UA79294C2 - Use of metal complexes containing perfluoroalkyl as contrast agents in magnetic resonance imaging for representing intravascular thrombi - Google Patents

Abstract

The invention relates to the use of metal complexes containing perfluoroalkyl as contrast agents in MR imaging for visualizating intravascular thrombi. Said complexes have a critical micelle-formation concentration <10-3 mol/l, a hydrodynamic micellediameter (2 Rh) > 1 nm and a proton relaxivity in plasma (R1) > 10 l/mmol-s.

Description

Description of the invention

The present invention relates to the object described in the claims, namely, the use of 2 perfluoroalkyl-containing metal complexes, which are characterized by a critical micelle formation concentration of less than 10 Zmol/l, a hydrodynamic diameter of micelles (2B) over nm and a relaxation of protons in plasma (B) of more than 1Ol/ mmol-s as contrast agents in magnetic resonance (MR) tomography for visualization of intravascular thrombi.

Thrombosis refers to the process of formation of a blood clot (thrombus) in a blood vessel, which leads 70 to the narrowing of its lumen, corresponding to its blockage. Most often, blood clots form in veins (phlebothrombosis). In this case, the veins in the lower half of the body (deep veins of the lower limbs and pelvic area) are mainly exposed to thrombosis. However, other parts of the vascular system can be subjected to thrombosis, namely, heart valves, the apex of the heart, coronary vessels of the heart, vessels of the brain, arteries in the intestine, arteries of the lower extremities, as well as veins of the lower extremities and pelvic area, the rectum ( hemorrhoids) and upper extremities. The movement of a thrombus through the vascular system can lead to a pulmonary embolism, which (embolism) in the worst case can be fatal.

Deep vein thrombosis is a serious social and medical problem. Yes, in particular, in only one

In Germany, more than 60,000 people are treated annually for thrombosis and its consequences. In the United States, 48 out of every 100,000 residents develop acute thrombosis of the deep veins of the lower extremities and pelvis every year. Approximately 1,295 of the total number of patients receiving inpatient treatment develop thrombosis of the internal veins of the lower extremities or the pelvic region, which are clinically evident. Approximately 20-3095 of all general surgery patients and more than 5095 of all orthopedic surgery and accident patients suffer from deep vein thrombosis of the lower extremities, with approximately 195 of these patients developing pulmonary embolism with clinical 29 symptoms (|(see "Recommendations for diagnosis and therapy in vascular surgery" (Cheyipieep gy Oiadpovik (3 tspa Tpegarie ip deg Seigapbsnigigdieye)"), issued by the Board of the German Society of Vascular Surgery (SOI. Sev. y.

Segapspigygodie), species Oetsivspeg Agliemetigiad, Koip 1998).

The mechanisms that play a decisive role in the occurrence of thrombosis were described as early as 185br. Rudolph

Virkhov (Kidoii Migsp/) and were named in his honor as Virkhov's triad. At the same time, we are talking about damage to the vessel wall, slowing of blood flow and increased blood coagulation due to changes in its composition. If (Ge) the occurrence of venous thrombosis (phlebothrombosis) is caused mainly by the slowing down of blood flow and increased blood coagulation, then the main cause of the occurrence of arterial thrombosis, which occurs less often, is damage to the vessel wall, usually due to arteriosclerosis, which is accompanied by Ge) deposition of platelets.

The formed thrombus remains in its original form only for a few days. After a change in the structure, the thrombus in its final state turns into a scar, and the patency of the vessel is partially restored again (vessel recanalization occurs). The first goal of thrombosis therapy is to restore blood flow.

Such therapy depends on the age of the thrombus and is effective only during the first 10 days from the moment of its formation. « du It is possible to restore blood flow, first of all, by medical dissolution of blood clots (thrombolysis). Secondly, it is also possible to restore blood flow through surgical intervention, either by eliminating the blockage of a vessel with the removal of a blood clot (thrombectomy), or by applying a bypass anastomosis to bypass the blocked section of the vessel by conducting plastic surgery on the vessels (bypass). The second goal of thrombosis therapy is the prevention of further growth of the thrombus and the prevention of distant consequences of thrombosis, respectively, related complications. -1 395 In clinical practice, the diagnosis of thrombosis is based mainly on methods of visualization of the parts of the vascular system affected by it. One of the most effective methods of detecting thrombosis, as well as establishing (Ce) its size, is an x-ray examination with the introduction of a radio-contrast substance into the blood (phlebography). The disadvantage of this method is the irradiation of the patient with ionizing radiation and the manifestation of side effects associated with the use of iodine-containing radiopaque substances. Therefore, in case of suspicion of deep vein thrombosis (se) 50 of the lower extremities, in many medical institutions, an initial examination is carried out by the method of color-coded

I" of duplex ultrasound (B-scan in combination with pulse ultrasound), which, however, largely depends on the qualifications and experience of the doctor who conducts the study. Other non-invasive research methods for visualization of changes that have occurred in the vessel lumen include arteriography, computed tomography (CT) angiography and magnetic resonance (MR) angiography, as well as methods of 59 radiation medicine.

GF) So, in particular, as contrast agents for visualization of blood clots can be used labeled with indium-111 t form elements of blood , p. 9381.

Iodine isotopes .)-125 and 9-131 are also suitable for use with the same purpose, that is, for visualization of blood clots.

IRapo, O5 5011686, 1991). Technetium Ts-99t isotope has become widely used as a label. It is used 60 for labeling peptides and, first of all, monoclonal antibodies (Vegdeg, O5 5024829, 1991; Reap et al., 5 4980148, 1990; 05 5508020, 1996; 05 5645815, 1997; MO 00/611955 005 61617, 1661011, ER161578 20021. Compounds that can be used both for scintigraphy and for MR-tomography are described in Abeitap (05 5656600, 1997). UMO application 01/77102 in the name of OyRopi RIaptaseciisaiv describes conjugates of metal complexes and pyridinones, suitable for use as contrast agents for the diagnosis of thrombosis using scintigraphy, computer tomography or MR tomography.

Many publications are devoted to the use of MR angiography for visualization of intravascular thrombi.

So, for example, in the application M/O 95/09013 in the name of Suiodep, polypeptides are described as complex formers of paramagnetic metal ions.

In the application MO 95/24225 in the name of Musotei, polymer complex formers for visualization of blood clots are considered.

Similar complexing agents, such as DOTK (1,4,7,10-tetraazacyclododecane-M,M,M",M'"-tetraacetic acid) or roZA, are linked to a framework, for example, polylysine.

Paramagnetic conjugates based on DtTPK (diethylenetriaminepentaacetic acid) suitable for visualization of blood clots are described in the application MUO 95/20603 under the name "bBapdo". 70 In the patent OB 5780010 in the name of Vagpe-demzhizpi NozriiaIP, conjugates are described that specifically bind (with complexes of biotin with avidin) as contrast agents for visualization of thrombi. IMO application 98/16256 to Vygpiyat Ipziyshe also describes residues that specifically bind (to integrin) to visualize thrombi. Such conjugates contain paramagnetic complexes of DTPC, EDTC (ethylenediaminetetraacetic acid) or DOTC as signal-forming residues.

In the application MUO 01/04117 in the name of Z-Oitepviopa! Conjugates of a guanidine derivative and paramagnetic complexes, which are used as contrast agents for visualization of blood clots, are described in detail.

In applications UMO 01/09188 and EP 1203026 in the name of ERICH, conjugates of complexes of DTPC, DOTK or ROZA and polypeptides, which are used as contrast agents for visualization of blood clots, are described.

Application EP 885545 named after Riidgitt describes the use of superparamagnetic iron oxides as contrast agents for the diagnosis of thrombosis by MRI.

In the form of particles (OUTLINE) there is also a contrast agent for MRI, which is described in MO application 02/22011, in which it is proposed to be used for the diagnosis of blood clots.

The disadvantage of conjugates is that, along with the diagnostically effective fragment, an additional component (peptide or medicinal substance) is also present in them, which is why side effects, such as reduced tolerance, are often found during their use.

In the application EP 885545, although it refers to the possibility of using the particles of contrast agents described in it presented in the form of i) for visualization of blood clots, this possibility is not confirmed by experimental data.

MO application 02/22011 presents images that, however, are obtained on the basis of T 0 25"-weighted "Ezo sequences according to the RIH ABZN technique, and therefore thrombi after the introduction of a contrast agent give only a weak signal. Me

Recently, the examination of patients' blood for the presence of an increased concentration of O-dimers in it has acquired a more important clinical significance. According to the data of in-depth studies, it was established that the concentration of U-dimers in the blood is less than 5OOmkg/l with a high degree of probability, indicating the absence of Me thromboembolism in the examined individual (R.5. UMeiyiv, R. Vgy-Eadmagaz, R. Ziemepz, etc. . on the basis of data on the increase of their concentration in the blood, it is impossible to draw a conclusion about the presence or absence of thrombosis.

Tomography, based on the method of nuclear magnetic resonance (NMR-tomography or MRI), is a modern, non-invasive radiological method that allows to visualize physiological and pathophysiological structures with an exceptionally high spatial and temporal resolution. In diagnostic studies of the deep veins of the lower extremities and the pelvic area, an alternative to phlebography and color-coded ultrasound ultrasound (CUS) is;" MR venography (MRV), which has long been well established as an effective method of studying suprapopliteal veins. In recent years, the results of the study of the veins of the lower leg with the help of

MRV -I In principle, on the basis of a set of data obtained during three-dimensional MR angiography with contrast enhancement, it is possible to selectively visualize the venous system by subtracting the signals that correspond to the phases of perfusion, and also directly visualize it after injecting a diluted paramagnetic contrast agent into the vein back to foot With MR angiography using traditional, extracellular paramagnetic substances, it is not always possible to achieve uniform contrast in the image of the vessel, which in some cases makes it difficult to evaluate the results of the study. However, with the currently expected use of contrast agents with a higher concentration or so-called "agents for visualization of blood pools" ("Viooa Ros! Adepiv"), the effectiveness of faster methods of three-dimensional MR angiography with contrast enhancement may increase significantly in the future.

A fairly high-level signal can also be obtained on a tomograph of low magnetic field intensity in the Open type on the basis of To-weighted pulse sequences of the turbo-spin response and the passage time of the sequences (without contrast material) (S. Kopid and others, MK-Mepodharpie at oPepep MiedepeIdiotoadgarnep

F) tspieg Meglepdypd tapieiIeg Riizzapdtenpiayop, Koio, Rogizspg. Mar. Kopidepvzig,. Metsep Wiiidder. Maps 173, ka 2001, p. 810-814). MR-angiography methods, which are sensitive to the speed of blood flow, are not suitable for the diagnosis of thrombosis, because in veins, primarily in veins with thrombosis, the speed of blood flow in their non-thrombosed part is often too low.

The use of special contrast agents capable of selectively accumulating in certain tissues and organs allows to significantly increase the value of MRI as a method of diagnostic research. It is obvious that the compositions based on contrast substances capable of selectively accumulating in intravascular blood clots would allow to determine the location of the disease focus and the degree of its development at an earlier moment and thereby 65 would provide the possibility of targeted treatment and prevention.

Therefore, in this field there is still a need for a well-tolerated human body,

highly effective contrast agent suitable for visualization of arterial and venous thrombosis.

Based on the above, the basis of this invention was the task of offering such contrast substances for visualization of intravascular thrombi using MR tomography, which would meet the necessary requirements for selective accumulation in the thrombus, high tolerance, significant increase in the intensity of the signal generated by them, complete removal from the body and good solubility in water.

According to the invention, it was unexpectedly established that perfluoroalkyl-containing metal complexes, which are characterized by a critical micelle formation concentration of less than 10 "Zmol/l, a hydrodynamic diameter of micelles (22) greater than nm, and a relaxation of protons in plasma (B) greater than 1Ol/mmol-s, are highly suitable 70 for use as contrast agents in MR tomography for visualization of intravascular thrombi.

Compounds with similar properties are already described in the application MUO 02/13874, according to which they were proposed to be used as diagnostic tools for visualization of plaques using MR tomography.

In the images obtained with the help of MRI, however, it is clearly visible that plaques and thrombi can be clearly distinguished from each other. This fact is all the more important because blood clots in the early stage of their formation can move through the vascular system and for this reason can lead to fatal embolisms.

In the experiments described below, gadolinium complexes were used, since among all paramagnetic ions, gadolinium affects the signal enhancement during MRI.

According to the results of the ip mio experiment (binding to fibrin gel), it was possible to confirm that the degree of binding of the compounds used according to the invention to fibrin gel at a concentration of ca equal to 0.01 mmol/l reaches 7995, and at a concentration of ca that is equal to 0.1 mmol/l, reaches 39905, and therefore such compounds make it possible to reliably distinguish thrombi from plaques.

Along with this, the properties of the compounds used according to the invention in terms of their ability to enhance the contrast of images were also investigated by ip mimo. In rabbit experiments with photochemically induced thrombus (FIT, thrombus induced by intravenous injection of pink bengal and irradiation with light from a xenon lamp) in images obtained from T /y-weighted pulse sequences at o different time points after i.v. of the compound used according to the invention at the rate of O.Tmmol ba per kg of body weight (after 2-48 hours after administration), a significant amplification of the signal formed by an artificially induced thrombus was observed. 24 hours after the introduction of the compound used according to the invention, the concentration of gadolinium in the thrombus was approximately 4 times higher than its concentration in the blood. "AND

The concentration of gadolinium in the thrombus, where the accumulation of the compound occurs, necessary for obtaining images with the help of MRI, should be a minimum of bOmmol/l and a maximum of 2500mmol/l. Obtaining Ф contrast images is possible after 15 minutes and within 48 hours after the injection of the compounds used according to the invention. Since the gadolinium complexes used according to the invention affect mainly the relaxation time of the protons in the tissue, T/-weighted pulse sequences make it possible to detect an increase in the intensity of the signal formed in the thrombus with the greatest efficiency. -

Perfluoroalkyl-containing metal complexes suitable for use in accordance with the invention mean amphiphilic compounds, the molecule of which has a perfluoroalkyl side chain as a non-polar fragment, which is not necessarily connected to the entire molecule by a lipophilic linker. The polar fragment of the compounds proposed in the invention is formed by one or more metal complexes and optionally other polar groups. - c In aqueous systems, similar amphiphilic molecules exhibit properties characteristic of traditional surfactants (such as, for example, sodium dodecyl sulfate, DSN). So, for example, these molecules reduce the surface tension of water. With the help of tensiometry, it is possible to determine the so-called critical concentration of micelle formation (CCM, in mol/l). For this purpose, the surface tension is determined depending on the concentration of the analyzed substance. KCM can be calculated on the basis of the change characteristics of the obtained surface tension function (c). Critical - the concentration of micelles in the compounds used in accordance with the invention should be less than 10 mol/l, preferably less than 107 mol/l.

The amphiphilic compounds used according to the invention are associated in solution and are presented in the form of aggregates. The size (2KIA) of such aggregates (which have, for example, the shape of micelles, rods, wafers, etc.) can be determined with the help of photon-correlation spectroscopy (PHS).

The second criterion, in accordance with this, is the hydrodynamic diameter of the 2KI micelles, which must be greater than nm. More preferred according to the invention are those perfluoroalkyl-containing metal complexes whose 2KA value is equal to or exceeds Znm, most preferably exceeds 4nm.

The method of determining CCM, as well as photon-correlation spectroscopy, is described in IN.-0O. OO bteg, "OgepliPasnepa KoPoidspetie", ed-vo MES, U/eippeit, Mem HogKk, Vaze!, Satrbigdde, ToKuo, 1994).

GF) The third criterion is the relaxation of protons in plasma (B) at 402C and a field strength of 0.47 tesla.

Relaxability, which is expressed in |l/mmol-cY, is a quantitative measure that characterizes the decrease in the relaxation time T/ of protons.

For the application envisaged by the invention, such relaxation should be extremely high and should be more than 1bl/mmol-s, preferably more than 1Zl/mmol-s, most preferably more than 15l/mmol-s.

Relaxation B! (l/mmol-s) used according to the invention for MR-tomography contrast agents were determined using the Mipisres P 20 device of the VgyKeg company. Measurements were carried out at 409С and a field strength of 0.47 tesla. For each T /4-sequence: 1809-ТИ -902, the "inversion-recovery" mode, and the measurements were carried out at 8 points. Bovine plasma supplied by Kgaebreg was used as the medium for the measurements. The concentration of the contrast agent in the analyzed mixtures was from 0.30 to

1.1 bmmol/l.

In one of the variants of implementation of this invention, compounds of the general formula I according to paragraphs 8-11 of the claims are preferred for use. At the same time, we are talking about known compounds (described in UMO application 50 91126017). The method of obtaining such compounds is also described in this application. According to the invention, it was unexpectedly found that these compounds are also suitable for use as contrast agents in MRI for visualization of blood clots. It is most preferable to use compounds that are metal complexes marked as MK 2, C and 4, as well as MK 8, 9, 10 and 11 (see also table 1).

In another variant of the implementation of this invention, compounds of the general formula 7/o and according to paragraphs are preferred for use. 12-21 of the claims. These compounds are also known (described in MO application 99/01161). However, the possibility of using such compounds as contrast agents in MRI for visualization of thrombi has not been described in the literature so far. Among these compounds, it is particularly preferable to use a metal complex designated as MK 12 (see Table 1).

According to another preferred embodiment of the invention, it is possible to use macrocyclic 7/5 perfluoroalkyl compounds of the general formula II

Kk

KN (o), in which /K is a complexing agent or a metal complex of the common minced meat t t v zvi | sm ar zho (8) c. h zo "their Fo de

IN! means a hydrogen atom or the equivalent of a metal ion with serial number 23-29, 42-46 or 58-70, c 22 and C mean a hydrogen atom, C.-Stalkyl group, benzyl group, phenyl group, -CHOH or o) -CH. -ОосСНзи m 2 is a residue of I 1, while I1102 independently of each other can have identical or different values,

AND! represents a hydrogen atom, a linear or branched C 1 -C 1 -C 2 alkyl group, which is optionally interrupted by 1-15 oxygen atoms and/or optionally substituted by 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group and /or by 1-5 -OKU-groups, where KU means a hydrogen atom or a C.-Stalkyl residue, or - с --в, с» Y7 represents a linear or branched C 1-C 2 -alkylene group, which is optionally interrupted by 1- 10 oxygen atoms, 1-5 -МН-СО-groups, 1-5-СО-МН-groups, an optionally substituted СООН-group with a phenylene group, 1-3 sulfur atoms, 1-2 -М(Б7)-5О »5-groups and/or 1-2 -505-M(B')-groups, where B! has the values -1 specified for A" which either means the МНСО-group, СОМН-group, М(В7)-805- group or -505-М(В)-group, and/or is optionally substituted by the В residue, and ee , B" represents a linear or branched perfluorinated alkyl residue of the formula CoEopE, where ka n means numbers from 4 to 30, and

E means the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, while optionally present acid o groups can under certain conditions be presented in the form of salts with organic and/or inorganic bases

T" or amino acids or amides of amino acids, as defined in application MO 02/13874, which also describes the preparation of such compounds.

Metal complexes MK 17, MK 18, MK dv 19, MK21 and MK 23 are the most preferred for the application envisaged by the invention (see Table 1).

These compounds of the general formula 16, when used as contrast agents in MRI, are most suitable for (F, visualization of blood clots.) According to another preferred embodiment of the invention, perfluoroalkyl-containing complexes with sugar residues of the general formula I can be used (see UUO 02/13874) where 65 K means a mono- or oligosaccharide residue attached through the 1-OH- or 1-5H-position,

B means a perfluorinated, straight or branched carbon chain of the formula -SeEopE, where

E represents the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n means the numbers 4-30,

K means a metal complex of the general formula Is

DY V. so s - Still m y

In ' and re | yan! ki) 70 tea; wok! in which

Whew! represents a hydrogen atom or the equivalent of a metal ion with the sequence number 23-29, 42-46 or 58-70, provided that at least two B residues represent equivalents of metal ions,

B2 and BZ independently of each other mean hydrogen, C1-C7 alkyl, benzyl, phenyl, -SNOH or -CHNOOCH»z and

M represents -SeNu/-О-СН»-о-, "(СНо) 1.5 -о-, phenylene group, -СНоО-МНСО-СН-СН(СНСООН)-С вНа-о, -SenН-(оСННСНою .l -M(СНСООН)-СНо-о- or optionally interrupted by one or more oxygen atoms, 1-3 -МНОСО-groups, 1-3 -СОМН-groups and/or substituted by 1-3 -СН2) 05СООН-groups C.-C.-oalkylene or C7-C12-SeH./-O-group, while o means the place of attachment to -СО-, or the general formula Shs i-y r z - T, Es r se; tei (5)

SCHI hu She, . I: "in which F

B has the above values, 4 . 1 equiv; : with

Kk" means hydrogen or the metal ion equivalent specified for K' and

ШТ means -СеНА-О-СН2-о-, where o means the place of attachment to -СО-, or the general formula IMs Me) and - yam, « and shi s sos khz in which В! and 22 have the values specified above, or the general formula Msa or MeV shk v. The same thing happened

OP VC which "Ok "vno o vi se) that cha- and ZH ke . (se) 50 and No in which VE! has the values indicated above, or of the general formula Mis o kogo r: y she: z k in which V! has the above values, or the general formula MIs 60 drink b5 and in which

B has the above values, and

ShЦs means -С6Н/-0-СН»-о-, where o means the place of attachment to -СО-, or the general formula MPs ж... ш- и

Slys - topics in which V! has the above values, while the free acid groups optionally present in the K residue may optionally be represented in the form of salts with organic and/or inorganic bases or amino acids or amino acid amides, in the event that K represents one of the metal Po-MIs complexes, is at least a three-fold functionalized residue selected from the following residues a)-)): (y and z | (8) shi s - im - y? y chi -I ime) B M. so 50. y

T" name) 60 b5

WITH

70 and in I a s | , And oh and oh. : o se : Ge) 35 . them- | - with Sh » y

Also - and . Y Sche so nn a VA A ko so so 20

And" ooo Mik ono shchi ma . o ' z-- SN Me ko V. because two things

And g. "m b5 t ih y g y she, and M Po ! I 70 . nya give

Сb in the case that K means the metal complex MIs, is at least a three-fold functionalized residue selected from the residues k) and 1): pF 4 (8) ach --nrobn M i (22) s while o means the place of attachment C to complex K, p means the place of attachment of C to residue У, and y means the place of attachment of OS to residue 7, -

U means -СНо-, 5-(СН2)и-5СО-р, 5-СНо-СНОН-СО-р or 5-СН(ИСНОН-СНоООН)-СНОН-СНОН-СО-р, where 5 means the place of attachment to sugar residue K, and p means the place of attachment to the residue c, 27 means the group "b i-Shshsh L-vog z c". . "» and -i . ime) уУ-МНенНоСНХ-О-СНоСН»2-е, с 50 where у means the place of attachment of 7 to the residue 0, and е means the place of attachment of 7 to the perfluorinated residue вт и» 1 ti: spi E

And, t" independently of each other mean the integers 1 or 2 and p" means the integers from 1 to 4.

Among the compounds of the general formula Is, it is most preferable to use according to the invention the metal complex MK 13, presented in Table 1.

GF) According to another preferred embodiment of the invention, it is proposed to use 7 perfluoroalkyl-containing complexes with polar residues of the general formula Ia, see MO 02/138741 60 sh 0ah in which

B" means a perfluorinated, straight or branched carbon chain of the formula -CoEopE, where

E represents the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and 65p means numbers from 4 to 30,

K means a metal complex of the general formula Pa carries ah in which

IN! means a hydrogen atom or the equivalent of a metal ion with sequence number 23-29, 42-46 or 58-70, provided that at least two residues of B! mean metal ion equivalents,

B2 and 23, independently of each other, mean hydrogen, S-Stalkyl, benzyl, phenyl, -SNOH or -СНоОСН" and

O means -СеН/-О-СНо-о-, -(СН»)/5-ою-, phenylene group, -СНо--МНСО-СНо-СН(СНХСООН)-С вНа-о-, -SenН-( oСНСН»o)yu. -M(СНСООН)-СНо-о- or optionally interrupted by one or more oxygen atoms, 75.1-3 -МНСО-groups, 1-3 -СОМН-groups and/or substituted by 1-3 -СНо)ю. 5СООН-groups C.-Sioalkylene or С7-С15-СеН/аО-group, where о means the place of attachment to -СО-, or the general formula Sha chi (y,

And soov! cm in which Ge)

Whew! has the above values,

VE stands for hydrogen or indicated for B! equivalent of a metal ion and

ShЦs means -СеН./-О-СН»-о-, where o means the place of attachment to -СО-, or the general formula ma «г т 1 то ; F s au. F

And: and - in which B! and B? have the values indicated above, "or the general formula MaA or Uav: shi s --( . . and they are in " . 45 . - and WHOSE tower, y (se) t va. ' -5 Shh o "v t Esh CHON Seavu ,

Shchi uki se)

T" where V! has the values indicated above, or the general formula MIi viv in М «М , . where V! has the above values, or the general MI formula

Ov ime) in D 6.

El and in which one

В has the values indicated above, and ШЙ means -СеНу/-О-СНо-о-, where о means the place of attachment to -СО-, while the free acid groups optionally present in the K residue may optionally be represented in in the form of salts with organic and/or inorganic bases or amino acids or amino acid amides, means at least a three-fold functionalized residue selected from the following residues a)-Her):

M) 70 yak; mouths: il yu V s h. i « : (o) a a g. s i ; Fig. 9 «! - with

I.Y and? -And. se) o se) s" ; ko: 60 b5

. i- - "t these links ': m l I " r nat DY i ; here cha Ya tyu ad in sh sa: v. ; | сч with (8) - where о means the place of attachment of c to complex K, D means the place of attachment of C to the residue of K, and Г means "E

З The place of attachment of b to residue 2 means the group o pn svea

And (o) from RON IISN, where y means the site of attachment of 7 to the C residue, and y means the site of attachment of 7 to the perfluorinated residue of

K is a polar residue selected from the K complexes of the general Pa-Mia formulas, and in this case B! means a hydrogen atom or the equivalent of a metal ion with serial number 20, 23-29, 42-46 or 58-70, and 40 residues VK, BU, B", y and 0! acid "" or attached via -CO-, -505- or a direct bond to the C residue a carbon chain with 2-30 C-atoms, "which is straight or branched, saturated or unsaturated and which is optionally interrupted by 1-10 by oxygen atoms, 1-5 -MHSO-groups, 1-5 -СОМН-groups, 1-2 sulfur atoms, 1-5 -МН-groups or 1-2 phenylene 45 groups, which may optionally be substituted by 1-2 OH-groups, 1-2 MH o-groups, 1-2 -СООН-groups or 1-2 - -5О3Н-groups, or optionally substituted with 1-8 ОН-groups, 1-5 -СООН-groups, 1 -2 ZO zH-groups, 1-5

He) МН»-groups, 1-5 С.-Slalkoxy groups, and юю И, т, р2 independently of each other mean the integers 1 or 2.

Especially preferred compounds of the general formula Id include compounds that contain the general macrocycle K

FO 50 formulas id, Sha, Mav or Mid.

Among the compounds of the general formula Id, it is most preferable to use according to the invention the metal complex MK12, presented below in Table 1.

In another preferred embodiment of the invention, it is possible to use galena compositions containing paramagnetic and diamagnetic perfluoroalkyl-containing substances. Such paramagnetic and diamagnetic perfluoroalkyl-containing substances are preferably used in the form of a solution in an aqueous solvent.

HF) As paramagnetic perfluoroalkyl-containing compounds in such compositions, all the above metal complexes of the general formulas I, Ia, IB, Is and/or Ia can be used in accordance with the present invention.

Diamagnetic perfluoroalkyl-containing substances are compounds of the general formula XX | see UMO 02/138741: 60 ВР412-в2 (ХХ), in which B means a linear or branched perfluoroalkyl residue with 4-30 carbon atoms,! 2 means linker, and B? means a hydrophilic group. Linker 7 is a direct bond, a -ZO group or a straight or branched carbon chain containing up to 20 carbon atoms and which can be substituted by one or more groups -OH, -SOO", -503 and/or neobo necessarily contains one or more -О-, -5-, -СО-, -СОМН-,

-MnNeo-, -SOMV-, -MaEZso-, -80»5-, - РО, -, -«МН-, -ME groups, aryl ring or piperazine, while KE? means

C.i-Soralkyl residue, which in turn may contain one or more O-atoms and/"or may be substituted by -SOO or 503 groups.

Other acceptable diamagnetic perfluoroalkyl-containing compounds are conjugates of cyclodextrin and perfluoroalkyl-containing compounds. Such conjugates consist of o-, rD- or y-cyclodextrin and compounds of the general formula XXI! | see UUO 02/138741|:

KI Liu

Al so, 70 in which A! means an adamantane, biphenyl, or anthracene molecule, IS means a linker, and BP means a linear or branched perfluoroalkyl residue with 4-30 carbon atoms. Linker I Z is a straight hydrocarbon chain with 1-20 carbon atoms, which can be interrupted by one or several oxygen atoms, one or several CO-, 505-, СОМН-, МНОСО-, СОМК-, MKСО-, МН- , MA-groups or piperazine, while K is a C.i-Svalkyl residue.

Summarizing all of the above, it can be noted that the gadolinium complexes MK 1-30 presented below in Table 1 meet the criteria provided for by this invention, which are the most preferable for the use of compounds proposed in the invention. Table 1 also shows the physical characteristics of these metal complexes.

It should also be noted that the paramagnetic compounds of the general formulas |

MR-tomography for visualization of blood clots.

Table 1: The most preferred metal complexes (MK) for the application envisaged by the invention, the publications in which they are described, and their physical characteristics are: 11. zov i! 2, Six i r.v. и И? ZK A; i) scrap one Gmol/ti. yak ki 0 GEESE : А.Й ШЕ Ж 5 Z ІІ ю ИМЕЖ ГИ Бы 1 Я | 351 - MA R tet tya ih) a pi Shchi Ж sei y:

Ma GO ULMIU| i 1 and | ME | Z 1 "Te yashke y Yad TI u : no te p ry 22 IN - : st t -

TE eh v p still d y - s - y? -I se) ime) so 50 s»

F) name) 60 b5 nyah. toast PO TYA | you three E ii K i | ri

SKI a 1 TE plo i mir Ach - y Kz y Kak i - ka ioya| 35 1 M 1 AYU 1 45

R ' te tr pe le i y Chi with MORE. and had GshOyaI 19 valu 1 k - I (You and dishchd would; Pi t. M s with (ME OF THE YEAR | I | ke | ZNM | 46

Petidna: Mf I ner:

Ports 7: t i 7 R "g GA ii "dy I p H 7 g: | "y " " Я зо |В AT ГОД MYII b | M | ZY s 7 In sta yam pri g ii Zh: y As the same: and koh obla z | do» | a | 54 | sch " MmEL mom Z | my | a" | a | o masta GKO UT in them » Mk: GzhObyshyaye 1. 1 azh | dao | and

M II Z. | La SHE Ya s va - In sch

MKOi SHOFYAMEY| 85 1 5 | o M o t. ' Ky reich "DI ' - g z" (KO; GZHOUMYANI| Z | Z | I | I | in ko riklkioe g 1 | 259 | I i

And I don't have a wall, a union

ME2 Irena, | 2 1 ii 1 18 TI, zhi shi

In the above table, the abbreviation "KKM" means the critical concentration of micelle formation, 2KP means c is the hydrodynamic diameter of micelles, and B! means relaxation. "» Measurements were carried out in plasma at 402C and a field strength of 0.47 tesla.

Example 1 a) Methyl ether of b-benzyloxycarbonyl-2-M-2H,2H4H,4H,5H,5H-3-oxaperfluorotridecanoyl-i-lysine -i To a solution of 50 g (95.8 mmol) 2H,2H.4H,4H,5H ,5H-3-oxaperfluorotridecanoic acid (obtained from 2H.2H,ZH.ZH-perfluorodecanol and tert-butyl ether of bromoacetic acid with subsequent cleavage of the complex ether) add 2 drops of dimethylformamide to 250 ml of thionyl chloride and heat under reflux for 5 hours. After that, the reaction mixture is concentrated in a vacuum, the residue is dissolved in 250 ml of 50 dichloromethane, and this solution is added dropwise at 09C with stirring to a solution of 34.74 g (105 mol) of 6-M-benzyloxycarbonyl-! -lysine (commercially available product, Vaspet company), and also 46.85 ml (3500 mmol) of triethylamine in 400 ml of dichloromethane. The mixture is left to stir overnight, after which it is mixed with 1 l 2 n. of hydrochloric acid, the organic phase is extracted by shaking, the aqueous phase is extracted twice with dichloromethane in portions of 100 ml, the solution is dried over sodium sulfate, filtered through a desiccator and concentrated in a vacuum. The crude product is purified by silica gel chromatography. A mixture of dichloromethane and 395% ethanol is used as an eluent. After concentration, the desired product is obtained as a colorless product

F) gel. ime) Output: 67.Ohm (87.695 from theory).

Elemental analysis: 60 divisions. С40.61 НЗ.А1 40.45 М3.51 detected: С40.48 НЗ.54 40.61 М3.37 b) Hydrochloride of methyl ether 2-М-2Н,2Н.4Н4Н,5Н,5,Н-3- oxaperfluorotridecanoyl-lysine 65 To a solution of 63.5 g (79.5 mmol) of the substance specified in the title of example Ta) in a mixture with 100 ml of methanol and 30 ml of 1Tn. of hydrochloric acid, add 10g of a catalyst (109o Pa/sС) and hydrogenate at normal pressure and room temperature until one equivalent of hydrogen is absorbed. Then the catalyst is filtered off, it is washed three times with hot methanol in portions of 5 Oml and the combined solutions are concentrated. The residue is dissolved in methanol and crystallized by adding isopropyl ether. In this way, the title compound is obtained in the form of colorless crystals.

Output: 55.7Ω (quantitative).

Elemental analysis: div. С32,56 НЗ,16 СИБ,Об РА6б,09 MA,00 70 detected: С32,44 НЗ,28 SIM,95 РАб,21 МА11 c) Methyl ether 6-M4-3,6,9,12,15- pentaoxahexadecanoyl-2-M-2H,2H 4H,4H,5H,5H-3-oxaperfluorotridecanoyl-and-lysine 13.31g (50.Omoles) 3,6,9,12,15-pentaoxahexadecanoic acid (commercial product) dissolve in 100 Oml of thionyl chloride, mix with two drops of dimethylformamide and stir overnight at room temperature. After that, it is heated to 6523 for an hour, the excess thionyl chloride is removed on a rotary evaporator and the residue is dissolved in 150 ml of dichloromethane. This solution at 02C is added dropwise to a solution of 35.04g (50.00mmol) of the compound indicated in the title of example 16) and 15.18g (150mmol) of triethylamine in 350ml of dichloromethane. After that, the mixture is stirred for 72 hours at room temperature. After that, the reaction mixture is concentrated and after column chromatography on silica gel, the desired product is obtained. A dichloromethane/ethanol mixture in the ratio of 9:11 is used as an eluent. The title compound is obtained as a viscous, yellowish oil.

Output: 37.Ohm (81.195 from theory).

Elemental analysis: sch 29 div. С 39.48 НА.53 Е 35.39 М3.07 He) detected: С 39.61 Н 4.50 Е 35.50 М3.16 g) 6-М-3,6,9,12,15- pentaoxahexadecanoyl-2-M-2H,2H.4H 4H,5H,5H-3-oxaperfluorotridecanoyl-and-lysine 17.90 g of the compound indicated in the title of example 1c) is stirred overnight in a mixture of 5 bOml of methanol and - 25 Bml of 2n. caustic sodium solution. After that, the reaction mixture is acidified with 2N. hydrochloric acid, concentrate in Ge"! vacuum and the residue is extracted five times with a mixture of tetrahydrofuran/ethyl acetate (in a ratio of 2:1) in portions of BOml. The combined extracts are dried over sodium sulfate. After that, the desiccant is filtered off and the solution is concentrated. The residue is purified by column chromatography on silica gel. A mixture of dichloromethane/methanol/water in the ratio of 160:40:1 is used as an eluent. In this way, the title compound is obtained in the form of a waxy residue, which has a light yellow color. -

Yield: 14.7g (83.495 from theory).

Elemental analysis: div. C 38.76 H4.37 E 35.94 M3.12 h detection: C 38.87 H 4.25 E 36.07. M3,21 With c "n) "" 6-M4-3,6,9,12,15-pentaoxahexadecanoyl-2-M-2H,2H4Hn,4H,5H,5H-3-oxaperfluorotridecanoyl-i -lysine-M- 11,4,7-triscarboxylatomethyl/-1,4,7,10-tetraazacyclododecane-10-(2-hydroxy-3-yl), gadolinium complex amide

8.0g (8.9mmol) of the acid obtained in example 1g) and 2.05g (17.8mmol) of hydroxysuccinimide are dissolved in 5Oml of dimethylformamide and mixed with 4.60g (22.25mmol) of dicyclohexylcarbodiimide at 09C. Mixture c is stirred for another 10 minutes at 02C, and then for the next 2 hours at room temperature. After re-cooling to 0 9C, add a solution of 3.93 g (6b,bmmol) of gadolinium complex 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane (MO 95/17451), as well as 20 0.58 g (13.7 mmol) of lithium chloride and 2.77 g (27 4 mmol) of triethylamine in 40 ml of dimethyl sulfoxide. Then the mixture is stirred for two days at room temperature, after which it is mixed with 50 ml of acetone and the suspension is poured into 2 l of methyl tert-butyl ether. Next, the mixture is stirred for about 30 minutes and then the solid is separated by vacuum filtration. This solid is dissolved in distilled water and treated with activated carbon. The solution is filtered, concentrated in vacuo and the residue is chromatographed on 22 silica gel. A mixture of methanol and dichloromethane in a ratio of 2:1 is used as an eluent.

F! Yield 5.47g (54.590 from theory).

Moisture content: 7,390. o Elemental analysis (in terms of anhydrous substance): 60 divisions. C 37.97 NA,71 sa10.81 g22.19 M 6.74 found: С 38.16 H 4.83 с410.72 22.32 Mb,83

Example 2 a). 10-(3-carboxy-3-ylpropionic acid)-1,4,7,10-tetraazacyclododecane 150g (76b1mmol) of bromobutric acid 65 is neutralized with caustic sodium (1095) and the solution is concentrated to dryness. 65.55 g (38 mmol) of cyclene are dissolved in 300 ml of distilled water and mixed with disodium salt (obtained from 150 g of bromuric acid, which corresponds to 7 b1 mmol). After that, it is heated to 502 and left to stir overnight. Then the solution is concentrated to dryness and distilled together with ethanol. The residue is dissolved in butanol and extracted with water. The aqueous phase is concentrated and chromatographed on silica gel. A mixture of methanol and ammonia (in a ratio of 20:1 to 2:1) is used as an eluent. The fractions containing the product are combined and concentrated to dryness.

Yield: 54.8g (50.495 from theory).

Elemental analysis: div. C 50.34 H 7.74 M 19.57 70 detected: C 50.46 H 7.83 M 19.69 b) 1,4,7-tris(carboxymethyl)-10-(3-carboxy-3- ylpropionic acid)-1,4,7,10-tetraazacyclododecane

11g (38.14mmol) of 10-(3-carboxy-3-ylpropionic acid)-1,4,7,10-tetraazacyclododecane is dissolved in 10ml of distilled water and mixed with 18.03g (190.74mmol) of chloroacetic acid. Next, the mixture is heated to 702 and its pH value is set to 9-10 by adding caustic sodium (3295). Then the mixture is stirred overnight at 702, after which its pH value is again set to 10 and 7.2 g (76.19 mmol) of chloroacetic acid is added. After that, the mixture is stirred for another hour at 70 C. Then the mixture is concentrated to dryness, evaporated with methanol, dissolved in methanol and the salts are filtered off. The filtrate is concentrated and chromatographed on an Atbegiye 252C ion exchange column using a water/ammonia mixture as a 20 eluent. Fractions containing the product are combined, concentrated, redissolved in distilled water and lyophilized. In this way, the compound specified in the title is obtained in the form of a white foam.

Yield: 13.12g (82.390 from theory).

Moisture content: 9.690.

Elemental analysis (calculated per anhydrous substance): C 46.75 H 6.54 M 12.12 o detection: C 46.87 H 6.62 M 12.24 c) Gadolinium complex 10-11-carboxy-2-carbonyl (piperazin-1-yl-4- -(perfluorooctylsulfonyl)|) ethyl-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, sodium salt C

10.0 g (16.21 mmol) of gadolinium He) complex of tetraazacyclododecane (obtained from the ligand by complexation with gadolinium oxide) and 3.0 g of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide under moderate heating. After cooling to room temperature, add 9.21 g (16.21 mmol) of perfluorooctylsulfonylpiperazine. After that, it is cooled to 0 9C, 12.3 g (46.63 mmol) of EEDH Ge) (ethyl ether of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid) are added and stirred overnight at room temperature. Then the reaction mixture is poured into a mixture of 800 ml of methyl tert-butyl ether and 100 ml of acetone and mixed. The precipitate is purified by chromatography on silica gel. A dichloromethane/methanol/ammonia mixture in a 2:2:1 ratio is used as an eluent. The fractions containing the product are combined and concentrated.

The residue is dissolved in 200 ml of distilled water, the pH value is set to 7.2 using caustic sodium "du" and lyophilized. In this way, the compound specified in the title is obtained in the form of a white foam. -

Output: 7,b4g (39905 from theory). c Moisture content: 7,890. :z» Elemental analysis (in terms of anhydrous substance): disp. C30.31 H2.80 27.17 са13.23 M 7.07 Ma 1.93 8 2.70 - 45 found: С 30.42 H2.91 E 27.04 sd13.29 M 7.15 Ma 2, 04 8 2.59 so Example C a) and 1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(2-hydroxy-3-(M-benzyloxycarbonyltriglycid) so 20 yl)amino |propyl, gadolinium complex

In 100 ml of dimethylformamide, dissolve 12.68 g (39.121 mmol) of M-benzyloxycarbonyltriglycine (a commercially available product, Vasneg company) and mix with 9.03 g (78.42 mmol) of M-hydroxysuccinimide. Next, the mixture is cooled to 02C and then 32.36 g (156.84 mmol) of dicyclohexylcarbodiimide is added. After that, it is stirred for 20 minutes at 02C, and then for another hour at room temperature. This suspension is then added with stirring to 25 g of a solution of 15 g (26.14 mmol) of gadolinium complex 10-(3) cooled to 0

HF)-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (obtained according to UMO with 95/17451) in 40 ml of distilled water and 15 ml (14 mmol) of triethylamine in bOml of isopropanol. After completion of this addition operation, the mixture is stirred for 1 h at room temperature. After that, urea is filtered off, washed with n-butanol and concentrated in a vacuum. The residue is repeatedly extracted with water. 60 The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel. A mixture of dichloromethane, methanol, and ammonia is used as an eluent. The fractions containing the product are combined, concentrated in a vacuum, redissolved in distilled water and subjected to freeze-drying.

In this way, the compound specified in the title is obtained in the form of a white foam.

Yield: 12.94g (56.390 from theory). because Elemental analysis:

distr. С 42.36 Н 5.16 Са17.89 М12.75 detected: С 42.44 Н 5.22 417.78 М12.80 95 b) 1,4,7-tris(carboxylatomethyl)-1,4,7 ,10-tetraazacyclododecane-10-(2-hydroxy-3-aminotriglycidyl)propyl, gadolinium complex

In a mixture of 1000 ml of ethanol and 30 ml of distilled water, dissolve 8.53 g (9./mmol) of the compound specified in the title of Example 1a) and mix with 2 g of a catalyst (10906 palladium on activated carbon), as well as with 3 ml of acetic acid. Next, they are hydrogenated until one equivalent of hydrogen is absorbed. Then the catalyst is separated by vacuum filtration 70, after which it is washed with ethanol and the solution is concentrated to dryness under vacuum. In this way, the compound specified in the title is obtained in the form of a foam.

Yield: 7.22g (quantitative).

Elemental analysis: div. C 37.08 H 5.28 bag21.11 M15.04 detected: C 37.21 H 5.33 sa21.25 M15.15 c) 1,4,7-tris(carboxylatomethyl)-1,4,7, 10-tetraazacyclododecane-10-(2-hydroxy-3-M-(triglycidyl-M-(2H,2H,4H an

H,5H-3-oxaperfluorotridecanoyl))amino)propyl, gadolinium complex

7.60 g (14.55 mmol) of 2H,2H.4H.4H,5H,5H-3-oxaperfluorotridecanoic acid are dissolved in 900 ml of dimethylformamide and mixed with 3.35 g (29.1 mmol) of M-hydroxysuccinimide. Next, it is cooled to 029 and then mixed with 11.71 g (56.71 mmol) of dicyclohexylcarbodiimide. After 20 minutes, the cooling bath is removed and the mixture is stirred for the following minutes at room temperature. After that, the resulting suspension with 29 stirring is added to a cooled to 02C solution of 7.22 g (9.7 mmol) of the compound indicated in the title of Example 36) in a mixture with 10 ml (36./mmol) of triethylamine, 2 ml of distilled water and 30 ml of 2-propanol . The mixture is left to stir overnight at room temperature, after which dicyclohexylurea is filtered off, washed with a mixture of 2-propanol/distilled water in a ratio of 3:2, and the combined solutions are concentrated in vacuo. The residue is dissolved in a mixture of water and butanol and extracted with butanol. in

The combined organic solutions are dried and concentrated in vacuo. The residue is purified by silica gel chromatography. Gee!

A mixture of ethanol/2-propanol/concentrated ammonia in a ratio of 15:10:1 is used as an eluent. Fractions containing the product are combined, concentrated to dryness in a vacuum, redissolved in distilled water and lyophilized. In this way, the compound specified in the title is obtained in the form of a white foam. Gee!

Yield: 7.52g (62.195 from theory).

Elemental analysis: - div. C 33.66 H 3.55 E 25.86 Ca12.59 M 8.97 found: C 33.55 H 3.67 E 25.99 sa12.43 MO.09 «

Example 4: Binding to fibrin gel - c Fibrinogen is mixed with thrombin and incubated for 30 minutes (at room temperature), obtaining a coagulant (fibrin gel). It is mixed with 0.5 ml of SFR (phosphate-buffered saline) and with 0.5 ml of the solution of the compound specified in the title of example 21 in MO 02/13874, which in this description is designated as metal complex MK 13 (with a concentration (for 0, 01 and O.Tmmol/l), and incubated for 16 hours at room temperature.

After removing the supernatant from the fibrin gel layer, the amount of the compound proposed in the invention, which did not bind to it, is separated from the fibrin by ultrafiltration (1,200 g for 30 minutes). The content of gadolinium in fibrin gel is determined by atomic emission spectroscopy with inductively coupled plasma (AES-IZP). binding of the compound proposed in the invention to fibrin gel was 79.195 for a solution with a 50 concentration of Ca of 0.001 mmol/l and 38.595 for a solution with a concentration of Ca of 0.Tmmol/l.

Example 5: Visualization of a venous thrombus (ip mimo) using MRI after intravenous administration

I" to a rabbit of contrast material

In the MRI imaging experiment, a rabbit with photochemically induced thrombus (PIT) was used. Animals were injected with pink bengal (2Omg/kg) by intravenous injection and after that thrombus formation in the left femoral vein was induced by exposure to light from a xenon lamp (54Ohm, 1.1O0Oclk, 25min). Blood flow in the femoral vein was monitored using an ultrasound probe. The images were obtained using a Madpeyut Nagptopu tomograph (bietepv company, 1Gl) using a pulse sequence based on the phase contrast technique (TK/TE-104/14ms) as well as T.i-weighted pulse sequences of gradient response (MRKade: TE/TELI/ ou-11/4/120 ms/v8h and ZO RGABN: TK/TE/a-5/2ms/50)2 before 60 (control image), as well as After 25 min, 40 min, h, 2 h, Zhd, 4 h, 24 h and 48 hours after intravenous administration (approximately one hour after the induction of thrombus formation) indicated in the title of example 21 in the application MO 02/13874 of the compound at the rate of O.Tmmol ba per kg of body weight.

After imaging, the left femoral vein (with a thrombus) was dissected, fixed in formalin, and stained with hematoxylin/eosin (HE), respectively, with phosphotungstic acid/hematoxylin (FPC) for 65 histological studies.

In MR-tomography (MRA) study, the thrombus could be detected already at an early stage (25 minutes after the injection). Images 1 and 2 shown in Fig. 1 show MRI images of the pelvic region 24 hours after intravenous administration to rabbits with FIT (photochemically induced thrombus) of the compound proposed in the invention at the rate of 0.0 mmol of ba per kg of body weight. Snapshot taken using

The Ti-weighted sequence based on the ZO Pav technique indicates a significant increase in signal intensity, which is formed by a thrombus in the area of the left femoral vein. A thrombus in the left femoral vein significantly reduces blood flow in it (see image obtained by MRI using a phase-contrast sequence).

Staining with both dyes (GE and FVKG (Fig. 2, images C and 4)) made it possible to detect the presence of red 7/o blood clots (thrombi) in the areas of the left femoral vein. At the same time, blood clots fill almost the entire lumen of a blood vessel. The images clearly show exfoliation of vascular endothelial cells and adhesion of blood clots.

Intima and adventitia almost completely disappeared.

With the help of this experiment, it was possible to confirm the suitability of the compounds proposed in the invention for use as a substance-marker of venous thrombi.

Example 6: Visualization of a venous thrombus (ex mimo) using MRI after intravenous administration of a contrast agent to a rabbit

In the MRI imaging experiment, a rabbit with photochemically induced thrombus (PIT) was used. Animals were injected with pink bengal (2Omg/kg) by intravenous injection, and after that thrombus formation in the left femoral vein was induced by exposure to light from a xenon lamp (54 Ohm, 1.10Occl, 25min). 24 hours after the intravenous administration (approximately one hour after the induction of thrombus formation) of the compound specified in the title of example 21 in the application UUO 02/13874 at the rate of 0.1 mmol per kg of body weight, the animal was killed and the left femoral vein (with a thrombus) was dissected. The image of the damaged area of the vein was obtained using a Madpeyut Nagtopu tomograph (Zietep5v company, 1Gl) using

Ti-weighted pulse sequence of spin response (TK/TE/9-300/12 ms/902, with and without suppression of the signal from adipose tissue).

Artificially induced thrombus as a result of the color acquired by it was clearly visible in the preparation. Blood clots were additionally located outside the vessel. When obtaining echo images using MRI based

A significant increase in the intensity of the signal generated by the thrombus is observed in the Ti-weighted pulse sequence of the spin response (see Fig. 3, images 5-7). "AND

Example 7: Determination of the accumulation of gadolinium in a thrombus after intravenous administration of the contrast agent Me to a rabbit.

An experiment to determine the content of gadolinium was performed on a rabbit with a photochemically induced thrombus (FIT). sou

Animals were injected with pink bengal (2Omg/kg) by intravenous injection, and after that thrombus formation in the left femoral vein was induced by exposure to light from a xenon lamp (54Ohm, 1.10O0cl, 25min). ia

24 hours after the intravenous administration (approximately 1 hour after the induction of thrombus formation) of the compound indicated in the title of example 21 in the MO application 02/13874, the animal was killed, and to determine the content of gadolinium in the animal's body, various its organs and tissues, namely, blood, femoral veins (with and without thrombus), muscle tissue. After preparation of the tissue samples, the concentration of gadolinium (in parts/million) was determined in them using AES-ISP. "

According to the obtained data, the concentration of gadolinium in the left femoral vein (with a thrombus) was 8 parts per million, and in the control vessel - only 1 part per million. A high content of gadolinium, equal to 16 parts per million, was detected in the blood clot, which is outside the blood vessel. The concentration of gadolinium in the blood, detected 24 hours after the injection of the tested compound, was only 15 parts per million, and in the muscle tissues, which do not amplify the signal, it was 1 parts per million.

Claims (50)

The formula of the invention se) GI 1. The use of perfluoroalkyl-containing metal complexes, which are characterized by a critical concentration of micelle formation of less than 103 mol/l, a hydrodynamic diameter of micelles (22) of more than 1 nm, and a relaxation of protons in the plasma (BE) of more than 10 l/mmol-s, as of contrast material during magnetic resonance imaging (MRI) CT" for visualization of intravascular thrombi. 2. Application according to claim 1, which differs in that the specified metal complexes are used as a contrast agent in MRI for visualization of venous thrombi. C. Application according to claim 1 or 2, which differs in that the indicated metal complexes are used as a contrast agent in MRI for visualization of arterial thrombi. o 4. Application according to any of claims 1-3, which differs in that the specified metal complexes are used as a contrast agent in MRI for early detection of thrombotic obliterative disease. 5. The application according to claim 1, which is characterized by the fact that metal complexes are used, which are characterized by a micelle formation concentration of less than 107 mol/l. 6. Application according to claim 1, which is characterized by the fact that metal complexes are used, which are characterized by a hydrodynamic diameter of micelles equal to or greater than 3 nm, preferably greater than 4 nm. 7. The application according to claim 1, which differs in that metal complexes are used, which are characterized by the relaxation of protons in plasma more than 13 l/mmol-s, preferably more than 15 l/mmol-s. 65 8. Application according to any of claims 1-7, which is characterized by the fact that as perfluoroalkyl-containing metal complexes compounds of the general formula ВР-И-К (0, in which В" means a perfluorinated, straight or branched carbon chain of the formula -СеЕопЕ are used , where E is a terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n means numbers from 4 to 30, Y means a direct bond, a methylene group, a -MNSO group, a Ka group, 10--"snagnnsosny( sni;- -m-v80,7- Ge where p means the numbers from 0 to 10, 4 and i independently of each other mean the numbers 0 or 1 and KK? represents a hydrogen atom, a methyl group, a benzyl group, a phenyl group, - "СНо-ОН-group, СН»ОСН»з-group, -СНо-СО»Н-group or СО-С-в-chain, which is optionally interrupted by 1-3 oxygen atoms, 1-2 "СО- groups or an optionally substituted aryl group and/or substituted by 1-4 hydroxyl groups, 1-2 C.-C; alkoxy groups, 1-2 carboxy groups, -503H- group, or means straight, branched, saturated or unsaturated C 5- Co-carbon chain, which n necessarily contains from 1 to 10 oxygen atoms, from 1 to 3 -MK C-groups, 1 or 2 sulfur atoms, piperazine, -somMkK -group, from 1 to 6 -MKEZSO-groups, -5O05-group, -MK2 -CO»-group, 1 or 2 -CO-groups, group c with -600-8-t -mschkh (lyh 5-v80,- o or 1 or 2 optionally substituted aryl groups and/or interrupted by the specified groups , and/or "g zo is optionally substituted by 1-3 -OK З-groups, 1 or 2 oxo groups, 17 or 2 -МН-СОК-groups, 1 or 2 -СОоМНЕ -groups, 1 or 2 -""СНо )p-СО»Н-groups, 1 or 2 groups "(СНо)р-(О)д4-СсНоСсНо-В where Ф ве, В, р and 4 have the above values, and с T represents С 5-Сио- which is optionally interrupted by 1 or 2 oxygen atoms or 1 or 2 Fu -MNOO groups, and 3 K means a complexing agent or a metal complex, or its salts with organic and/or inorganic bases or amino acids or amino acid amides, namely a chain , means a complexing agent or a complex of the general formula HER I), sn.sNn, - em « ra / - s M so-n : х и" ke ve ЦИ sozh V y t Fo Ya-s6o0 z Ov sh t sg M y M sov in which KS, V and B have independent one from one value and 27 has the values specified for KZ or means "Sno)t A, where (F. t means 0, 1 or 2, and where Y and BP have the above values, B! in each case independently means a hydrogen atom or the equivalent of a metal ion with the ordinal number 22-29, 42-46 or 58-70, and 60 В means the group -ОВ! or the group of the stump | NE rya sn.en, в - M 65 Sh- dz or -M m-50,--1-8 where В", И, В and ВО have the above values, or a complexing agent or a complex of the general formula ПИ 1 с, -- со М Но в Мч and х сом с-м М м-н, and а - -с3к М с х--.2с2025 о in which ВВ! have the above values, and (o) ; and in E" has the values indicated for K?", or a complexing agent or a complex of the general formula IM (22) 1 M, - Я-жк сч (22) M and - that ich n! som " with a M - Fo ;» ; M-vo sh M o M sov ime) sya z . in which K' has the values indicated above, is) or a complexing agent or a complex of the general formula M c» Ф) ime) 60 b5 YaA- so M and sor! os ---u iv rani ru sn (SNI so! in which VE! has the values indicated above, and o and d mean the numbers 0 or 1, while the sum is 4-1, or a complexing agent or a complex of the general formula MI s (MU), (o) i m 1 voi M M m /I sov « Fo s M M F t m, tu - ' sok so " in which V! has the above values, - s or a complexing agent or a complex of the general formula МИЙ k (MI), and pl YM and ten kos z | M -I se) ime) so 50 M M -» ; / m , h sov ov so F) where in which B! and B have the above values, or a complexing agent or a complex of the general formula MI 60 b5 (MI, then M kh ra so M M | M i SBNYUN; dm M ' I sov ve in which Viv! has the values indicated above, and B? has the values indicated above for KZ, or a complexing agent or a complex of the general formula IX (x ), 1 tu oh / khy sov M M sch y r o) " M Son M Fo Go y (22) so! ke m in which VS and B! have the values indicated above, or a complexing agent or a complex of the general formula X (0), « с М М - и? -I Se M M sn t t hy so 50 ge sodi! n in which VS and B! have the above values, Ge! or a complexing agent or a complex of the general formula ХИ име) 60 b5 sho -- yu MM M y r o y ImN-snuNI SOI so Sum 5z0.-x (XI), in which B", p and 4 have the values indicated above, and E? has the values indicated above for KZ, or a complexing agent or a complex of the general formula XII a (XII), c c; and M M- 1- 8 M u i "shi c 1 - - - sov" in which Y, VV have the above values, 15 or a complexing agent or a complex of the general formula ХИЙХІІ! - ut so: ss, se) yuyu M o Y mch I» so so o r M 50, z F) ney yu udo M 60 -- --o0o50252 in which B! has the above values. 9. Application according to claim 8, which differs in that compounds of the general formula I are used, in which |. 65 means А-СНо-Б, А-СНСНо-Б, А-(СНо)-Б where 8-3-15, А-СНО-О-СНСНоО-Б, А-СНо-«(0-СНо-СНо- X-B, where (-2-6, А-СНО-МН-СО-В, А-СНО-МН-СО-СНО-МЖСНСООН)-505-В, А-СНО-МН-СО-СНо-М(СоН)-505-В, А-СНО -МН-СО-СНО-М(Сл0Н2»1)-505-8,.. А-СНО-МН-СО-СНо-М(СеНиз3)-5025-8, | А-СНоО-МН-СО-(СН»)1о-М(СоН)-505-В, А-СНО-МН-СО-СНО-М(-СН»-СеНв)-505-В, А-СНО -МН-СО-СНо-МЩ(-СНо-СНо-ОН)БО»-В, 8500 А-СНО-МНСО-СН2)10о-5-СНоСН»о-В, А-СНОМНСОСНо-О-СНХСН»-В . -СНО-ОСНо-СНо-В, "-СНАМНСОСН.СНИСОМСН.сННСОосНИСН-ВО. snAsnAnSOsSNnA S. Nn,.nZO,V A-SN.-O-СНО-СН(ОС 10Н24)-СНЯ-О-СНСН»о.В, A-«(СНоМНСО) |-СНХО-СНСНО-В, 18 A -"СНоМНСО)3-СНО-СНСНО-В, А-СН.-ОСНС(СННОН)"-СНоО-0О-СНСН»о-В, and ente-i den - 0-en-- sn, (x :іІій pan. СНО-М(СНСООН)-5О»-В, А-МН-СО-СНо-М(СоН)-505-В8, А-МН-СО-СНо-М(С0Н»1)-505-В, А - МН-СО-СНо-М(СевНи1з3)-505-В8, А-МН-СО-(СН»)10о-М(С»Нв)-505-В, А-МН-СО-СНо-М(- СН»-СеНв)-505-В, cm А-МН-СО-СНО-М(-СНо-СНо-ОН)ВО2-В, А-МН-СО-СНоо-В,. А-СНо-О-СеН .-О-СНо-СНо-В, А-СНо-СеН/-О-СНо-СНо-В, СО А-М(СоНв)-З05-В, А-М(СеНв)-505-В, А- М(С1оН»4)-505-В8, А-М(СеНі1з3)-505-В8, А-МЖ(СНОН.ОН)-5О5-В, А-ХСХНСООН)-505-8, А-М(СНоСеНвъ) -505-8, A-M-ISN(SNYON)21-505-8,. А-М-ИСН(ИСНООНИСН(СННОН)ІІ-505-8, where A means the place of attachment to the complexing agent or metal complex K, and B means the place of attachment to the fluorine-substituted residue. h 10. The application according to claim 8 or 9, which differs in that compounds of the formula I are used, in which p in (o) of the formula -C.RorpE means numbers from 4 to 15 and/or E in this formula means a fluorine atom. 11. Application according to any of claims 8-10, which differs in that the following compounds are used: cm - gadolinium complex o) 10-(1-methyl-2-oxo-3-aza-5-oxo--4- perfluorooctylsulfonylpiperazine-1-ylpentyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, - - gadolinium complex 10-(2-hydroxy-4-aza-5-oxo-7- oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17-heptadecafgorheptadecyl/-1,4,7-tris(carboxymethyl)-1, 4,7,1 O-tetraazacyclododecane, "du-gadolinium complex with 10-(2-hydroxy-4-aza-5,9-dioxo-9-14-perfluorooctylpiperazin-1-yl-inonyl-1,4,7-tris (carboxymethyl)-1,4,7,10-tetr c azacyclododecane, :z" - gadolinium complex 10-(2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)nonyl|c- 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazac iclododecane, - 395 - gadolinium complex 10-(2-hydroxy-4-oxa-1Н,1Н,2Н,ЗН.ЗН,5Н, 5H,bH,bH-perfluorotetradecyl-1,4,7-tris(carboxymethyl)-1,4,7,10-tetra (Ce) azacyclododecane, t - gadolinium complex 10-(2-hydroxy-4-aza-5- oxo -7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19-genicosafluornone (se) 50 adecyl/-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, T" - gadolinium complex 10-(2-hydroxy-4-aza-5-oxo-11-aza-11- "(perfluorooctylsulfonyl)tridecyl-1,4,7-tris(carboxymethyl)-1,4,7,10-tetra azacyclododecane, - gadolinium complex 10-(2-hydroxy-4-aza-5-oxo-7-aza- 7-(perfluorooctylsulfonyl)-8-phenyloctyl/i-1,4,7-tris(carboxymethyl)-1,4,7,10-t HF) tetraazacyclododecane. 7 12. Application according to any of claims 1-7, which is characterized by the fact that as perfluoroalkyl-containing metal complexes compounds of the general formula Ia and A-BN (iv) are used, in which A is a fragment of a molecule containing 2-6 metal complexes , which are directly or through a linker attached to the nitrogen atom of the cyclic chain-skeleton, and B" is a perfluorinated straight or branched carbon chain 65 of the formula -SpPropE, where E means the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and n means numbers from 4 to 30, while the indicated fragment of molecule A has the following structure: Кк , Й У И "Ох | 1 M/Ч Кк сч in which Ге) д means the number 0, 1, 2 or 3, K means a complexing agent or a metal complex or their salts with organic and/or inorganic bases or amino acids or amides of amino acids, X means a direct connection a bond with a perfluoroalkyl group, a phenylene group or a C.-C.dalkylene chain, which M optionally contains 1-15 oxygen atoms, 1-5 sulfur atoms, 1-10 carbonyl groups, 1-10 (ME 9)-groups , 1-2. FI) MAU8O"-groups, 1-10 SOMKU-groups, 1 piperidine group, 1-3 ZO"-groups, 1-2 phenylene groups or optionally substituted by 1-3 HG residues, while BZ is a hydrogen atom, phenyl, benzyl, or C alkyl group, which optionally contains 1-2 MNeO groups, 1-2 CO groups, 1-5 oxygen atoms and is optionally substituted with 1-5 hydroxy groups , 1-5 methoxy groups, rch - 1-3 carboxy groups, 1-3 HG residues, M means a direct bond or a chain of the general formula Ia or Sha o (Pa), "Y - is d8-mnusn)- Mu (sna: » re -I o (Sha), F yuyu v-zhmSn.SM 0 I I se) n N Y Her" -ky-a (snid s 7 o 0 knMSeN,ASM ime) I I 60 N NN de V? represents a hydrogen atom, a phenyl group, a benzyl group, or a C /-Alkyl group that is optionally substituted by a carboxy-, methoxy-, or hydroxy group, 65 MU represents a direct bond, a polyglycol group that contains up to 5 glycol units, or a fragment of a molecule of the general formula Ma -CH(B ")- (Ma), in which B" means a C.-C/carboxylic acid, a phenyl group, a benzyl group or a -(CH2»)4.5-MH-K group, and A means a bond with an atom nitrogen of the skeleton chain, B means a connection with a complexing agent or a metal complex K, K and t mean natural numbers from 0 to 10, and Y means 0 or 1, and O is a CO- or 5O»-group. 13. Application according to claim 12, which differs in that 710 compounds of the general formula Ia are used, in which d means the number 1. 14. The application according to claim 12, which differs in that compounds of the general formula Ia are used, in which the fragment of the X molecule is an alkylene chain containing 1-40 СНХСН»О-groups or 1-5 СОСНОМН-groups, or is a direct connection or one of the following structures: тв "7 сНнаВ(СНИ)» 8 У-снН,М8О,- in: И 2 си, и сн; пи -- - с р» 7 СНУ ---снАМЗО,- 8 I (o) n "-(СНаго-СН2 h Fo у-сН,М80,- s (22) s «y i - У сНаМАМ5О,- 5 shi s zo U-SNAVO,- В -i S.g se) zi , UuU-snNAMVO,-5 t І shchi sn, і" And where Г means joining to 0, and 5 means joining to B". 15. Application according to claim 12, which differs in that compounds of the general formula Ia are used, in which Mo is a fragment of a molecule that has one of the following structures: o ? at 9-5 SNUIMN--th b5 - a--«5-snN.-y8 snsOoN a , then II a Te otN - 8 sn, Her , and tzhotiN - and 7 sNsnu); about DREAM ' / | сч в- 0сНниИСНМН--y o o snsOoon. ! « зов - «2 -«« NeASNANN - 8 F o : s F zv y pesen - ich- (sndennk 16. Application according to claim 12, which differs in that compounds of the general formula Ia are used, in which K "represents a complex of the general formula Ma, Mia, Ma or Misha - sh o isoov Shcho z no -I M 5 ime) so "- М M lit s» os or more o y o re their vi Ssoov 60 b5 height what? no no »- m M nt y ts o M v soom: dra Se, M sot sch g vh o i cho ni her (22) sov s M (22) and - soov o (MISHA), « -7 tros | Z "» M Z shoos soog' i-o som: ime) de (Se) 50 V" in each case independently means a hydrogen atom or the equivalent of a metal ion with serial number I» 23-29, 42-46 or 58-70, BB means a hydrogen atom or a straight, branched, saturated or unsaturated C .-Szralalkyl chain, which is optionally substituted by 1-5 hydroxy groups, 1-3 carboxy groups or 1 phenyl group and/or optionally interrupted by 1-10 oxygen atoms, 1 phenylene group or 1 phenyleneoxy group, VZ means a hydrogen atom, a linear or branched C.-Stalkyl residue, a phenyl residue or (F. a benzyl residue, where B'/ means a hydrogen atom, a methyl or ethyl group, which is optionally substituted by a hydroxy or carboxy group, 60 IZ means a linear, branched, saturated or unsaturated C.i-Soralkylene group, which is optionally contains 1-5 imino groups, 1-3 phenylene groups, 1-3 phenyleneoxy groups, 1-3 phenyleneimino groups, 1-5 amide groups, 1-2 hydrazide groups, 1-5 carbonyl groups, 1-5 ethyleneoxy groups, 1 urea group, 1 thiourea group, 1-2 carboxyalkylimino groups, 1-2 ester groups, 1-10 oxygen atoms, 1-5 sulfur atoms and/or 1-5 nitrogen atoms, and/or optionally substituted with 1-5 hydroxy groups, 1-2 mercapto groups, 1-5 oxo groups, 1-5 65 thiooxo groups, 1-3 carboxy groups, 1-5 carboxyalkyl groups, 1-5 ester groups and/or 1-3 amino groups, while optionally present phenylene groups can be substituted 1 -2 carboxyl groups, 1-2 sulfonic groups or 1-2 hydroxy groups, and T" means the group -CO-B, the group -MNSO-B or the group -MNSOZ-B, where B means the place of attachment to UM. 17. The application according to claim 16, which differs in that it is indicated as the value for OZ Si-Soralkylene chain Contains the groups -СНОМНСОСО-, -МНСОСНЙО-, -МНСОСнООоСсеНН,-, -М(СНСО»Н)-, -СНиОСН» o-, -МНСОСНЈН,-, -МНОЗМНС vНа-, -СНОсС»в Well -, -СНСН»О- and/or replaced by groups -СНОСОН, -СНСООН. 18. Application according to claim 16, which differs in that Z means -СН»о-, -СНоСН»-, -СНоСНоСН»-, -СвНа-, -СоНио- «СНоСену-, «СНОМНСОоСнНосСН(СНСО»Н)- SeNa-, -"SNAOMNSOSNoOSN"- or "СНоОМНСОСН"СеNa-group. 19. Application according to claim 12, which differs in that compounds of the general formula Ia are used, in which K has one of the following structures: M-... with | o soov: « o , Fo pros | sch / u ly utshe F M i yishtoos | | juice « soov: - with its own I.Y i"? ra M shame - EE te) ra yu M ra---.- se) shi s» M o soot ime) 60 b5 soone 70 | p /7 M M I se -tot tOoOs o o M - hundred sovs with M o Her. Mch dno g--- zo; Mrya zh F kos an s M n F sh - soon: « 40: p. . shsh s 20. Application according to any of claims 12-19, which is characterized by the fact that compounds of the general formula Ia are used, in which the perfluoroalkyl chain B" is -Се13, -СвЕх7, -С1оЕой or -С12Еов-. :з" 21. Application according to any of claims 12-20, which differs in that the gadolinium complex 1,4,7-tris/1,4,7-tris(M-(carboxylatomethyl)-10-(M-1- methyl-3,6-diaza-2,5,8-trioxooctane-1,8-diyl)|-1,4,7,10-tet raazacyclododecane, -1 Сd-complex)-10-(М-2Н,2Н ,4H 4H,5H,5H-3-oxaperfluorotridecanoyl|-1,4,7,10-tetraazacyclododecane. 22. Application according to any of claims 1-7, which differs in that as perfluoroalkyl-containing metal complexes d) compounds of the general formula IB with d! (Iv), I se) KAKNO-A c» in which K is a complexing agent or a metal complex of the general formula Ir F) ime) 60 b5 sov (p), M no GE) o M shk NN sha so g! am I ..soon de V! means a hydrogen atom or the equivalent of a metal ion with serial number 23-29, 42-46 or 58-70, 22 and Z mean a hydrogen atom, C.-Stalkyl group, benzyl group, phenyl group, -CHNOH or -СН.-ОСН,» and c 2 is a residue of I 1, while I1102 independently of each other can have identical or different o values, A! represents a hydrogen atom, a linear or branched C 1 -C 1 -C 2 alkyl group, which is optionally interrupted by 1-15 oxygen atoms and/or optionally substituted by 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group and/ or by 1-5 -OKU-groups, where KU means a hydrogen atom or a C.-C7 alkyl residue, or in the left, FI is a linear or branched C.4-Czoalkylene group, which is optionally interrupted by 1-10 atoms with oxygen, 1-5 -МН-СО-groups, 1-5 -СО-МН-groups, an optionally substituted СООН-group with a phenylene group, 1-3 sulfur atoms, 1-2 -М(Б7)-5О» 5-groups and/or 1-2-505-M(B)-groups, where B' has the values specified for A", Me. a branched perfluorinated alkyl residue of the formula CoEopE, where n means the numbers from 4 to ZO, and E means the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, while optionally present acid groups can under certain conditions be represented in the form of salts with organic and/or n organic bases or amino acids or amino acid amides. - p 23. The application according to claim 22, which differs in that compounds of the general formula IB are used, in which z» ke, VZ and 9 independently of each other mean hydrogen or the S.-Sulfyl group. 24. Application according to claim 22, which differs in that compounds of the general formula IB are used, in which A! means hydrogen, C1-Sivalkyl residue, residue. СоНу-О-СН»З, -1 75 residue СзНе-О-СНу, residue СоН/-О-(С2Н/-0)-С2оНА-ОН, residue С2Ну/-О-(С2НА-0)4-С2Н. -OSN»z, residue C»nNAOnH, S3zNeOH, residue SANeOH, residue SeNioOH, residue CeN.oOH, residue SU./AOH, residue (Ce) CH(OONeSNOOH, residue CH(IONCH(OH)SNHON, residue yuyu СНаИСН( OH)CISNOOnH, residue СНСНаОНИСН(ОНИСНООН, residue СоННАСН(ОН)СННОН, residue (СНО) 8СООН, residue СОНу/-0О-(С2Н/-0)-СНХСООН or residue СоН)/-0О-(С2Н/-0) 3-С2Н/-СуРодЕ, where 5 means и), integers from 1 to 15, и means integers from 0 to 13, и! means integers from 1 to 10, n means integers T» from 4 to 20 and E means an atom of hydrogen, fluorine, chlorine, bromine or iodine, and their branched isomers are used, if possible. 25. Application according to claim 22, which differs in that compounds of the general formula IB are used, in which A" ов means hydrogen, С4-Siralkyl, С2Нн/-О-СН», СзНе-О-СН»у, Сн/-0 -(С2Н/-0),-С2Н/-ОН, СН,-0о-(С5нН/-0),-С2Н.-ОСН», сно,Он, сЗНнеОоН, снаИсн(онуусноно, сниСН:ХЖ«ОНИСН(ОНСНОН) . to 5, y means integers from 1 to b, m means integers from 1 to 10, n means integers from 4 to 15, and E means a fluorine atom, and is also used if it is br. Possibly their branched isomers. 26. Application according to claim 22, which differs in that compounds of the general formula IB are used, in which 1 07 means А-(СНО)5-В, А-СНо-СНо-(О-СНо-СНоу-В, А-сНн .(о-сн.-сН. В, А-СНО-МН-СО-В, А-СНО-СНО-МН-505-8, А-СНО-МН-СО-СНо-МЩ(СНСООН)-505- B8, А-СНо-МН-СО-СНо-М(С»Н)-505-8, А-СНО-МН-СО-СНо-М(СлоН»г41)-505-8, А-СНО-МН- СО-СНо-М(СеН4з3)-505-В8, 65. А-СНо-МН-СО-(СН»)1о-М(СоНв)-505-В, А-СНо-МН-СО-СНо-М(-СНо-СеН5»)-505-В, А- СНО-МН-СО-СНО-М(-СНо-СНО-ОН)ЗО-В, А-СНО-МНСО-(СН»)0-5-СНоСНо-В, А-СНОМНСОСНо-О-СНСН»-В, А-CH.-СНОМНСОСНоО-О-СНХСНо-В, А-СНХ- (СНо-СНх-0).А(СНо)зЗЗМнНоСО-СНо-О-СНьСНе-В, А-СНМНСО(СН»)о-О- СНХСНО-В, А-СНОСНМНСО(СН»)о-О-СНХСНО-В, А-СНо-С6Н/-О-СНХСН»о-В, where the phenylene group is attached in position 1,4 or 1,3, A- СН.-О-СНО-С(СН.-ОСНСНо-СевЕ43)2-СНо-ОСНо-СН»о-В, 8500 А-СНО-МНСОСноСНоСОМ-СНоСНо.МНСО СНО M(СоН)ЗО» Св 417-В, А-СН»СНоМНСОСНОМ(СоНв)-зО2-В, А-СН.-О-СНО-СН(ОС 10Н»2341)-СНО-О-СНСНО-В, А-"СНОМНСО)-СНО-СНСН»О- В, А-«СНоМНСО)3-СНО-СНСНО-В, А-СН.-ОСНС(СНОН)»-СНоО-0О-СНОСН»о-В, their che ' 70 ad - o to Chch svon A-СНоМНСОСНМ( SeNv)-505-B8, А-МНСО-СНО-СНо-В, А-МНСО-СНО-О-СНСН»о-В, А-МН-СО-В, А-МН-СО-СНО-М(СНСООН )-5O»-B, А-МН-СО-СНо-М(СоН)-505-В8, А-МН-СО-СНо-М(С0Н»1)-505-В, А-МН-СО- СНоО-М(СевНиз3)-505-8, А-МН-СО-(СН»)10о-М(СоНв)-505-В, А-МН-СО-СНО-МЩ(-СН»-СеНв)-505 -В, А-МН-СО-СНо-М(-СНо-СНо-ОН)ЗО2-В, А-МН-СО-СНо-В, А-СНО-ОО-СеН/-О-СНо-СНо-В . , A-M(SeNi1z3)-505-B8, A-MZh(ChN.OH)-5O5-B, A-ShShNSO ОН)-505-8, А-МЖ(СН»бСеНв)-505-В, А-М-ИСН(СННОН)2»И-505-В, А-М-ИСН(СН»ОНСН(ОНУСНОН)|-505- B, where z means integers from 1 to 15 and y means integers from 1 to 6. 27. Application according to claim 22, which differs in that compounds of the general formula B are used, in which I! means А-СНО-О-СНоСНо-Б, / А-СНО-СНо-(О-СНо-СНо)у-Б, / А-СНо-(0-СНо-СН2))-Б, 0 А-СНо- СНо-МН-ЗО»-В, А-СНОМНСОСН.о-о-СНХСНо-В, А-СНО-СНОМНСОСН.о-О-СНоСН»е-В, с А-СНО-(СНо-СНо-0), (СН2)зхНСО-СНо-О-СНоСНо-В, А-СНоМНОСО(СН2)10-0-СНоСН»-В, о А-СНСННМНСО(СН»)10-0О-СНСНО-В, А-СНО-О- СНО-СН(ОС 10Н21)-СН-О-СНСНО-В, А-СНО-О-С8Н.-О-СНо-СНо-В or А-СНо-СвНи-О-СНо-СН»-В, where in means integers from 1 to 6. 28. The application according to claim 22, which differs in that compounds of the general formula IB are used, in which B means a linear or branched perfluorinated alkyl residue of the formula CoPorE, where n means numbers from 4 to 15, and E represents a terminal fluorine atom. b 29. Application according to any of claims 22-28, which differs in that the following compounds are used: - c 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxohexan-5-yl) -acid-M-(2,3-dihydroxypropyl)-M-(1H1 НН. 2Нн.н, Ge! 4Н,5Н,5Н-3-oxa)perfluorotridecylamide-1,4,7,10-tetraazacyclododecane, gadolinium complex, - and - 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxohexan-5-yl)-acid-M-(3,6,9,12,15-pentaoxa)-hexadecyl) -(1H, 1nH,2H.2H,4H an, 5H,5H-3-oxa)perfluorotridecyl-amide)-1,4,7,10-tetraazacyclododecane, gadolinium complex, - « 1,4,7-tris(carboxylatomethyl )-10-(3-aza-4-oxohexan-5-yl)-acid-M-5-hydroxy-3-oxapentyl-M-(1Н,1Н,2Нн.2н4 N.YAN,5H,5H-3-oxa)perfluorotridecyl/-amide)-1,4,7,10-tetraazacyclododecane, gadolinium complex, c) with . "» 1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxohexan-5-yl)-acid-|M-3,6,9,15-tetraoxa-12-aza-15- oxo-С 47-С "ovheptadecafluoro)hexacosyl|amide)-1,4,7,10-tetraazacyclododecane, gadolinium complex, -1 395 1,4,7-tris(carboxylatomethyl)-10-((3-aza-4 -oxohexan-5-yl|-acid-M-(2-methoxyethyl)-M-(1H1H,2n2NnaNnNn IBN, 5H-3-oxa)perfluorotridecylamide)-1,4,7,10-tetraazacyclododecane, gadolinium complex. (Se ) 30. Application according to any of claims 1-7, which differs in that as perfluoroalkyl-containing metal complexes compounds with sugar residues of the general formula I are used; (IS oyu Fu1--6-- (VY i" Si-vur in which 52 K means a mono- or oligosaccharide residue attached through the 1-OH- or I-ZN-position, GF) B" means a perfluorinated, straight or branched carbon a chain of the formula -SeEopE, where c E represents the terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and p means the numbers 4-30, and K means the metal complex of the general formula Ps b5 cOOok (o), M t-- MM M in which B! represents a hydrogen atom or the equivalent of a metal ion with sequence number 23-29, 42-46 or 58-70, provided that at least two residues of B! mean equivalents of metal ions, B2 and B3 independently from each other mean hydrogen, C.i-C7alkyl, benzyl, phenyl, -CHNON or -СНоОСН", and си represents -С. 6Н/-О-СН»о-о-, "(СН»)4- 5-o-, phenylene group, -"СНо-МНСО-СНО-СН(СНСОН)-СвНу-о-, d) -SenН-(оСНСНО)у. -М(СНСОН)-СНо-о- or optionally interrupted by one or several oxygen atoms, 1-3 -МНОСО- groups, 1-3 -СОМН-groups and/or substituted by 1-3 -(СНо)юБ5СООН-groups of C.-Sioalkylene or C7- C12-SeNA-O-group, while o means the place of attachment to -СО-, З or the general formula Shs (He) Sho), sook! (po) сч Ге) - Ж - s М M 1 i / у а kos ik -I Ф щ ко ю соог! re) .. in which iz" B has the above values, B means hydrogen or the metal ion equivalent specified for B, and ря ЦТ means -СбН.-О-СН»-о-, where o means the place of attachment to -СО-, or the general formula IMs (F) ko bo b5 Soot (mo), ? y ST U to / MM M kos S. whatever M yu ..svon in which V! and 22 have the values specified above, or the general formula MсA or MeV -- 'da-my (MsA), M s Y S -- ooo o g m « 1 schoos S. ka soon iy pen. OO F (m'eV), - rani M « - I -eoroly shi s o G.Y M 7 I -- - 6 ool s sh M t -- 0 dO which V! has the values indicated above, from 50 or the general formula Mis (Se) so (Mis), ho vsyuos-. and MYH M M d 5 dos kt be DOV! which in which B! has the values specified above, or the general formula Mis 60 b5 o (Mis), nora r Os Oovsh-A-ya, M oo --ya in which B has the values specified above, and ЦT means -СбН.-О-СН»- o-, where o means the place of attachment to -СО-, or the general formula MPShs soog (Uto) and M s o MM "Me / nn 'on « r MOOS MF s (22) soog! m in which V! has the above values, while the free acid groups optionally present in the K residue may optionally be represented in the form of salts with organic and/or inorganic bases or amino acids or amino acid amides, "b, in the event that K means one of of IPo-MiYs metal complexes, is at least a three-fold 70 functionalized residue selected from the following residues a)-Y): s a! ) ke and so 50 Ge 2 I" (ag) Ye ik y - - j M - "ONA, 0-с0--В N I (F) o sh y i 60 " (c) b5 N , uko - s (SN, -k glkcniV " MN ve (c) a , Y V ma- I -"M M-4ku o, sch | o her (a) "Y G. | (o) se Ge) zv che; U shchi azh - - y I M- y u " "zh - s z IN V. (is) (se) t , ko sg І І» Со (Ф) ко во в | z--e RA (9 65 nn , Yuk. co -- o. (SNU, -k gaka Y i chn 70 M ey y i n . Sh--so - 6 - (sna, -k ped I Mch 2 V (9) s v , (o) iy - N | Fo m- -khs20-en- - -(sna,- M ti V sch nn F i - m-s0-sn--(СН),- M -ek a « ' Н 2 с МН ;» 2 у - Н -со0- - sn- (snu3,-M -m8 He; | H o Mn so 50 : ! (p) Hn H , 2) and pzhchn- M - (sn; m-so-s-- (SNU, MV o H IN bo so MN and ; at 65 () ay , y yu min -M-(Page 9-53 sa0-M M-eku N I o, and V and F 20. use МН--СН- - оо В сх и о b, in the case that K means the metal complex Mis, is at least a three-fold functionalized residue selected from Yui residues (yu h - - 2 t- t-o, (22) ву -МНА- (СНИ), СН--б0-ар а с МН Ф 2 i - 7 () " - ' - s ame sosnu vno; SOKU - » " MN : y V se) yuyu at the same time means the place of attachment of C to the complex K, B means the place of attachment of C to the residue Y, and Г means the place of attachment of C to the residue 7, ре) У means -Сно-, 5-(СН2)1-5)СО-Б, БАСН2Хи- 5СО-6, 8-СнН.-СнНОон-СО-Б T» or 5-СН(ИСНОН-СНОН)-СНОН-СНОН-СО-В, where 5 means the place of attachment to the sugar residue K, and B means the place of attachment to of the residue 0, 27 means the group "Ф) и и ю У-М М--80,-- it is Г-сСОССО-М(СоНвъ)-505-Е, г-сОоСссНно-О-(СНо)»-505- E, b5 or g o, Zh. o M m-z0, 7E ? 7 in and Г-МНненНХсСНноО-О-СНХСН»О-Е, where Г means the place of attachment of 7 to the residue 0, and E means the place of attachment of 2 to the perfluorinated residue E tyu B, I, t! independently of each other mean the integers 1 or 2, and p" means the integers 1 through 4. 31. Application according to item 30, which differs in that compounds of the general formula I are used, in which K means a monosaccharide residue with 5-6 C atoms or its deoxy compound, preferably glucose, mannose or 75 galactose. 32. The application according to paragraph ZO, which differs in that compounds of the general formula I are used, in which K2 | 3 independently of each other mean hydrogen or C.-Alalkyl and/or E in the formula -CoER»pE means a fluorine atom. 33. Application according to item 30, which differs in that compounds of the general formula I are used, in which (z means the residue of lysine (a) or (B). 34. Application according to item 30, which differs in that compounds of the general formula I are used, in which 7 means the group c 5-M M-80,--e where G means the place of attachment of 7 to the residue C, and E means the place attachment of 7 to the perfluorinated residue B and/or B means the group 5-SNHCO-B, where 5 means the site of attachment to the ER sugar residue, and B means the site of He»! joining to remainder 0. 35. The application according to claim 30, which differs in that compounds of the general formula are used, in which O in the metal complex K means -CH»- or -CH./-О-CH»-o, and o means the place of attachment to -CO-. Gee! 36. Application according to item 3, which differs in that it uses the gadolinium complex (1-4-perfluorooctylsulfonyl)piperazineamide 6-IR-I 1,4,7-tris(carboxylatomethyl)-1,4,7, 10-tetraazacyclododecane-10-M-(pentanoyl-3-aza-4-oxo-5-methyl-b-yl)|-2-M-11-0-A-O-carbonylmethylmannopyranose|-I-lysine. 37. Application according to any of claims 1-7, which differs in that as perfluoroalkyl-containing metal complexes "and compounds with polar residues of the general formula Id -o (Iv), c (ku1---- 2) are used I.Y » re -1 45 in which B means a perfluorinated, straight or branched carbon of the formula -SeEopE, where (se) E is a terminal atom of fluorine, chlorine, bromine, iodine or hydrogen, and kup means numbers from 4 to a chain 30, K means the metal complex of the general formula Ia se) c» F) ime) 60 b5 SOog: (1), but A, kos o M sov in which B! represents a hydrogen atom or the equivalent of a metal ion with sequence number 23-29, 42-46 or 58-70, provided that at least two residues of B! mean equivalents of metal ions, B2 and BZ independently of each other mean hydrogen, C1-C7 alkyl, benzyl, phenyl, -CHNON or -СНоОСН», and c and represents -С. 6Н/-О-СН»о-о-, "(СН")4-5-о-, phenylene group, -"СНо-МНСО-СНО-СН(СНСООН)-СвНу-о-, d) -SenН- (оСНІСНо)ю. -M(СНСООН)-СНо-о- or optionally interrupted by one or more oxygen atoms, 1-3 -МНОСО- groups, 1-3 -СОМН-groups and/or substituted by 1-3 -(СНО)юБ5СООН-groups C.-Sioalkylene or C7-C12-SeNA-O-group, where o means the place of attachment to -СО-, З or the general formula а (Ге) соог что сч Ге) m. Zh - s M M 1 i / u a os ik -I F shko yu soog! d) .. in which iz" B has the above values, B means hydrogen or the metal ion equivalent indicated for B, and ЦТ means -СбН.-О-СН»-о-, where o means the place of attachment to -СО-, 55 . or the general formula ma (F) ko bo b5 Soot (ma) ? y ST U to / MM M kos S. whatever M yu ..svon in which V! and 22 have the values specified above, or the general formula MaA or Uav -- 'da-my (mal), M s Y S -- ooo o g m « 1 schoos S. ka soon iy pen. OO F (mav), - rani M « - I -eoroly shi s o G.Y M 7 I -- - 6 ool s sh M t -- 0 dO which V! has the values indicated above, from 50 or the general formula Ma i-o (MIF) to vshyuos-.0y MY M M d 5 dos kt be DOV! which in which B! has the values indicated above, or the general formula Ma 60 b5 o (Mpa), nora r Os os -А- M жо --- in which B has the values indicated above, and ЦТ means -СбН.-О-СН»-о- , where о means the place of attachment to -СО-, while free acid groups optionally present in the K residue can optionally be represented as salts with organic and/or inorganic bases or amino acids or amides of amino acids, о means at least triple functionalized the residue selected from the following residues a)-Yii): (at) H , and also M- (SNI, 0-0 mu Hn I zv MH sch i (8) (ag) "I Hn ; Fo amy M (СНО; 0 --so in sch Mn y i i - y (in) " N ' t - khz" | nn MN i - - (se) her o (s) so 2 a I" Y F) yu yy- -6 m-mmu 65 y V ' Y 7 dl M M-----y E yu z Y h so o "I z0 Fo Ge V --- pnia AV F (8 i- N ' ach m-n Mo Tena "- s so chn :" ; i v sh I so (9) yu y cha chn s NM M her Z A o (n) umi wa -(snd.- sN- so y 60 I NN 65 them () В or со -(СН)ИА- СН- СО mu ХН and where A means the place of attachment of OS to complex K, B means the place of attachment of CO to residue K, and Г means the place of attachment of OS to residue 7, 27 means the group and and У-М М-30,--is or Г-ФС«О)СНоО(СНО)-Е, where Г means the place of attachment of 7 to the residue b, and E means the place of attachment of 7 to the perfluorinated residue c, K is a polar the residue selected from the complexes K of the general formulas Pa-mIia, and in this case B! means a hydrogen atom or the equivalent of a metal ion with serial number 20, 23-29, 42-46 or 58-70, and the residues B2, BZ, 27, 0 01 have the above values, or is a residue of folic acid, or attached through -СО-, -505- or a direct bond to a C residue, a carbon chain with 2-30 C-atoms, which is straight or branched, saturated or unsaturated and which is optionally interrupted by 1-10 oxygen atoms, 1-5 - МНСО-groups, 1-5-СОМН-groups, 1-2 sulfur atoms, 1-5-МН-groups or 1-2 phenylene " groups, which may optionally be replaced by 1-2 OH-groups, 1-2 МН with o-groups, 1-2 -СООН-groups or 1-2 b-5О3Н-groups, or optionally substituted with 1-8 ОН-groups, 1-5 -СООН-groups, 1-2 ЗО зН-groups, 1-5 MH"-groups, 1-5 C.-C; alkoxy groups, and c i, t, p2 independently of each other mean integers 1 or 2. Ge"! 38. Application according to claim 37, which differs in that compounds of the general formula Id are used, in which K means a metal complex of the general formula Pa, Sha, Mav or MPa. - 39. Application according to claim 37, which differs in that compounds of the general formula Id are used, in which the polar residue K has the values indicated for the complex K, preferably means the complex K of the general formula pa, Sha, MaA or Ua. " 40. The application according to claim 37, which differs in that compounds of the general formula y are used, in which - t0 the polar residue K has the following values: -С(О)СН 2снЗООЗзн.-АСК(О)СНОоСнНХСНьОСньСНООН, с -косн»ОосньсСнНоОон, -К(О)СснН»осн(ОонеСНноон, -КОо)СНМнН-С(О)СНьСОоОНн, -С(ОСнН.снН(ОонеСНнооНн, з» -«осСнНОоснБсСоонН, 5ОСННСНСООН, -С(0)-SeНз-(m- СОН)», -ФО)СНоО(СНо)»-СеНаз-(m-СООН)», -ФО)СНХО-SeНу-м-5ОЗН, -ко)сначнесноМнеоснооснсон, -Кко)сн»оснсснНОоснссон, -"Оо )SsnH»OosSnNsSn(OnSnNYO-СНСНоОН, 0 -КО)СНоОосСнНССН(nСsНnoIosnNoO-СН(ОН)-СННОН, /-ФКО)СНЗОЗЗН, 35 -«О)СНьСнСнНосСОоОонН, -СКОСН(ОНШСНООНСНОН, 0 -СКСНоОСНОИ»ОЙ9- СН3, 0/0 -С(О)СНоОКСНОИ»О о-Н, -ФО)СнNoОоссн(СНООН)», -Кко)сносн(СНОСНОСОН)», -С(0)-SeНаз-(m-ОСНОСООН) », (Се) -б0о-снё-(сСног)б с(СНо»О-(СНоИ» С(СНИ)»ОСсН», preferably -С(О)СНоОИ(СНо)»О)/-СН»з. 41. Application according to claim 37, which differs in that compounds of the general formula y are used, in which the polar residue K is a residue of folic acid. (Se) 20 42. Application according to claim 37, which is characterized by the fact that compounds of the general formula Id are used, in which (a) or (b) is a lysine residue. T" 43. Application according to claim 37, which differs in that compounds of the general formula Id are used, in which О У , dr Х У У рму. In the metal complex, K represents the group -СН»- or -СН/-О-СН»о-о, and o means the place of attachment to -СО-. 44. Application according to any of claims 37-43, which differs in that the gadolinium complex 59 (1-4-perfluorooctylsulfonylpiperazine|amide HF) 2,6-M,M'-bisi1,4,7-tris(carboxylatomethyl )-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5- from ilulysine. 45. Application according to any of claims 1-7, which differs in that as perfluoroalkyl-containing metal complexes galena compositions are used, which contain paramagnetic perfluoroalkyl-containing metal complexes of general 60 formulas I!, Ia, IB, Is and/or Ia and diamagnetic perfluoroalkyl-containing substance, preferably in the form of a solution in an aqueous solvent. 46. Application according to claim 45, which is distinguished by the fact that as diamagnetic perfluoroalkyl-containing substances such general formulas ХХ and ВР-И2-В2 (ХХ) are used, in which ВР means a linear or branched perfluoroalkyl residue with 4-30 carbon atoms, I2 means linker and B2 means hydrophilic group. 47. Application according to claim 46, which differs in that the linker Y is a direct bond, a -50 5-group or a straight or branched carbon chain containing up to 20 carbon atoms and which can be replaced by one or more -OH groups , -СОО-, -5О3 and/or optionally contains one or more -О-, -5-, -со-, - СоМнН-, -МНеО-, -СОМУ-, -МЕУсСо-, -80»5- , -PO,-, -МН-, -MVZ-groups, an aryl ring or piperazine, while VZ means a C.-Soralalkyl residue, which in turn may contain one or more O-atoms and/or may be substituted by -СОО - or 5O3 groups. 48. Application according to claim 46, which differs in that the hydrophilic group B? is a mono- or disaccharide, one or more adjacent -СОО- or -5О3-groups, dicarboxylic acid, isophthalic acid, picolinic acid, benzenesulfonic acid, tetrahydropyrandicarboxylic acid, 2,6-pyridinedicarboxylic acid, quaternary ammonium ion, aminopolycarboxylic acid, aminodipolyethyleneglycolsulfonic acid acid, an aminopolyethylene glycol group, a 5O5-(CH.)"-OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups, or one or more polyethylene glycol chains with at least two glycol 19 links, while the polyethylene glycol chains end with a -OH or -OSH" group. 49. Application according to claim 45, which differs in that, as diamagnetic perfluoroalkyl-containing substances, conjugates A, B- or G of cyclodextrin and compounds of the general formula XXII A2-13-B (XXII, in which A? means a molecule of adamantane, biphenyl or anthracene, IZ means a linker, and B means a linear or branched perfluoroalkyl residue with 4-30 carbon atoms, while the IZ linker is a straight hydrocarbon chain with 1-20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or by several CO-, 505-, SOMN-, MNOO-, SOM. o MA oso-, MN-, ME O-groups or piperazine, where KZ is a C.4-Svalkyl residue. 50. Application according to claim 45, which is distinguished by the fact that as diamagnetic perfluoroalkyl-containing substances such general formulas XXI VR-X (XXI) are used, in which B means a linear or branched perfluoroalkyl residue with 4-30 carbon atoms, M and Fo X! means a residue selected from the group of the following residues (where n means a number from 1 to 10): сч (22) звон о "аншни 20 о for them with с I.Y z» o on o - | an I I ren F no -- o ce i yo o NO i-o M sh a i F) t On 7 no al vvnny b5