¬ tion can be achieved by a replacement of this hydroxyl group by an OR group, a halogen atom, especially a fluor¬ ine atom, a hydrogen atom or an amine radical, especially by an amino group. Radical R of the alkoxy group stands, in this case, for a straight-chain or branched alkyl radical with 1 to 20 C atoms, such as methyl, ethyl, pro¬ pyl, isopropyl, butyl, tert-butyl, pentyl or hexyl or a cyclic unsubstituted or substituted alkyl radical with 4 to 20 C atoms, such as cyclopentyl or cyclohexyl. Another stabilization of the polynucleotide takes place in that the phosphodiesters being used as internuc¬ leotide bond are replaced partially or completely, and independently of one another, by phosphorothioates, phos- phorodithioates or alkylphosphonates, especially prefer- ably lower alkylphosphonates, such as methyl phosphonate. These internucleotide bonds can also be linked to the terminal radicals in 3'- and 5'-positions or else also connect 3'-3'- or 5' -5' -positions. The phosphodiester bond makes possible further linkages by hydroxyalkyl radicals, which are present on nitrogen or carbon atoms of the nucleobases, thus, for example, two thymidines can be linked by the hydroxyalkyl chains present in 3-posi¬ tion or two purine bases by the radicals present in 8-positions. The linkage can also take place to hydroxyl groups in 2'- or 3'- or 5' -position. The modified inter¬ nucleotide bonds can optionally occur preferably on the ends of the polynucleotide, and they are especially pre¬ ferably bound on the thymidine. According to the invention, oligonucleotide radicals N used are not limited to specific oligonucleotide sequences. But preferred are those oligonucleotides that bond specifically with high bonding affinity to other target structures. A process for identifying suitable oligonucleotides, which are required as initial substances for the conju¬ gates according to the invention, is described in US Patent 5,270,163. This process, termed SELEX, can be used to make a nucleic acid ligand to any desired target molecule. The SELEX method involves selection from a mixture of candidate oligonucleotides and step-wise iterations of binding, partitioning and amplification, using the same general selection scheme, to achieve virtually any desired criterion of binding affinity and selectivity. Starting from a mixture of nucleic acids, preferably comprising a segment of randomized sequence, the SELEX method includes steps of contacting the mixture with the target under conditions favorable for binding, partition¬ ing unbound nucleic acids from those nucleic acids which have bound specifically to target molecules, dissociating the nucleic acid- arget complexes, amplifying the nucleic acids dissociated from the nucleic acid-target complexes to yield a ligand-enriched mixture of nucleic acids, then reiterating the steps of binding, partitioning, dissocia¬ ting and amplifying through as many cycles as desired to yield highly specific, high affinity nucleic acid ligands to the target molecule. The basic SELEX method has been modified to achieve a number of specific objectives. For example, U.S. pat¬ ent application Ser. No. 07/960,093, filed October 14, 1992, describes the use of SELEX in conjunction with gel electrophoresis to select nucleic acid molecules with specific structural characteristics, such as bent DNA. U.S. patent application Ser. No. 08/123,935, filed Sep¬ tember 17, 1993, describes a SELEX-based method for selecting nucleic acid ligands containing photoreactive groups capable of binding and/or photocrosslinking to and/or photoinactivating a target molecule. U.S. patent application Ser. No. 08/134,028, filed October 7, 1993, describes a method for identifying highly specific nuc¬ leic acid ligands able to discriminate between closely related molecules, termed Counter-SELEX. U.S. patent application Ser. No. 08/143,564, filed October 25, 1993, describes a SELEX-based method which achieves highly efficient partitioning between oligonucleotides having high and low affinity for a target molecules. U.S. pat¬ ent application Ser. No. 07/964,624, filed October 21, 1992, describes methods for obtaining improved nucleic acid ligands after SELEX has been performed. U.S. patent application Ser. No. 08/400,440, filed March 8, 1995, describes methods for covalently linking a ligand to its target. The SELEX method encompasses the identification of high-affinity nucleic acid ligands containing modified nucleotides conferring improved characteristics on the ligand, such as improved in vivo stability or improved delivery characteristics. Examples of such modifications include chemical substitutions at the ribose and/or phosphate and/or base substitutions. SELEX-identified nucleic acid ligands containing modified nucleotides are described in U.S. patent application Ser. No. 08/117,991, filed September 8, 1993, that describes oligonucleotides containing nucleotide derivatives chemically modified at the 5- and 2'-positions of pyrimidines. U.S. patent application Ser. No. 08/134,028, supra, describes highly specific nucleic acid ligands containing one or more nucleotides modified with 2' -amino (2'-NH 2 ), 2' -fluoro (2'-F), and/or 2'-0-methyl (2' -OMe). U.S. patent appli¬ cation Ser. No. 08/264,029, filed June 22, 1994, describes oligonucleotides containing various 2'-modified pyrimidines. The SELEX method encompasses combining selected oli¬ gonucleotides with other selected oligonucleotides and non-oligonucleotide functional units as described in U.S. patent applications Ser. No. 08/284,063, filed August 2, 1994, and Ser. No. 08/234,997, filed April 28, 1994, respectively. These applications allow the combination of the broad array of shapes and other properties, and the efficient amplification and replication properties, of oligonucleotides with the desirable properties of other molecules. In its most basic form, the SELEX process may be defined by the following series of steps: 1) A candidate mixture of nucleic acids of differ- ing sequence is prepared. The candidate mixture gener¬ ally includes regions of fixed sequences (i.e., each of the members of the candidate mixture contains the same sequences in the same location) and regions of randomized sequences. The fixed sequence regions are selected either: (a) to assist in the amplification steps described below, (b) to mimic a sequence known to bind to the target, or (c) to enhance the concentration of a given structural arrangement of the nucleic acids in the candidate mixture. The randomized sequences can be totally randomized (i.e., the probability of finding a base at any position being one in four) or only partially randomized (e.g., the probability of finding a base at any location can be selected at any level between 0 and 100 percent) . 2) The candidate mixture is contacted with the selected target under conditions favorable for binding between the target and members of the candidate mixture. Under these circumstances, the interaction between the target and the nucleic acids of the candidate mixture can be considered as forming nucleic acid-target pairs between the target and those nucleic acids having the strongest affinity for the target. 3) The nucleic acids with the highest affinity for the target are partitioned from those nucleic acids with lesser affinity to the target. Because only an extremely small number of sequences (and possibly only one molecule of nucleic acid) corresponding to the highest affinity nucleic acids exist in the candidate mixture, it is generally desirable to set the partitioning criteria so that a significant amount of the nucleic acids in the candidate mixture (approximately 5-50%) are retained during partitioning. 4) Those nucleic acids selected during partitioning as having the relatively higher affinity to the target are then amplified to create a new candidate mixture that is enriched in nucleic acids having a relatively higher affinity for the target. 5) By repeating the partitioning and amplifying steps above, the newly formed candidate mixture contains fewer and fewer unique sequences, and the average degree of affinity of the nucleic acids to the target will generally increase. Taken to its extreme, the SELEX process will yield a candidate mixture containing one or a small number of unique nucleic acids representing those nucleic acids from the original candidate mixture having the highest affinity to the target molecule. The SELEX patents and applications describe and ela¬ borate on this process in great detail. Included are targets that can be used in the process; methods for partitioning nucleic acids within a candidate mixture; and methods for amplifying partitioned nucleic acids to generate enriched candidate mixture. The SELEX patents and applications also describe ligands obtained to a num¬ ber of target species, including both protein targets where the protein is and is not a nucleic acid binding protein. Therefore, the SELEX process can be used to provide high affinity ligands of a target molecule. Target molecules are preferably proteins, but can also include among others carbohydrates, peptidoglycans and a variety of small molecules. As with conventional proteinaceous antibodies, nucleic acid antibodies (oligo¬ nucleotide ligands) can be employed to target biological structures, such as cell surfaces or viruses, through specific interaction with a molecule that is an integral part of that biological structure. Oligonucleotide lig- ands are advantageous in that they are not limited by self tolerance, as are conventional antibodies. Also nucleic acid antibodies do not require animals or cell cultures for synthesis or production, since SELEX is a wholly in vitro process. As is well-known, nucleic acids can bind to complementary nucleic acid sequences. This property of nucleic acids has been extensively utilized for the detection, quantitation and isolation of nucleic acid molecules. Thus, the methods of the present inven¬ tion are not intended to encompass these well-known bind- ing capabilities between nucleic acids. Specifically, the methods of the present invention related to the use of nucleic acid antibodies are not intended to encompass known binding affinities between nucleic acid molecules. A number of proteins are known to function via binding to nucleic sequences, such as regulatory proteins which bind to nucleic acid operator sequences. The known ability of certain nucleic acid binding proteins to bind to their natural sites, for example, has been employed in the detection, quantitation, isolation and purification of such proteins. The methods of the present invention related to the use of oligonucleotide ligands are not intended to encompass the known binding affinity between nucleic acid binding proteins and nucleic acid sequences to which they are known to bind. However, novel, non- naturally-occurring sequences which bind to the same nucleic acid binding proteins can be developed using SELEX. In particular, the oligonucleotide ligands of the present invention bind to such target molecules which comprise a three dimensional chemical structure, other than a polynucleotide that binds to said oligonucleotide ligand through a mechanism which predominantly depends on Watson/Crick base pairing or triple helix binding, where- in said oligonucleotide ligand is not a nucleic acid hav¬ ing the known physiological function of being bound by the target molecule. It should be noted that SELEX allows very rapid determination of nucleic acid sequences that will bind to a protein and, thus, can be readily employed to determine the structure of unknown operator and binding site sequences which sequences can then be employed for appli¬ cations as described herein. SELEX is thus a general method for use of nucleic acid molecules for the detec- tion, quantitation, isolation and purification of pro¬ teins which are not known to bind nucleic acids. In addition, certain nucleic acid antibodies isolatable by SELEX can also be employed to affect the function, for example inhibit, enhance or activate the function, of specific target molecules or structures. Specifically, nucleic acid antibodies can be employed to inhibit, enhance or activate the function of proteins. The oligonucleotides used in the conjugates according to the invention are obtained in a preferred embodiment according to the process described below. Thus, suitable oligonucleotides can be obtained in that a mixture of oligonucleotides containing random sequences is brought together with the target structure, and certain oligonucleotides exhibit an increased affin¬ ity to the target structure relative to the mixture of the oligonucleotides, the latter are separated from the remainder of the oligonucleotide mixture, then the oligo¬ nucleotides with increased affinity to the target struc¬ ture are amplified to obtain a mixture of oligonucleo¬ tides that exhibits an increased portion of oligonucleo¬ tides that bond to the target structures. In the process, a DNA strand is first produced in a preferred way by chemical synthesis. On the 3'-end, this DNA strand has a known sequence, which is used as promo¬ ter for an RNA polymerase and at the same time is comple¬ mentary to a primer sequence for the polymerase chain r ction (PCR) . In an especially preferred embodiment, tiiis is the promoter for the T7 RNA-polymerase. Then, on this promoter, a random sequence is synthesized on the promoter. The random sequence can be obtained in that the suitable four bases are fed in the same ratio in the synthesis machine. Thus, completely random DNA sequences result. In a preferred embodiment, the length of the random sequence is about 15 to 100 nucleotides. On this DNA piece with the random sequence, another DNA sequence is synthesized which can be used for the polymerase chain reaction (PCR) . After synthesis of this DNA strand, the latter is transcribed with the help of an RNA polymerase in a com¬ plementary RNA strand. In a preferred embodiment, in this case, the T7 RNA polymerase is used. In the tran- scription, the nucleotides that are modified are offered to the RNA polymerase. In an especially preferred embod¬ iment, the ribose is modified in 2' -position. In this case, this can be a substitution of the hydrogen atom or the hydroxyl group by an alkoxy group, preferably meth¬ oxy, amino or fluorine. The RNA oligonucleotides pro¬ duced in this manner are then introduced in the selection process. In the selection process, the RNA oligonucleotides are brought together with the target structure. Target structure is defined as a structure on which the oligo¬ nucleotide is to bond specifically and with high affin¬ ity. Such structures are, e.g., macromolecules, tissue structures of higher organisms, such as animals or humans, organs or parts of organs, cells, especially tumor cells or tumors. For this purpose, the target structure must not absolutely be in pure form, it can also be present on a naturally occurring organ or on a cell surface. Strin¬ gency may applied to the selection process by the addi¬ tion of polyamino (tRNA, heparin) , plasma or whole blood to the SELEX reaction. If an isolated protein is involved here, the latter can be bound to a solid phase, for example, a filter. In the selection, an excess of the target structure relative to the RNA mixture is used. In the incubation, the spe¬ cific oligonucleotide molecules bond on the target struc- tures, while the unbound oligonucleotides are separated from the mixture, for example by washing. Then, the oli¬ gonucleotide molecules are separated from the target molecules or removed by washing with suitable buffers or solvents. With the help of the reverse transcriptase, the RNA oligonucleotide found is then transcribed in the comple¬ mentary DNA strand. Since the DNA strand to be obtained exhibits primer sequences (or promoter sequences) on both ends, an ampli- fication of the DNA sequences found can be performed sim¬ ply with the help of the polymerase chain reaction. The DNA oligonucleotides amplified in this way are then transcribed with the help of the RNA polymerase again in RNA oligonucleotides and the thus obtained RNA oligonucleotides can be used in a further selection step (as described above) . After separating the bonding RNA oligonucleotides, obtained in the second selection step, from the target molecules, the latter are again transcribed in DNA with the help of the reverse transcriptase, the thus obtained complementary DNA oligonucleotides are amplified with the help of the polymerase chain reaction and then tran- scribed again with the help of the RNA polymerase to the RNA oligonucleotides, which are available for a further selection step. It has turned out that the desired high specifici¬ ties and high bonding affinities can be obtained if the selection steps are repeated several times. Rarely will the desired oligonucleotide sequence be obtained as early as after one or two selection steps. As soon as the desired specificity and bonding affinity between target structure and oligonucleotide is obtained, the oligonuc- leotide(s) can be sequenced and as a result, the sequence of the specifically bonding oligonucleotides can be determined. Especially advantageous in this process is that this process can be used not only with suitable proteins, but also in vivo. But the above-mentioned selection process can also be performed on purified target structures. But it is essential, especially for the in vivo diagnosis, that the specificity of the oligonucleotides is provided for the target structure in the living environment. Therefore, the selection processes can also be performed on cells or cell cultures, on tissues or tissue sections, on perfused organs and even on living organisms. In this case, it is advantageous that the modified oligonucleotides can withstand the degradation by the almost omnipresent RNAs. As a result, the desired oligo¬ nucleotide sequences are themselves accumulated on living organisms in the selection processes, since corresponding naturally occurring oligonucleotides would be degraded by the RNAs. Oligonucleotide radical N can exhibit one or more connecting components B, or substituents B-K, which can be selected independently of one another. Claimed are oligonucleotide conjugates, which contain 1 to 30 identi¬ cal or 2 to 30 different connecting components B. Connecting component B connects oligonucleotide radical N with a complexing agent or complex K. Advantageously, polydentate, open-chain or cyclic complexing ligands with 0, S and N donor atoms can be used. As examples for complexing agent-radicals K, there can be mentioned the polyaminopolycarboxylic acids reduced by a hydrogen, a hydroxy group and/or an acetic acid group ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, trans-1,2-cyclohexanediaminetetraacetic acid, 1,4,7,10-tetraazacyclododecanetetraacetic acid, 1,4,7-triazacyclononanetriacetic acid, 1,4,8,ll-tetraazatetradecanetetraacetic acid, 1,5,9-triazacyclododecanetriacetic acid, 1,4,7, 10-tetraazacyclododecanetriaacetic acid and 3,6,9,15-tetraazabicyclo- [9,3,1] -penta-l(15) ,11,13- trienetriacetic acid. Suitable complexing agents are described, e.g., in EP 0 485 045, EP 0 071 564 and EP 0 588 229, in DE 43 10 999 and DE 43 11 023. To illustrate the various possibilities for complex¬ ing agents K according to this invention, reference can be made to figures 1 and 2, in which some advantageous structures are compiled. These figures are meant as a selection and do not limit this invention in any way in the represented complexing agents. Complexing agent K can contain all paramagnetic metal ions usual in NMR diagnosis. Suitable isotopes according to the invention are selected from the elements of atomic numbers 21-29, 42, 44 or 58-70. These are especially the divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58- 70. Suitable ions are, for example, the chromium(III) , iron(II) , cobalt(II), nickel(II), copper(II), praseo- dymium(III), neodymium(III) , samarium(III) and ytter¬ bium(III) ion. Because of their very great magnetic moment, especially preferred are the gadolinium(III) , terbium(III) , dysprosium(III) , holmium(III) , manganese (II), erbium(III) and iron(III) ion. Those carboxylic acid groups that are not required for complexing the above-mentioned elements can option- ally be present as salts of an inorganic or organic base, such as alkali- or alkaline-earth metal hydroxides and -carbonates, especially sodium- and potassium hydroxide, or ammonia and alkylamines, or amino acid or as ester or amide. The invention further relates to processes for the production of the conjugates according to the invention. Thus, conjugates in which the substituent is bound on the 5'-end of the oligonucleotide can be obtained by reaction of the oligonucleotide with a phosphoramidite derivative (Tetrahedron 4j?, 1925-1963 (1993)). To this end, the 5'-hydroxy group of the oligonucleotide is reacted with a phosphoramidite of general formula PR' (NR 2 ' ' )0R' ' ' . In this case, R' stands for an alkyl, alkoxy or arylalkoxy group, optionally containing N, N0 2 , Si or S0 2 , with 1 to 20 C atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propyloxy, butyloxy, benzyloxy or phenylethoxy, which optionally can be substituted. As substituents, especially cyano and nitro groups are used. Advantageously, for example, methoxy, / 9-cyanoethoxy or nitrophenylethoxy groups can be used. Especially preferred are 3-cyanoethoxy groups. R' ' is a C.-C, alkyl radical, and ethyl and propyl radicals are especially suitable. Preferred are isopropyl radicals. R' ' ' is an alkyl or arylalkyl group, optionally containing S, O, N, CN, N0 2 or halogen, with 1 to 20 C atoms. Preferably, protected amino and thioalkyl radi¬ cals as well as protected amino and thiooxaalkyl radicals are used. Especially preferred are 6-amino-hexyl, 6-thiohexyl, 3,6, 9-trioxa-ll-amino-undecyl and 3,6-dioxa- 8-amino-octanyl groups. As protective groups, generally usual N- or S-protective groups can be used. For exam¬ ple, trifluoroacetyl, phthalimido and monomethoxytrityl groups are suitable. In an especially preferred embodiment of this invention, 3-cyanoethyl-N,N-diisopropylamino-6- (tri- fluoroacetamido) -1-hexyl-phosphoramidite is used as phosphoramidite derivative. In another preferred embodiment of this invention, ■3-cyanoethyl-N,N-diisopropylamino- (3,6,9-trioxa-ll- phthalimido-1-undecyl) -phosphoramidite is used as phos¬ phoramidite derivative. In a further embodiment of the invention, connecting component B is bound on the 3'-end of oligonucleotide N in a way analogous to the one described above by a phos- phorus-containing group. The above-described reaction between oligonucleotide and phosphoramidite can take place as solid-phase reac¬ tion, and the oligonucleotide can also be present on the column o'f an automatic synthesizer. After an oligo- nucleotide of the desired sequence has been obtained and exposure of the 5' -hydroxy group of the oligonucleotide has taken place, e.g., with trichloroacetic acid, it is reacted with the phosphoramidite and the reaction product is oxidized and released. Then, the thus obtained oligo- nucleotide derivative is coupled on the terminal amino or thiol group with the complexing agent or complex K optionally by another linker group. The radical bound in the first step by the phosphorus-containing group on the oligonucleotide then forms, together with the optionally present additional linker group, connecting component B. The linkage between oligonucleotide and the complex¬ ing agent can also take place so that the free 5' -hydroxyl group of the oligonucleotide is reacted with a complexing agent or complex, which terminally carries a bondable phosphorus radical. Such a one can be described by the formula in which R a stands for a C^ alkyl radical, which optionally carries a cyano radical in /3-position, R b stands for a secondary amino group and K and B have the indicated meaning or the formula in which R c stands for a trialkylammonium cation and K and B have the mentioned meaning, or the formula c) O S || || K-B-P-0-R c or K-B-P-0-R c in which R d stands for an aryl radical, optionally substituted with one or more halogen atom(s) and/or one or more nitro group(s), or a C x -C 6 alkyl radical, which optionally is substituted in 3-position with a cyano radical, and K, B and R c have the mentioned meaning, and when using a radical of formula a) , an oxidation step to phosphate takes place after completion of the coupling reaction. In both cases, radical -0R a or -OR c optionally can be cleaved off in a hydrolysis. The linkage of the oligonucleotide derivative by the linker with the complexing agent or complex K can take place also as a solid-phase reaction on the column of an automatic synthesizer. The compound according to the invention can then be isolated from the solid vehicle by dissolving. The linkage of the oligonucleotide with the linker can take place not only by the 5' -OH group of the sugar of the terminal nucleotide, but also by other functional groups, which can be generated from the 5' -OH group, such as, e.g., an amino or carboxy group. Such nucleotides carrying amino or carboxy groups are known and can be produced easily. The synthesis of a 5' -deoxy-5-amino- uridine is described in J. Med. Chem. 22. 1273 (1979) as well as in Chem. Lett. ___., 601 (1976) . 4' -Carboxy-5' - deoxy-uridine is accessible as described in J. Med. Chem. 21. 1141 (1978), or Nucleic Acids Symp. Ser. 2, 95 (1981) . The linkage with the complexing agent then takes place by a linker carrying a carboxylic acid or amino group in a way known to one skilled in the art. The linker then forms connecting component B together with the -NH-CH 2 -4' or the -CO-4' group. It can be pointed out that the distribution of the conjugates according to the invention into a nucleotide radical, a connecting component and a complexing agent or complex takes place purely formally and thus independent- ly of the actual synthetic structure. Thus, e.g., in the above-mentioned case, the group -NH-CH 2 -4' or -CO-4' is considered necessary to connecting component B, while the oligonucleotide reduced in 4'-position by a CH 2 -OH group is designated as oligonucleotide radical N. A process for the production of conjugates, in which the connecting component takes place on the phosphodi- ester or phosphorothioate bridges reduced by the OH groups, consists in the fact that first two sugar units are linked to a dinucleotide (see, e.g., Chem. Lett. 1305 (1993)) . In this case, there first results a triester of formula in which U stands for a corresponding alkylene radical and V stands for a protected amino or sulfur group. After cleavage, e.g., of the amino protective group, the complexing agent can optionally be linked, in a way known to one skilled in the art, by a linker with the amino group -- e.g., in the form of an amide bond. The linker then forms connecting component B together with group O-U-V (in which V stands for a group -NH) . An alternative process consists in that the phospho- triester passed through intermediately (e.g., by reaction with 1, 5-diaminopentane) is subjected to an aminolysis (see Biochemistry 22/ 7237 (1988) or J. Am. Chem. Soc. 110. 4470 (1988) ) . The thus obtained compounds of formula can be linked as described above with the complexing agent optionally by a linker. For coupling purposes, dinucleoside-phosphate-mono- thiotriesters are also suitable (see J. Am. Chem. Soc. 111. 9117 (1983) and Nucl. Acids Res. 23., 5205 (1992)) . The nucleobases offer an especially great variety for linking the complexing agents with the nucleotides. A linkage by the amino groups in 2-position in the pur¬ ines and in 4-position in the pyrimidines can take place directly. But it is often more advantageous first to modify the purines or pyrimidines and to link these deri- vatized bases with the complexing agents (optionally by additional linkers) . Suitable derivatized nucleobases are described, e.g., in Biochemie [Biochemistry] 7_l, 319 (1989), Nucl. Acids Res. 16., 4937 (1988) or Nucleosides Nucleotides 10., 633 (1991) . An alternative process for linking by the nucleo¬ bases consists in the palladium-catalyzed coupling of bromine or iodine nucleobases with functionalized radi¬ cals (Biogenic and Medical Chemistry Letter V, 361 (1994)) . By these functionalized radicals, the complex¬ ing agent, according to known methods, can then option¬ ally be linked with the nucleobase by another linker. As functionalized radicals in 5-position of the pyrimidine and in 8-position of the purine, an acrylic ester or an allylamine can be mentioned as examples (see Nucl. Acids Res. Ii, 6115 (1986) and Nucl. Acids Res. 1£, 4077 (1988) ) . Another alternative process for preparing 5-position modified pyrimidines, especially for intro¬ ducing functional groups such as carbonyl, alkenyl or aryl groups at the 5-position, and an improved palladium catalyst capable of coupling modifying groups at the 5-position of pyrimidines is described in U.S. patent application Ser. No. 08/076,735, filed June 14, 1993. The halogen derivatives used as precursors can be obtained as described, e.g., in Biophys. J. 44., 201 (1983), J. Am. Chem. Soc. j5£, 1242 (1964) or Chem. Commun. 17 (1967) . The production of the metal complexes from the metal-free oligonucleotide conjugates according to the invention takes place as disclosed in DE 34 01 052, by the metal oxide or a metal salt (for example, the nitrate, acetate, carbonate, chloride or sulfate) of the desired metal isotope in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) being dis¬ solved or suspended and reacted with the solution or suspension of the equivalent amount of the oligonucleo¬ tide conjugate containing the complexing agent and then, if desired, present acidic hydrogen atoms being substitu¬ ted by cations of inorganic and/or organic bases or amino acids or free carboxylic acid groups being converted to amino acid amides. The neutralization of possibly still present free acid groups takes place with the help of inorganic bases (e.g., hydroxides, carbonates or bicarbonates) of, e.g., sodium, potassium, lithium, magnesium or calcium and/or organic bases, such as, among others, primary, secondary and tertiary amines, such as, e.g., ethanolamine, morpho- line, glucamine, N-methyl- and N,N-dimethyl-glucamine, as well as basic amino acids, such as, e.g., lysine, argi¬ nine and ornithine, or of amides of originally neutral or acid amino acids. The production of the pharmaceutical agents accor¬ ding to the invention also takes place in a way known in the art, by the oligonucleotide conjugates according to the invention -- optionally by adding the additives usual in galenicals -- being suspended or dissolved in aqueous medium and then the suspension or solution optionally being sterilized or sterilized by filtration. Suitable additives are, for example, physiologically harmless buf¬ fers (such as, for example, tromethamine) , additives of complexing agents (such as, for example, diethylenetri- aminepentaacetic acid) or -- if necessary -- electro¬ lytes, such as, for example, sodium chloride or -- if necessary -- antioxidants, such as, for example, ascorbic acid, or, especially for oral forms of administration, mannitol or other osmotically active substances. If suspensions or solutions of the agents according to the invention in water or physiological salt solution are desired for enteral administration or other purposes, they can be mixed with one or more adjuvant (s) usual in galenicals (e.g., methyl cellulose, lactose, mannitol) and/or surfactant (s) (e.g., lecithins, Tween tR1 , Myrj tR1 ) . The pharmaceutical agents according to the invention preferably contain 0.1 μmol/1 to 3 mmol/1 of the oligo¬ nucleotide conjugates according to the invention and are generally dosed in amounts of 0.1 μmol/kg - 1 mmol/kg (relative to the contained paramagnetic metal) . They are intended for enteral and parenteral administration. This invention further relates to a process for detecting target structures. In this case, one or more of the above-described compounds are brought together in vivo or in vitro with the sample to be studied. In this case, oligonucleotide radical N bonds specifically and with high bonding affinity to the target structure to be detected. If the target structure is present in the sample, it can be detected there based on the signal. The process is especially suitable for a noninvasive diagnosis of diseases. In this case, one or more of the above- described compounds is administered in vivo and it can be detected based on the signal whether the target struc¬ ture, on which oligonucleotide radical N bonds specifi- cally and with high affinity, is present in the organism to be studied. Another embodiment of this invention comprises a diagnosis kit for in vivo detection of target structures, which contains one or more of the above-mentioned com- pounds as freeze-dried material as well as the physiolog¬ ically compatible liquid necessary to prepare the agent. The conjugates and agents according to the invention meet the many requirements that are to be set for a phar¬ maceutical agent for NMR diagnosis. They are distin- guished especially by a high specificity or affinity relative to the target structure in question. Relative to known oligonucleotide conjugates, the conjugates according to the invention exhibit an especially high in vivo stability. This was achieved by a substitution of the 2' -hydroxy group and the incorporation of modified thymidine sequences on the terminal hydroxyl groups of the oligonucleotides. Surprisingly, the specificity of the oligonucleotide is significantly impaired neither by this modification nor by the coupling with the complexing agent. Other advantages are the controllable pharmaco- kinetics as well as the necessary compatibility. Brief Description of the Drawings Various other objects, features and attendant advan¬ tages of the present invention will be more fully appre¬ ciated as the same becomes better understood when consid- ered in conjunction with the accompanying drawings, wherein: Figure 1 shows a selection of cyclic complexing agents K, which can be used advantageously for this invention. "b" marks the bonding site on connecting component B. Figure 2 shows a selection of open-chain complexing agents K, which can be used advantageously for this invention. The following examples are to illustrate these inventions in more detail. The polynucleotides described in the examples contain modified compounds. They mean: A, U, C, G the nucleotides contain 2'-OCH 3 * : the internucleotide bond is a methyl phosphonate **: the internucleotide bond is a monothiophosphonate ***: the internucleotide bond is a dithiophosphonate The elementary analyses are performed with material dried on P 2 O s at 0.1 m bar. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. The entire disclosures of all applications, patents and publications, cited above and below, including DE 44 24 923.3, filed 14 July 1994, are hereby incorporated by reference. E X A M P L E S Example 1 a) 5' - (6-Amino-1-hexyl-phosphoric acid ester) of the 32mer-oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUAT3 ' -3'T-5' (modified ligand for nerve growth factor NGF, seq. no. 21) (described in US Patent No. 5,270,163) The 30mer-oligonucleotide 5'-CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' with the modifica- tion of a -T'3-3'T-5', identified according to the SELEX process, oligonucleotide which is bound by 5'-position on the vehicle, is produced in the usual way in an automatic synthesizer of the Pharmacia company (see Oligonucleo¬ tides and Analogues, A Practical Approach, Ed. F. Eck- stein, Oxford University Press, Oxford, New York, Tokyo, 1991) , and the oligonucleotide is also present on the column of the solid vehicle. By reaction with trichloro- acetic acid solution in dichloromethane, the 5' -hydroxy group is opened. The load on the column is about 10 mg of the 32mer-oligonucleotide. To join the linker, the column is reacted with a solution of 50 μmol of /8-cyano- ethyl-N,N-diisopropylamino-6- (trifluoroacetamido) -1- hexyl-phosphoramidite (produced according to Nucl. Acids. Res. 1£, 2659-2669 (1988)) in the presence of tetrazole. The oxidation of the formed phosphite to the completely protected phosphotriester takes place with iodine in tetrahydrofuran. Then, the column is washed in succes¬ sion with methanol and water. To remove the modified oligonucleotide from the solid vehicle, the contents of the column are conveyed in a multivial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze-drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml ethanol, it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 8 mg of the title compound is obtained as colorless powder. b) 10- [5- (2-Carboxyphenyl) -2-hydroxy-5-oxo-4-aza-pen- tyl] -1,4, 7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclo¬ dodecane 50 g (144.3 mmol) of 1,4,7-tris (carboxymethyl) - 1,4,7, 10-tetraazacyclododecane (D03A) is dissolved in 250 ml of water and the pH is adjusted to pH 13 with 5N sod¬ ium hydroxide solution. Then, a solution of 38.12 g (187.6 mmol) of N- (2,3-epoxypropyl) -phthalimide in 100 ml of dioxane is instilled within an hour, stirred for 24 hours at 50°C and the pH is kept at pH 13 by adding 5N sodium hydroxide solution. The solution is adjusted to pH 2 with 10% hydrochloric acid and evaporated to dryness in a vacuum. The residue is dissolved in some water and purified on an ion exchange column (Reillex (R) = poly- (4- vinyl) -pyridine, it is eluted with water) . The main fractions are concentrated by evaporation in a vacuum, and the residue is given a final purification by chroma¬ tography on RP-18 (LiChroPrep 1 * 1 /mobile solvent: gradient of tetrahydrofuran/methanol/water) . After concentration by evaporation of the main fractions, 63.57 g (71% of theory) of an amorphous solid is obtained. Water content: 8.5% Elementary analysis (relative to the anhydrous substance) : Cld: C 52.90 H 6.57 N 12.34 Fnd: C 52.65 H 6.68 N 12.15 c) 10- (3-Amino-2-hydroxy-propyl) -1,4,7-tris (carboxy¬ methyl) -1,4,7,10-tetraazacyclododecane 50 g (88.1 mmol) of the title compound of example lb is refluxed in 300 ml of concentrated hydrochloric acid for 24 hours. It is evaporated to dryness, the residue is dissolved in some water and purified on an ion exchange column (Reillex tR) = poly- (4-vinyl)pyridine (it is eluted with water) ) . The main fractions are evapor¬ ated to dryness. Yield: 39.0 g (95% of theory) of a vitreous solid. Water content: 10.3% Elementary analysis (relative to the anhydrous substance) : Cld : C 48 . 68 H 7 . 93 N 16 . 70 Fnd : C 48 .47 H 8 . 09 N 16 . 55 d) 10- [7- (4-Nitrophenyl) -2-hydroxy-5-oxo-7- (carboxy¬ methyl) -4-aza-heptyl] -1,4,7-tris (carboxymethyl) -1,4,7,10- tetraazacyclododecane 9.84 g (41.8 mmol) of 3- (4-nitrophenyl) -glutaric anhydride (J. Org. Chem. 2fL. 3856 (1961) ) is added to 14.6: (34.86 mmol) of the title compound of example lc) in 2 1 of dimethylformamide/20 ml of triethylamine and stirred overnight at room temperature. It is evaporated to dryness in a vacuum. The residue is recrystallized from isopropanol/acetic acid 95:5. Yield: 21.68 g (95% of theory) of a yellowish solid Water content: 0.9% Elementary analysis (relative to anhydrous substance) : Cld: C 51.37 H 6.47 N 12.84 Fnd: C 51.18 H 6.58 N 12.67 e) 10- [7- (4-Aminophenyl) -2-hydroxy-5-oxo-7- (carboxy¬ methyl) -4-aza-heptyl] -1,4,7-tris(carboxymethyl) -1,4,7,10- tetraazacyclododecane 21.0 g (32.07 mmol) of the title compound of example Id) is dissolved in 250 ml of methanol and 5 g of palladium catalyst (10% Pd on C) is added. It is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in a vacuum. Yield: 19.63 g (98% of theory) of a cream-colored solid Water content: 0.8% Elementary analysis (relative to anhydrous substance) : Cld: C 53.84 H 6.35 N 12.60 Fnd: C 53.73 H 6.45 N 12.51 f) 10- [7- (4-Isothiocyanatophenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) -4-aza-heptyl] -1,4,7-tris (carboxy-methyl) - 1,4,7,10-tetraazacyclododecane 12.4 g (19.27 mmol) of the title compound of example le) is dissolved in 200 ml of water and 6.64 g (57.8 mmol) of thiophosgene in 50 ml of chloroform is added. It is stirred for 1 hour at 50°C. It is cooled to room temperature, the organic phase is separated and the aque¬ ous phase is shaken out twice with 100 ml of chloroform. The aqueous phase is evaporated to dryness and the resi¬ due is absorptively precipitated in 100 ml of isopropanol at room temperature. The solid is filtered off and washed with ether. After drying overnight in a vacuum (40°C) , 12.74 g (97% of theory) of a cream-colored solid is obtained. Water content: 3.1% Elementary analysis (relative to anhydrous substance) : Cld: C 52.24 H 6.35 N 12.60 S 4.81 Fnd: C 52.37 H 6.44 N 12.48 S 4.83 g) Conjugate of 5' - (6-amino-1-hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3 '- 3' T' -5' and 10 [7- (4- isothiocyanato-phenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) - 4-azaheptyl] -1,4,7-tris(carboxymethyl) -1,4,7,10-tetraaza- cyclododecane 8 mg of the oligonucleotide obtained in example la) is dissolved in 2.5 ml of a mixture of a NaHC0 3 /Na 2 C0 3 buffer (pH 8.0) and mixed with 1 mg of 10- [7- (4-isothio- cyanatophenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) -4-aza- heptyl] -1,4,7-tris- (carboxymethyl) -1,4,7, 10-tetraaza- cyclododecane (title compound of example If) . It is stirred for 5 hours at room temperature, the pH is adjus¬ ted to 7.2 by adding 0.01 M hydrochloric acid and the solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) and then a freeze-drying. 7 mg of the desired conjugate is obtained. h) Gadolinium complex of the conjugate of 5' - (6-amino-l- hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3' - 3 'T-5' and 10 [7- (4- isothiocyanato-phenyl) -2-hydroxy-5-oxo-7- (carboxymethyl) - 4-azaheptyl] -1,4, 7-tris (carboxymethyl) -1,4,7, 10- tetraazacyclododecane 15 μl of an 111 indium(III) acetate solution (350 μCi) , (produced from 111 indium(III) chloride in 2 M sodium acetate solution and adjustment of the pH to pH 4.0 with 0.1 M hydrochloric acid) is added to 135 μl of a solution of 1 mg of the title compound of example lg) in MES buf¬ fer, pH 6.2 (MES = 2- (N-morpholino)ethylsulfonic acid) . The pH is brought to pH 4.2 by adding 0.01 M hydrochloric acid. It is stirred for 1 hour at 37°C at pH 4.2. It is brought to pH 6 with 2 M sodium acetate solution and 10 μl of a 0.1 M Na 2 EDTA solution (Na 2 EDTA ■ ethylenediamine- tetraacetic acid disodium salt) is added to complex excess 111 indium. The final purification of thus obtained conjugate (lh) takes place by HPLC (exclusion chromato¬ graphy: TSK-400/MES-buffer) . The fractions containing the labeled conjugate are ciluted with physiological com¬ mon salt solution, adjusted to pH 7.2 with 0.01 M sodium hydroxide solution and filtered. A thus produced solu¬ tion then represents a suitable preparation for radio- diagnosis. Example 2 a) Conjugate of 5' - (6-amino-l-hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3 '- 3' T-5' and - [2- amino-3- (4-isothiocyanatophenyl) -propyl] -trans-cyclo- hexane-l,2-diamine-N,N' ,N" ,N"' -pentaacetic acid 8 mg of the oligonucleotide obtained in example la) is dissolved in 2.5 ml of a mixture of a NaHC0 3 /Na 2 C0 3 buffer (pH 8.0) and 1 mg of N- [2-amino-3- (p-isothiocya- natophenyl)propyl] -trans-cyclohexane-1,2-diamine- N,N' ,N' ,N",N"-pentaacetic acid is added (produced according to Bioconjugate Chem. 1, 59 (1990)) . It is stirred for 5 hours at room temperature, then adjusted to pH 7.2 with 0.1 M hydrochloric acid and the solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) . After freeze- drying, 6 mg of thiourea conjugate 2a) is obtained. b) Gadolinium complex of the conjugate of 5' - (6-amino-l- hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3' - 3 'T-5' and N- [2- amino-3- (4-isothiocyanato-phenyl) -propyl] -trans-cyclo- hexane-l,2-diamine-N,N' ,N",N' "-pentaacetic acid The desired gadolinium complex is obtained according to the instructions, indicated under example lh) , by reaction of the title compound of example 2a) and gado¬ linium acetate. Example 3 Manganese complex of the conjugate of 5' - (6-amino-l- hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3 '- 3' T-5' and N- [2- amino-3- (4-isothiocyanato-phenyl) -propyl] -trans-cyclohex- ane-1, 2-diamine-N,N' ,N",N' "-pentaacetic acid The desired manganese complex is obtained according to the instructions, indicated under example lh) , by reaction of the title compound of example 2a) and mangan¬ ese (II) acetate. Example 4 a) Conjugate of 5' - (6-amino-1-hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3' - 3' T-5' and 2- (4- isothiocyanato-benzyl) -diethylenetriamine-N,N,N' ,N",N"- pentaacetic acid 8 mg of the oligonucleotide obtained in example la) is dissolved in 2.5 ml of a mixture of a NaHC0 3 /Na 2 C0 3 buffer (pH 8.0) and 1 mg of 2- (p-isothiocyanato-benzyl) - diethylenetriamine-N,N,N' ,N" ,N"-pentaacetic acid is added (produced according to: Bioconjugate Chem. 2 , 187 (1991)) . It is stirred for 5 hours at room temperature, then adjusted to pH 7.2 with 0.01 M hydrochloric acid and the solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM 3) . After freeze-drying, 6 mg of the thiourea conjugate is obtained. b) Europium complex of the conjugate of 5' - (6-amino-1- hexyl-phosphoric acid ester) of the 32mer oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-T 3' - 3 'T-5' and 2- (4- isothiocyanato-benzyl) -diethylenetriamine-N,N,N' ,N" ,N"- pentaacetic acid The desired europium complex is obtained according to the instructions, indicated under example lh) , by reaction of the title compound of example 4a) and euro¬ pium acetate. Example 5 a) 5' - (6-Mercapto-l-hexyl-phosphoric acid ester) of the 35mer-oligonucleotide 5'-T*T*T*T*T AGGAGGAGGAGGGAGAGCGCAAAUGAGAUU-3' (ligand for serine protease) The 30mer-oligonucleotide 5'-AGGAGGAGGAGGGAGAGCGCAAAUGAGAUU-3' (seq. no. 13 of US Patent No. 5,270,163), identified according to the SELEX process with the modification of a sequence 5'-τ*T*T*T*T placed in front, is produced in the usual way in an auto- matic synthesizer of the Pharmacia company (see Oligonuc¬ leotides and Analogues, A Practical Approach, Ed. F. Eck¬ stein, Oxford University Press, Oxford, New York, Tokyo, 1991) , and the oligonucleotide is also present on the column of the solid vehicle. By reaction with trichloro- acetic acid solution in dichloromethane, the 5'-hydroxy group is opened. The load on the column is about 10 mg of the 35mer-oligonucleotide. To join the linker, the column is reacted with a solution of 50 μmol of jβ-cyano- ethyl-N,N-diisopropylamino-S-trityl-6-mercapto) -phosphor¬ amidite in acetonitrile in the presence of tetrazole. The oxidation of the formed phosphite to the completely protected phosphotriester takes place with iodine in tetrahydrofuran. Then, the column is washed in succes- sion with methanol and water. To remove the modified oligonucleotide from the solid vehicle, the contents of the column are conveyed in a multivial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze-drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml of ethanol, it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 9 mg of the S-tritylated title compound is obtained. To cleave the trityl protective group, the product is dissolved in 0.5 ml of water, mixed with 0.1 ml of 1 M silver nitrate solution and stirred for 1 hour at room temperature. Then, it is mixed with 0.1 ml of 1 M dithiothreitol solution. After 15 minutes, it is centri¬ fuged, and the supernatant solution is extracted several times with ethyl acetate. After the freeze-drying, 8 mg of the desired title compound is obtained from the aque¬ ous solution. b) Conjugation of the oligonucleotide of 5' - (6-mercapto- l-hexyl-phosphoric acid ester) of the 35mer oligonucleo¬ tide T*T*T*T*T*AGGAGGAGGAGGGAGAGCGCAAAAUGAGAUU-3' and 1,4,7, 10-tetraazacyclododecane-2- [ (5-aza-8-maleimido-6- oxo) -octane] -1,4,7, 10-tetraacetic acid 1 mg of 1,4,7, 10-tetraazacyclododecane-2- [ (5-aza-8- maleimido-6-oxo) -octane] -1,4,7,10-tetraacetic acid (pro¬ duced according to J. Chem. Soc, Chem. Commun. 796, (1989) ) is added to a solution of 5 mg of the thiol-con- taining oligonucleotide, produced according to example 5a) , in 2 ml of phosphate buffer (pH 8) under N 2 . It is stirred for 3 hours at 35°C, mixed with 10 ml of isopropyl alcohol and the product is isolated by centrifuging. The purification takes place by reversed-phase chromatography on a 1 x 25 cm column with a 25 mmol triethylammonium acetate (pH 7) /acetonitrile gradient. The combined frac¬ tions are gently concentrated by evaporation in a vacuum, dissolved in a little water and desalted with the help of a Sephadex-G-10 column. By freeze-drying, 4 mg of the title compound is obtained as white powder. c) Gadolinium complex of the conjugate of 5' - (6-mercap- to-1-hexyl-phosphoric acid ester) of the 35mer oligonuc¬ leotide T*T*T*T*T*AGGAGGAGGAGGGAGAGCGCAAAAUGAGAUU-3' and 1,4,7, 10—tetraazacyclododecane-2- [ (5-aza-8-maleimido-6- oxo) -octane] -1,4,7, 10-tetraacetic acid The desired gadolinium complex is obtained according to the instructions, indicated under example lh) , by reaction of the title compound of example 5b) and gado¬ linium acetate. Example 6 a) Conjugate of 5' - (6-mercapto-l-hexyl-phosphoric acid ester) of the 35mer oligonucleotide T*T*T*T*T*AGGAGGAGGAGGGAGAGCGCAAAAUGAGAUU-3' and 1,4,7- triazacyclononane-2- [ (5-aza-8-maleimido-6-oxo) -octane] - 1,4,7-triacetic acid 1 mg of l,4,7-triazacyclononane-2- [ (5-aza-8-male- imido-6-oxo) -octane] -1,4,7-triacetic acid (produced according to J. Chem. Soc, Chem. Commun. 794, (1989)) is added to a solution of 5 mg of the thiol-containing oli¬ gonucleotide, produced according to example 5a) , in 2 ml of phosphate buffer (pH 8) under N 2 . It is stirred for 6 hours at 35°C, mixed with 10 ml of isopropanol and the product is isolated by centrifuging. The purification takes place by reversed-phase chromatography on a 1 x 25 cm column with a 25 mmol triethylammonium acetate (pH 7) /acetonitrile gradient. The combined fractions are gently concentrated by evaporation in -a vacuum, dissolved in a little water and desalted with the help of a Sepha- dex G-10 column. By freeze-drying, 3 mg of the title compound is obtained as white powder. b) Iron(III) complex of the conjugate of 5' - (6-mercapto- 1-hexyl-phosphoric acid ester) of the 35mer oligonucleo¬ tide T*T*T*T*T*AGGAGGAGGAGGGAGAGCGCAAAAUGAGAUU-3' and l,4,7-triazacyclononane-2- [ (5-aza-8-maleimido-6-oxo) - octane] -1,4,7-triacetic acid The desired iron complex is obtained according to the instructions, indicated under example lh) , by reac¬ tion of the title compound of example 6a) and iron(III) chloride. Example 7 a) Phosphitylation of 5' -0- (4,4' -dimethoxytrityl) -5- (prop-2-en-l-one) -2' -deoxyuridine 50 mg of 4-dimethylaminopyridine, 3 ml of diisopro- pylethylamine and 962 μl (4.31 mmol) of 2-cyanoethyl-N,N- diisopropylchlorophosphoramidite are added in succession to a stirred solution of 2.1 g (3.59 mmol) of 5'-0-(4,4'- dimethoxytrityl) -5- (prop-2-en-1-one) -2' -deoxyuridine (produced according to Nucleosides & Nucleotides 13_, 939- 944, (1994)) in 50 ml of tetrahydrofuran. After about 30 minutes, a white precipitate is formed. It is filtered, the solution is concentrated by evaporation in a vacuum and the residue is spread between dichloromethane and 5% sodium bicarbonate solution. The dichloromethane phase is dried on magnesium sulfate and concentrated by evapor- ation in a vacuum. The residue is purified by quick chromatography on silica gel, and it is eluted with dichloromethane/hexane/diisopropylethylamine (80:18:2) . 1.8 g of the desired compound is obtained as a white foam. Elementary analysis: Cld: C 64.28 H 6.29 N 7.14 P 3.95 Fnd: C 64.02 H 6.60 N 7.21 P 4.09 b) Conjugate of the 33mer oligonucleotide 5' -*U CUCAUGGAGCGCAAGACGAAVAGCVACAVAT 3 '- 3 'T-5' and 10- (4- aza-2-hydroxy-5-imino-8-mercapto-octane) -1,4,7-tris- (carboxymethyl) -1,4, 7,10-tetraazacyclododecane *U: 5- (prop-2-en-l-one) -2' -deoxyuridine The 30mer-oligonucleotide identified according to the SELEX process is produced in the usual way in an automatic synthesizer of the Pharmacia company (see Oli¬ gonucleotides and Analogues, A Practical Approach, Ed. F. Eckstein, Oxford University Press, Oxford, New York, Tokyo, 1991) , and the oligonucleotide is also present on the column of the solid vehicle. By reaction with tri- chloroacetic acid solution in dichloromethane, the 5'-hydroxy group is opened. The load on the column is about 10 mg of the 30mer-oligonucleotide. The 5'-hydroxy group is reacted in the presence of tetrazole with the phosphoramidite obtained according to example 13a) . Then, the phosphite is converted to the phosphotriester by treatment with iodine solution and the terminal DMT radical is cleaved by reaction with trichloroacetic acid solution in dichloromethane. For addition of a thiol group to the α, β-unsaturated carbonyl system present on the terminal 2' -deoxyuridine, it is reacted with a solu¬ tion of 10- (4-aza-2-hydroxy-5-imino-8-mercapto-octane) - 1,4, 7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane* in tetrahydrofuran and washed in succession with methanol and water. To remove the modified oligonucleotide from the solid vehicle, the contents of the column are con¬ veyed in a multivial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze-drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml of ethanol, it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 6 mg of the title compound is obtained as colorless powder. *10- (4-Aza-2-hydroxy-5-imino-8-mercapto-octane) - l,4,7-tris-(carboxymethyl) -1,4,7,10-tetraazacyclododecane is obtained as described below: 15.7 ml of IN sodium hydroxide solution and 480 mg (3.49 mmol) of 2-iminotetrahydrothiophenehydrochloride are added to a solution of 1.46 g (3.49 mmol) of 10- (3- amino-2-hydroxy-propyl) -1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane (see example lc) in a mixture of 50 ml of water and 50 ml of methanol and stirred for 3 hours at room temperature, concentrated by evaporation in a vacuum to about 1/4 of the initial vol¬ ume and mixed with stirring with an anion exchanger (IRA 410) until a pH of 11 is reached. The solution is fil- tered and mixed with stirring in small portions with enough cation exchanger IRC 50 until a pH of 3.5 is reached. After filtering, the solution is freeze-dried. 1.39 g of the desired substance is obtained as white powder with a water content of 4.9%. Elementary analysis (relative to the anhydrous substance) : Cld: C 48.45 H 7.74 N 16.14 S 6.16 Fnd: C 48.30 H 7.98 N 16.05 S 6.44 c) Gadolinium complex of the conjugate of 5'-*U CUCAUGGAGCGCAAGACGAAVAGCVACAVAT'- 'T-5' and 10- (4- aza-2-hydroxy-5-imino-8-mercapto-octane) -1,4,7-tris- (carboxymethyl) -1,4,7, 10-tetraazacyclododecane *U: 5- (prop-2-en-l-one) -2' -deoxyuridine The desired gadolinium complex is obtained according to the instructions, indicated under example lh) , by reaction of the title compound of example 7b) and gado- linium acetate. Example 8 a) 5- (ll-Amino-3,6,9-trioxo-undecyl-l-phosphoric acid- ester) of the 30mer-oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' (ligand for nerve growth factor NGF, seq. no. 21) (described in US Patent No. 5,270,163) The 30mer-oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' , identified accor¬ ding to the SELEX process, is produced in the usual way in an automatic synthesizer of the Pharmacia company (see Oligonucleotides and Analogues, A Practical Approach, Ed. F. Eckstein, Oxford University Press, Oxford, New York, Tokyo, 1991) , and the oligonucleotide is also present on the column of the solid vehicle. By reaction with tri- chloroacetic acid solution in dichloromethane, the 5'-hydroxy group is opened. The loading of the column is about 10 mg of the 30mer-oligonucleotide. To link the connecting component, the column is reacted with a solution of 50 μmol of f 3-cyanoethyl-N,N- diisopropylamino- (3,6, 9-trioxa-ll-phthalimido-l-undecyl) - phosphoramidite (produced according to: Proc. Natl. Acad. Sci. USA, 86., 6230-6234 (1989)) in the presence of tetrazole. The oxidation of the formed phosphite to the completely protected phosphotriester takes place with iodine in tetrahydrofuran. Then, the column is washed in succession with methanol and water. To remove the modi¬ fied oligonucleotide from the solid vehicle, the contents of the column are conveyed in a multivial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze- drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml of ethanol; it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 8 mg of title compound 8a) is obtained as white powder. b) Gadolinium complex of 10- (3-amino-2-hydroxy-propyl) - 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane 38 g (90.6 mmol) of the compound obtained according to example lc) is dissolved in 300 ml of water ' and 16.42 g (45.3 mmol) of gadolinium oxide is added. It is heated for 3 hours to 90°C. The cooled solution is stirred with 5 ml of acid ion exchanger (IR-120/H * form) each and 5 ml of basic exchanger (IRA-410/OH" form) each for 1 hour at room temperature. It is filtered off from the exchanger. Freeze-drying of the filtrate yields 57.23 g (98% of theory) of an amorphous solid. Water content: 11.3%. Elementary analysis (relative to the anhydrous substance) : Cld: C 35.59 % H 5.27 % N 12.21 % Gd 27.41 % Fnd: C 35.32 % H 5.38 % N 12.31 % Gd 27.20 % c) Gadolinium complex of 10- [7- (4-nitrophenyl) -2- (ben- zylcarboxy) -2-hydroxy-5-oxo-7- (carboxymethyl) -4-aza-hep- tyl] -1,4,7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclo- dodecane 9.84 g (41.8 mmol) of 3- (4-nitro-phenyl) -glutaric anhydride (J. Org. Chem. 2_£, 3856 (1961)) is added to 20 g (34.86 mmol) of the compound, obtained according to example 8b) , in 200 ml of dimethylformamide/20 ml of tri¬ ethylamine and stirred overnight at room temperature. It is evaporated to dryness in a vacuum. The residue is recrystallized from isopropanol/acetic acid 95:5. Yield: 27.46 g (94% of theory) of a yellowish solid Water content: 3.4% Elementary analysis (relative to the anhydrous substance) : Cld: C 41.58 % H 4.86 % N 10.39 % Gd 19.44 % Fnd: C 41.38 % H 4.97 % N 10.17 % Gd 19.28 % d) Gadolinium complex of 10- [7- (4-aminophenyl) -2- hydroxy-5-oxa-7- (carboxy-methyl) -4-aza-heptyl] -1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane 25 g (30.9 mmol) of the compound obtained according to example 8c) is dissolved in 250 ml of methanol and 5 g of palladium catalyst (10% Pd on C) is added. It is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in a vacuum. Yield: 24.07 g (97% of theory) of a cream-colored solid Water content: 3.0% Elementary analysis (relative to the anhydrous substance) : Cld: C 43.18 % H 5.31 % N 10.79 % Gd 20.19 % Fnd: C 43.27 % H 5.48 % N 10.61 % Gd 20.02 % e) Gadolinium complex of 10- [7- (4-isothiocyanato- phenyl) -2-hydroxy-5-oxa-7- (carboxymethyl) -4-aza-heptyl] - 1,4, 7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane 15 g (19.26 mmol) of the compound obtained according to example 8d) is dissolved in 100 ml of water and 6.64 g (57.8 mmol) of thiophosgene in 50 ml of chloroform is added. It is stirred for 1 hour at 50°C. It is cooled to room temperature, the organic phase is separated and the aqueous phase is shaken out twice with 100 ml of chloro- form. The aqueous phase is evaporated to dryness and the residue is absorptively precipitated in 100 ml of isopro¬ panol at room temperature. The solid is filtered off and washed with ether. After drying overnight in a vacuum (40°C) , 15.9 g (98% of theory) of a cream-colored solid is obtained. Water content: 3.5% Elementary analysis (relative to the anhydrous substance) : Cld: C 42.43% H 4.79% N 10.24% Gd 19.15% S 3.91% Fnd: C 42.23% H 4.90% N 10.05% Gd 19.01% S 3.96% f) Conjugate of 5' - (ll-amino-3,6,9-trioxo-undecyl-l- phosphoric acid ester) of the 35mer oligonucleotide 5'-CUCAUGGAGAGGCGCAAGACGAAVAGCVACAUAT*T*T*T*T-3' and the gadolinium complex of 10- [7- (4-isothiocyanato-phenyl) -2- hydroxy-5-oxo-7- (carboxymethyl) -4-aza-heptyl] -1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane 8 mg of oligonucleotide 8a) , obtained as described above, is dissolved in 2.5 ml of a mixture of a NaHC0 3 /- Na 2 C0 3 buffer (pH 8.0) and mixed with 1 mg of the gadolin- ium complex of 10- [7- (4-isothiocyanatophenyl) -2-hydroxy- 5-OXO-7- (carboxy-methyl) -4-aza-heptyl] -1,4,7-tris (carbox¬ ymethyl) -1,4,7,10-tetraazacyclododecane 8e) . It is stirred for 20 hours at room temperature, the pH is ad¬ justed to 7.2 by adding 0.01 M hydrochloric acid and the solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) and then a freeze-drying. 7 mg of desired conjugate 8f) is obtained. Example 9 a) 35mer-Oligonucleotide 5' - (U' ) 5 CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3 ' (U' = 5- [N- (6-aminohexyl) -3- (E) -acrylamido] -2' - deoxyuridine) The 30mer-oligonucleotide 5'-CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' , identified accor- ding to the SELEX process, is produced in the usual way in an automatic synthesizer of the Pharmacia company (see Oligonucleotides and Analogues, A Practical Approach, Ed. F. Eckstein, Oxford University Press, Oxford, New York, Tokyo, (1991)) , and the oligonucleotide is also present on the column of the solid vehicle. By reaction with trichloroacetic acid solution in dichloromethane, the 5'-hydroxy group is opened. The load .on the column is about 10 mg of the 3Omer-oligonucleotide. Corresponding to the standard methods of the synthe- sis of oligonucleotides (see F. Eckstein), 5' -O-dimeth- oxytrityl-5- [N- (6-trifluoroacetylaminohexyl) -3 (E) -acryl¬ amido] -2' phosphoramidite (see F. Eckstein, page 264) is linked five times in succession to the 30mer-oligonucleotide present on the vehicle. The oxidation of the formed phosphite to the complegeiycpcotedfeedrp_aoS___.oSiDl__dedehi- takes place with iodine in tetrahydrofuran. Then, the column is washed in succession with methanol and water; by reaction with trichloroacetic acid solution in dichloromethane, the 5'-hydroxyl group is opened. To remove the modifU-deoxyuridine-3' -/S-cyanoethyl-N,N-diisopropyl- cle, the contents of the column are conveyed in a multi- vial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze-drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml of ethanol; it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 8 mg of modified oligonucleotide 9a) is obtained as white powder. b) Conjugate of the 35mer oligonucleotide 5' - (U' *)jCUCAUGGAG- AGGCGCAAGACGAAUAGCUACAUAT*T*T*T*T-3' and 5 equivalents of the gadolinium complex of 10- [7- (4- isothiocyanato-phenyl) -2-hydroxy-5-oxa-7- (carboxymethyl) - 4-aza-heptyl] -1,4,7-tris(carboxymethyl) -1,4,7, 10-tetra¬ azacyclododecane (*U'=5- [N- (6-aminohexyl) -3- (E) -acrylamido] -2' -deoxy¬ uridine) 8 mg of oligonucleotide 9a) , obtained as described above, is dissolved in 2.5 ml of a mixture of a NaHC0 3 /- Na 2 C0 3 buffer (pH 8.0) and mixed with 3 mg of the gadolin- ium complex of 10- [7- (4-isothiocyanatophenyl) -2-hydroxy- 5-OXO-7- (carboxymethyl) -4-aza-heptyl] -1,4,7-tris (carboxy¬ methyl) -1,4,7,10-tetraazacyclododecane 8e) . It is stirred for 20 hours at room temperature, the pH is ad¬ justed to 7.2 by adding 0.01 M hydrochloric acid and the solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) and then a freeze-drying. 7 mg of desired conjugate 9b) is obtained. Example 10 a) 5 ' - (8 -Amino- 3 , 6 -dioxa-octyl-l-phosphoric acid ester) of the 30mer-oligonucleotide 5 ' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA- 3 ' The procedure is as described in example 8a) , but the ■3-cyano-ethyl -N, N-diisopropylamino- ( 3 , 6 -dioxa-8 -tri- f luoroacetylamido- 1 -octyl-phosphoramidite is used instead of j 3-cyano-ethyl -N, N-diisopropylamino- ( 3 , 6 , 9 -trioxa- ll - phthalimido-1-undecyl) -phosphoramidite and modified oligonucleotide 10a) is obtained. b) Conjugate of the 35mer oligonucleotide 5'-(8-amino- 3, 6-dioxa-octyl-1-phosphoric acid ester) of the 5-CUCAUGGAGAGGCGCAAGACGAAUAGCUACAUAT*T*T*T*T-3' and the gadolinium complex of diethylenetriamine-N,N,N' ,N" ,N"- pentaacetic acid 5 mg of compound 10a) is dissolved in 0.5 ml of aqueous sodium bicarbonate solution and stirred in an ice bath with 10 mg of diethylenetriamine-pentaacetic acid- bis-anhydride for 2 hours. By adding 0.01 M hydrochloric acid solution, it is adjusted to pH 7. The solution is subjected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) and then a freeze- drying. The further purification takes place by gel- electrophoresis on a 20% polyacrylamide gel. For com¬ plexing, the purified solution is mixed with 1 mg of gadolinium acetate, stirred for 10 minutes at room temperature and a further ultrafiltration is performed. The isolation of the substance takes place by freeze- drying. 3 mg of compound 10b) is obtained. Example 11 a) 31mer-Oligonucleotide 5' -U"CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' (U"=5- [N- (3,6-dioxa-8-amino-l-octyl) -3(E) -acrylamido] -2' - deoxyuridine) The 30mer-oligonucleotide 5' -CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' , identified accor¬ ding to the SELEX process, is produced in the usual way in an automatic synthesizer of the Pharmacia company (see Oligonucleotides and Analogues, A Practical Approach, Ed. F. Eckstein, Oxford University Press, Oxford, New York, Tokyo (1991)), and the oligonucleotide is also present on the column of the solid vehicle. By reaction with tri- chloroacetic acid solution in dichloromethane, the 5'-hydroxy group is opened. The load on the column is about 10 mg of the 30mer-oligonucleotide. Corresponding to the standard methods of the synthe¬ sis of oligonucleotides (see F. Eckstein), 5'-0-dimeth- oxytrityl-5- [- (3,6-dioxa-8-trifluoroacetylamido-l-octyl) - 3 (E) -acrylamido] -2' -deoxyuridine-3' -/3-cyanoethyl-N,N- diisopropyl-phosphoramidite (produced analogously to Nucl. Acids. Res. ϋ, 6115-6128 (1986)) is linked to the 30mer-oligonucleotide present on the vehicle. The oxida- tion of the formed phosphite to the completely protected phosphotriester takes place with iodine in tetrahydro¬ furan. Then, the column is washed in succession with methanol and water. By reaction with trichloroacetic acid solution in dichloromethane, the 5' -hydroxy group is opened. To remove the modified oligonucleotide from the solid vehicle, the contents of the column are conveyed in a multivial, mixed with 5 ml of 30% ammonia solution, the vessel is sealed and shaken overnight at 55°C. It is then cooled to 0°C, centrifuged, the vehicle is washed with 5 ml of water and the combined aqueous phases are subjected to a freeze-drying. For purification, the solid material is taken up in 2 ml of water, mixed with 2 ml of 0.5 M ammonium acetate solution and mixed with 10 ml of ethanol, it is allowed to stand overnight at -20°C, centrifuged, the residue is washed with 1 ml of ethanol (-20°C) and finally dried in a vacuum at room temperature. 12 mg of modified oligonucleotide Ila) is obtained as white powder. b) Conjugate of the 31mer oligonucleotide 5' -U"CUCAUGGAGCGCAAGACGAAUAGCUACAUA-3' and the gadolinium complex of 10- [7- (4-isothiocyanato-phenyl) -2-hydroxy-5- oxa-7- (carboxymethyl) -4-aza-heptyl] -1, ,7-tris(carboxy- methyl) -1,4,7,10-tetraazacyclododecane (U"=5- [N- (3, 6- dioxa-8-amino-l-octyl) -3 (E) -acrylamido] -2' -deoxyuridine) 10 mg of thus obtained oligonucleotide Ila) is dissolved in 2.5 ml of a mixture of a NaHC0 3 /Na 2 C0 3 buffer (pH 8.0) and mixed with 1 mg of the gadolinium complex of 10- [7- (4-isothiocyanatophenyl) -2-hydroxy-5-oxo-7- (car- boxymethyl) -4-azaheptyl] -1,4,7-tris(carboxymethyl) - 1,4,7,10-tetraazacyclododecane 8e) . It is stirred for 20 hours at room temperature, the pH is adjusted to 7.2 by adding 0.01 M hydrochloric acid, and the solution is sub¬ jected to an ultrafiltration through a membrane with the exclusion limit 3,000 (Amicon YM3) and then a freeze- drying. 8 mg of desired conjugate lib) is obtained. The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims: What is claimed is: 1. Oligonucleotide conjugates consisting of an oligonucleotide radical N and n substituents (B-K) , in which B stands for a direct bond or a connecting compo¬ nent to the oligonucleotide radical, and K means a com¬ plexing agent or complex of elements of atomic numbers 21-29, 42, 44 or 58-70, characterized in that oligonuc¬ leotide radical N exhibits a modification, which prevents or at least significantly inhibits the degradation by naturally occurring nucleases. 2. Compound according to claim 1, wherein the compound exhibits general formula N-(B-K) n (I) in which N is an oligonucleotide, which bonds specifi¬ cally with high bonding affinity to other target struc¬ tures and exhibits modifications that significantly reduce the degradation by naturally occurring nucleases, B is a chemical bond or a connecting component, which produces the connection between N and K, and K is a complexing ligand, which exhibits at least one element of the atomic numbers mentioned in claim 1 and n is a number between 1 and 30. 3. Compound according to claim 1 or 2, in which N is an oligonucleotide with 5 to 200 nucleotides, wherein a) the 2'-position of the sugar unit, independently of one another, is occupied by the following groups: a group -OR, in which R means an alkyl radical with 1 to 20 carbon atoms, which optionally contains up to 2 hydroxyl groups and which optionally is interrupted by 1-5 oxygen atoms, a hydrogen atom, a hydroxyl group, a fluorine atom, an amine radical, an amino group and hydroxyl groups present in 3' - and 5'-positions optionally are etherified with radical R and/or b) the phosphodiesters, being used as the internuc¬ leotide bond, independently of one another, are replaced by phosphorothioates, phosphorodithioates or alkylphos¬ phonates, especially preferably methyl phosphonate, and/or c) the terminal radicals in 3'- and 5'-positions are linked by an internucleotide bond as described in b) and/or d) it optionally contains an internucleotide bond as described in b) , which links 3' -3'- or 5'-5'-posi¬ tions, and/or e) it optionally contains a phosphodiester bond as described under b) , which connects, esterlike, two thymi¬ dines by a C 2 -C 10 hydroxyalkyl radical respectively in 3-position or connects an analogously substituted thymi¬ dine radical, esterlike, with a hydroxyl group in 2'- or 3'- or 5' -position and/or f) optionally modified internucleotide bonds are contained preferably on the ends of the polynucleotide, especially preferably on thymidines. 4. Compound according to claim 3, wherein oligonuc¬ leotide N comprises 10 to 100 nucleotides. 5. Compound according to one of claims 1 to 4, wherein N is an oligonucleotide, which bonds specifically with high bonding affinity to other target structures and which can be obtained in that a mixture of oligonucleo¬ tides containing random sequences is brought together with the target structure, and certain oligonucleotides exhibit an increased affinity to the target structure relative to the mixture of the oligonucleotides, the latter are separated from the remainder of the oligonuc¬ leotide mixture, then the oligonucleotides with increased affinity to the target structure are amplified to obtain a mixture of oligonucleotides that exhibits an increased portion of oligonucleotides that bond on the target structures. 6. Compound according to one of claims 1 to 5, wherein N is an oligonucleotide, which specifically bonds with high bonding affinity to other target structures and which can be obtained in that a) first, a DNA strand is produced by chemical syn¬ thesis, so that this DNA strand exhibits a defined sequence on the 3'-end, which is complementary to a pro¬ moter for an RNA-polymerase and at the same time comple¬ mentary to a primer of the polymerase chain reaction (PCR) , and in that this DNA strand exhibits a defined DNA sequence on the 5' -end, which is complementary to a pri¬ mer sequence for the polymerase chain reaction, and the sequence between the defined sequences contains a random sequence, and in that b) this DNA strand is transcribed in a complemen¬ tary RNA strand with the help of an RNA-polymerase, and nucleotides are offered to the polymerase, which are modified in the 2' -position of the ribose unit, and in that c) the RNA oligonucleotides, produced in this way, are brought together with the target structure on which the oligonucleotide specifically is to bond, and in that d) those oligonucleotides that have bound on the target structure are separated first together with the target structure from the nonbinding oligonucleotides and then the bound oligonucleotides are separated again from the target structure, and in that e) these target-structure-specific RNA oligonucleo¬ tides are transcribed with the help of reverse tran¬ scriptase in a complementary DNA strand, and in that f) these DNA strands are amplified when using the defined primer sequences with the polymerase chain reac¬ tion, and in that g) the DNA oligonucleotides amplified in this man¬ ner are then transcribed again with the help of the RNA- polymerase and with modified nucleotides in RΝA-oligonuc- leotides, and in that h) the above-mentioned selection steps c) to g) optionally are repeated often until the oligonucleotides, which are characterized by a high bonding affinity to the target structure, are sufficiently selected, and then the sequences of the thus obtained oligonucleotides option¬ ally are able to be determined. 7. Compound according to claim 6, wherein the target structure is selected among macromolecules, tissue structures of higher organisms, such as animals or humans, organs or parts of organs of an animal or human, cells, tumor cells or tumors. 8. Compound according to one of claims 1 to 7, wherein connecting component B is bound a) to the 4'-end of oligonucleotide radical Ν reduced in 4'-position by the CH 2 -0H group and/or b) to the 3' -end of oligonucleotide radical Ν reduced in 3' -position by a hydrogen atom and/or c) to the phosphodiester bridge(s), reduced by the OH group(s), between two nucleotides in each case and/or d) to 1 to 30 nucleobase(s) , which is (are) reduced by a hydrogen atom respectively in 5-, θ-position(s) and/or the amino group(s) in 2-, 4- and 6-position(s) . 9. Compound according to claim 8, paragraph a) or b) , wherein B has general formula X-Y-Z 1 , which is connec¬ ted on the X side with the complexing agent or complex and on the Z side with the oligonucleotide, in which X is a direct bond, an -NH or -S group, Y is a straight-chain or branched-chain, saturated or unsaturated C.-C 20 alkylene chain, which optionally contains 1-2 cyclohexylene, 1-5 imino, 1-3 phenylene, 1-3 phenylenimino, 1-3 phenylenoxy, 1-3 hydroxyphenylene, 1-5 amido, 1-2 hydrazido, 1-5 carbonyl, 1-5 ethylenoxy, a ureido, a thioureido, 1-2 carboxyalkylimino, 1-2 ester groups, 1-3 groups of Ar, in which Ar stands for a satur¬ ated or unsaturated 5- or 6-ring, which optionally con¬ tains 1-2 heteroatoms selected from nitrogen, oxygen and sulfur and/or 1-2 carbonyl groups; 1-10 oxygen, 1-5 nit¬ rogen and/or 1-5 sulfur atoms, and/or optionally is sub¬ stituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thi- oxo, 1-3 carboxy, 1-5 carboxy-C^^-alkyl, 1-5 ester, 1-3 amino, 1-3 hydroxy- ^C,-alkyl, 1-3 C 1 -C 7 -alkoxy groups, and Z 1 is -C0NH-CH 2 -4' , -NH-CO-4' , -O-P(0)R 1 -NH-CH 2 -4' , -0-P(0)R 1 -0-CH 2 -4' , -O-PΪSJR^O-S' or -0-P(0)R^O-S' , in which 4' or 3' indicates the linkage to the terminal sugar unit(s) and R 1 stands for O " , S " , a C 1 -C 4 alkyl or NR 2 R 3 group, with R 2 and R 3 meaning hydrogen and C^C,, alkyl radicals. 10. Compound according to claim 8, paragraph c) , wherein B has general formula X-Y-Z 2 , which is connected on the X side with the complexing agent or complex and on the Z side with the oligonucleotide, in which Z 2 , in the bridge linking two adjacent sugar units, 0 S Z -P II-0-5' and/or Z a 2 -P II-0-5' is the group -NR 2 -, -0- or -S-, X is a direct bond, an -NH or -S group, Y is a straight-chain, branched-chain, saturated or unsaturated C 1 -C 20 alkylene chain, which optionally contains 1-2 cyclohexylene, 1-5 imino, 1-3 phenylene, 1-3 phenylenimino, 1-3 phenylenoxy, 1-3 hydroxyphenylene, 1-5 amido, 1-2 hydrazido, 1-5 carbonyl, 1-5 ethylenoxy, a ureido, a thioureido, 1-2 carboxyalkylimino, 1-2 ester groups, 1-3 groups of Ar, in which Ar stands for a saturated or unsaturated 5- or 6-ring, which optionally contains 1-2 heteroatoms selected from nitrogen, oxygen and sulfur and/or 1-2 carbonyl groups; 1-10 oxygen, 1-5 nitrogen and/or 1-5 sulfur atoms, and/or optionally is substituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thioxo, 1-3 carboxy, 1-5 carboxy-C 1 -C 4 -alkyl, 1-5 ester, 1-3 amino, 1-3 hydroxy-C 1 -C 4 alkyl, 1-3 C 1 -C 7 -alkoxy groups, and R 2 is hydrogen or C 1 -C 4 alkyl radicals. 11. Compound according to claim 8, paragraph d) , wherein B has general formula X-Y-Z 3 , in which Z 3 is an -NH group or a direct bond to the nucleobase and X is a direct bond, an -NH or -S group, and Y is a straight-chain, branched-chain, saturated or unsaturated alkylene chain, which optionally contains 1-2 cyclohexylene, 1-5 imino, 1-3 phenylene, 1-3 phenylenimino, 1-3 phenylenoxy, 1-3 hydroxyphenylene, 1-5 amido, 1-2 hydrazido, 1-5 carbonyl, 1-5 ethylenoxy, a ureido, a thioureido, 1-2 carboxyalkylimino, 1-2 ester groups, 1-3 groups of Ar, in which Ar stands for a saturated or unsaturated 5- or 6-ring, which optionally contains 1-2 heteroatoms selected from nitrogen, oxygen and sulfur and/or 1-2 carbonyl groups; 1-10 oxygen, 1-5 nitrogen and/or 1-5 sulfur atoms, and/or optionally is substituted by 1-5 hydroxy, 1-2 mercapto, 1-5 oxo, 1-5 thioxo, 1-3 carboxy, 1-5 carboxy-C 1 -C 4 -alkyl, 1-5 ester, 1-3 amino, 1-3 hydroxy-C 1 -C 4 alkyl, 1-3 C 1 -C 7 -alkoxy groups. 12. Compound according to one of the preceding claims, wherein the metal complex contains gadolinium, manganese or iron as an imaging element. 13. Process for detecting a target structure, wherein one or more of the compounds according to one of the preceding claims are brought together with the sample to be studied in vivo or in vitro and based on the sig¬ nal, it is detected whether the target structure, on which oligonucleotide N bonds specifically and with high bonding affinity, is present in the sample. 14. Process for noninvasive diagnosis of diseases, wherein one or more of the compounds according to one of claims 1 to 12 is brought together with the target struc¬ ture to be studied in vivo and based on the signal, it is detected whether the target structure, on which oligonuc¬ leotide N specifically bonds, is present in the organism to be studied. 15. Compound according to one of claims 1 to 4, wherein N is a non-naturally occuring oligonucleotide ligand having a specific binding affinity for a target molecule, such target molecule being a three dimensional chemical structure other than a polynucleotide that binds to said oligonucleotide ligand through a mechanism which predominantly depends on Watson/Crick base pairing or triple helix binding, wherein said oligonucleotide ligand is not a nucleic acid having the known physiological function of being bound by the target molecule.

Inventors: BERNDORFF DIETMAR, GOLD LARRY, MUEHLER ANDREAS, NIEDBALLA ULRICH, PIEKEN WOLFGANG, PLATZEK JOHANNES, RADUECHEL BERND, SPECK ULRICH, BERNDORFF, DIETMAR, GOLD, LARRY, MUEHLER, ANDREAS, NIEDBALLA, ULRICH, PIEKEN, WOLFGANG, PLATZEK, JOHANNES, RADUECHEL, BERND, SPECK, ULRICH
Applicants: BERNDORFF DIETMAR, GOLD LARRY, MUEHLER ANDREAS, NEXSTAR PHARMACEUTICALS INC, NIEDBALLA ULRICH, PIEKEN WOLFGANG, PLATZEK JOHANNES, RADUECHEL BERND, SCHERING AG, SPECK ULRICH, BERNDORFF, DIETMAR, GOLD, LARRY, MUEHLER, ANDREAS, NEXSTAR PHARMACEUTICALS, INC., NIEDBALLA, ULRICH, PIEKEN, WOLFGANG, PLATZEK, JOHANNES, RADUECHEL, BERND, SCHERING AKTIENGESELLSCHAFT, SPECK, ULRICH
Application year: 1995
Main classification: C12Q1
IPC codes: A61K49, C07H21, C12N15, C12Q1