NO164458B - PHYSIOLOGICALLY COMPATIBLE, PARAMAGNETIC COMPLEX SALTS AND AGENTS FOR USE IN NMR DIAGNOSTICS. - Google Patents

Abstract

1. The use of at least one physiologically tolerable paramagnetic complex salt made from aminopolycarboxylic acids having the formulae I to IV see diagramm : EP0169299,P6,F1 N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA), see diagramm : EP0169299,P6,F2 N,N,N',N",N"-diethylenetriaminepenta-acetic acid (DTPA), HOH2 C-CH2 N(CH2 COOH)2 N-hydroxyethylimino-diacetic acid, see diagramm : EP0169299,P6,F3 wherein m represents the numbers 1 to 4, n the numbers 0 to 2, R**1 a saturated or unsaturated hydrocarbon radical having from 4 to 12 hydrocarbon atoms or the group -CH2 -COOH, and from the ions of the lanthanide elements having the atomic numbers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and, optionally from an inorganic base for the preparation of agents for NMR diagnostics.

Description

The invention relates to physiologically compatible, paramagnetic complex salts for use in NMR diagnostics,

as well as agents for use in NMR diagnostics which contain at least one paramagnetic, physiologically compatible complex salt. The complex salts and agents have an effect on relaxation

the times of the NMR diagnostics.

Certain aminopolycarboxylic acids are used for the complex formation. The physiologically compatible, paramagnetic complex salts according to the invention are thus characterized by the fact that they consist of aminopolycarboxylic acids with the formulas I - II

N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA),

where m is 1 - 4,

and the ions of the lanthanide elements with atomic numbers 57 70

or the ions of the transition metals with atomic numbers 21 - 29,

4 2 and 44,

and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine.

The invention further includes a means for applying

other in NMR diagnostics which is characterized by the fact that it contains at least one paramagnetic, physiologically compatible complex salt of aminopolycarboxylic acids with the formulas I - II

N , N , N ' ,N" ,N"-diethy Lontriaminpentci edd i k sy ro (DTPA),

where m is 1 - 4,

and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metals with atomic numbers 21 - 29, 4 2 and 44,

and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine,

possibly together with common additives in the art, such as physiologically compatible buffer solutions, surfactants and/or aromatic substances, dissolved or suspended in water or physiological salt solution, the agent containing 5 - 250 mmol/1, preferably 50 - 200 mmol/1, paramagnetic complex salt and has a pH in the range 6.5 - 8.0, preferably 6.5 - 7.5.

In addition, the invention includes a means for use in NMR diagnostics which is characterized in that it contains at least one physiologically compatible, paramagnetic complex salt of aminopolycarboxylic acids with the formulas I - II N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA),

where m is 1 - 4/

and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metal.e with atomic numbers 21 - 29, 4 2 and 4 4,

and optionally an inorganic base.

As bases, for the salt formation as mentioned, an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine is used, with N-methylglucamine being preferred. In the complex salts used in the agents according to the invention, as mentioned, an inorganic base, sodium hydroxide being preferred.

The production of the new agents takes place in a manner known per se, by dissolving the paramagnetic complex salt in water or physiological salt solution, possibly

with the addition of galenically common additives such as

e.g. physiologically tolerable buffer solutions (e.g. sodium dihydrogen phosphate solution) and sterilize the solution. The aqueous solutions can be applied orally, neurally and especially intravasally. If suspensions of the paramagnetic complex salts in water or physiological salt solution are particularly desirable for the oral delivery, the paramagnetic complex salt is mixed with one or more of the galenically common excipients and/or surfactants and/or flavoring agents for taste correction and suspended before oral use in water or physiological saline solution.

Hereby, 3 to 10 g of paramagnetic complex salt and 2 to 8 g of one or more excipients such as e.g. sucrose, highly dispersed silicon dioxide, polyoxylene polyoxypropylene polymers, starch, magnesium stearate, sodium aryl sulfate, talc, lactose or sodium carboxymethylcellulose.

For NMR diagnostics in humans, aqueous solutions or suspensions containing 5 to 250 mmol/1, preferably 50 to 200 mmol/1, of a paramagnetic complex salt are used. The aqueous solutions lie in the pH range between approx. 6.5 and 8.0, preferably between 6.5 and 7.5.

During the complex formation, the paramagnetic salts are detoxified and it is also achieved that the salts are also stable and well soluble in the physiological pH range in water.

The new agents in the form of complex salt solutions appear to be particularly suitable for better demarcation and localization of lesions in the pancreas and liver as well as tumors and bleeding in the cranial area. For diagnosis of that area; to be investigated, an aqueous solution of a paramagnetic complex salt that is isotonic with blood is applied, for example, in a dose of 1 to 100 umol/kg intravenously. At a concentration of the complex salt from 50 to 200 mmol/1, approx. 1 to 50 ml solution. Recording of the layer that is interesting takes place approx. 15 to 60 min. after the intra-venous application of the aqueous solution of the para-m-magnetic complex salt.

The physical diagnostic procedures common in medical practice, which can be carried out without or with little operative intervention, are, for example, irradiation of the body with X-ray light, scintigraphy and sonography. All these methods are either fraught with health risks or the area of application is restricted. The x-ray techniques and scintigraphy thus expose the patient to ionizing radiation, so that these methods cannot be used at will or not at all in risk groups, such as, for example, nursing infants and pregnant women.

It is true that sonography does not have the aforementioned disadvantages, but nevertheless their area of application is very limited, particularly in the cranial area.

Since, despite extensive research work, it has not yet succeeded in completely removing the described disadvantages, methods are being sought that provide images that do not have the disadvantages, but provide a comparable gain in information for the diagnosis.

One of these imaging procedures is nuclear spin tomography (Spin-Imaging, "Zeugmatographie") which depends on the physical effect of the so-called nuclear magnetic resonance ("Nuclear Magnetic Resonance"), this diagnostic procedure makes it possible to obtain cross-sectional images of the living body and insight into metabolic processes without the use of ionizing radiation. The effect of the nuclear resonance shows atomic nuclei, which, as e.g. hydrogen,

which in the biological tissue is mainly found as water, has a magnetic moment and with the help of. this aligns itself in a strong external magnetic field. By a high-frequency impulse (resonant frequency) they are brought out of their equilibrium state, to which they return with a characteristic speed again. The duration of the return to the equilibrium state, the so-called relaxation time, provides information about the degree of order of the atom and about their interaction with their surroundings.

The imaging, which is obtained by measuring proton thickness and relaxation times, is of high diagnostic value and provides information on the number and condition of the examined tissue. Thus, for example, tumor tissue exhibits longer relaxation times than healthy comparison tissue.

(A. Ganssen et al. Computertomographie 1, 1981. pp. 2-10; Georg Thieme Verlag, Stuttgart, New York).

It has now been established that paramagnetic ions, such as Mn 2 + (manganese) or Cu 2 + (copper), affect the relaxation times and thus increase the information content.

However, the heavy metal salt solutions that have so far been used on experimental animals are unsuitable for intravenous/application on humans due to their high toxicity. There is therefore a search for paramagnetic substances, which are well tolerated and have a favorable effect on the imaging. The latter can, for example, take place in that the spin-lattice relaxation time T is greatly reduced, while at the same time the spin-spin relaxation time T2 is kept essentially constant. It was now found that the desired detoxification of the otherwise toxic metal salts can take place by complexation, without the paramagnetic properties being adversely affected. The latter is surprising, as this, as is well known, changes the distribution of d- and f-electrons over the d- and f-orbital respectively. Thus, when testing rats in a detector with a magnetic field of 0.15 Tesla at an input energy of 300 Watt/impulse and a 180° pulse of 720 us with recording times of 2 min. sometimes 10 min. after intravenous injection of .20 umol/kg manganese edetate as an aqueous glucamine salt solution with a concentration of 6 mmol/1, a clearly stronger change in the signal in the area of the liver parenzyme is observed compared to the 0 uptake, while with an aqueous manganese (II) chloride solution with the same molarity under the same experimental conditions only a relatively small contrast could be achieved. On the other hand, the complex formation achieves the desired detoxification of the otherwise toxic paramagnetic salts. Thus, in rats, after intravenous injection of an aqueous solution of the N-methylglucamine salt of manganese edetate, an LD^g of 4 mmol/kg was found. Compared to this, manganese chloride under identical conditions in rats showed an LDj-q of only 0.5 mmol/kg.

The implementation of an NMR diagnostic examination using a complex salt shall be explained in more detail with the help of the following example: A sterile, aqueous solution of the N-methylglucamine salt of the gadolinium-III complex of diethylenetriaminepentaacetic acid with a concentration of 0.1 mol/l is prepared. The pH value of the clear solution was 7.2.

The (Siemens AG/Erlangen) whole-body scanner used for the NMR tomography works with a magnetic field of 0.1 T, which corresponds to a "Larmor proton frequency" of 4.99 MHz. The device was equipped with a high-frequency transmitter and receiver coil of small dimensions, in order to also be able to image objects of small size with satisfactory resolution. The examinations were carried out using a spin echo method. The time for a recording amounted to between 1 and 3 min.

The experiments are carried out with breeding male rats (Wistar-Han-Schering (SPF)) with a body weight of 250 g. 8 days before the examination, the animals received a Novikoff-Hepa-tom tumor cell suspension intraperitoneally (0.5 ml with

1 x IO<6> cells).

The animals are anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg body weight). The animals then had a wing cannula inserted into one of the tail veins.

Before application of the contrast agent, a recording is made

in the sagittal and horizontal planes of the body trunk (illustration 1, 2) .

The contrast agent is applied intravenously within 1 min. in a dose of 1 mmol/kg. In illustration 3 oq 4 which is between 22 and 25 min. after peritoneal application, a strong increase in opacity can be determined in the abdomen. After intravenous administration, the contrast agent enters the pathological fluid accumulations and here causes a strong shortening of the spin-lattice relaxation time (T^), which leads to an increase in the signal intensity. Only after application of the contrast agent is the tumorous fluid accumulation and an improved delineation of the organs recognisable. Without the addition of contrast medium, structures in the abdomen can hardly be recognized, as the organs only show small differences in proton thickness and relaxation times.

Also after oral administration of the contrast agent, the delineation of the structures is improved. For this purpose, 5 ml of the N-methylglucamine solution of the gadolinium complex of the diethylenetriaminepentaacetic acid in a concentration of 1 mmol/l is given by means of a probe with an anesthetized male rat (body weight 250 g). Only after administration of the contrast medium / (illustrations 5, 6, 7) is a clear demarcation of the stomach or the intestinal tract from the remaining organs visible.

Own pharmacokinetic studies in rats have shown that the N-methylglucamine solution of the gadolinium complex of diethylenetriaminepentaacetic acid after intravenous and subcutaneous administration is mostly eliminated renally within 24 hours. The gadolinium complex is excreted by glomerular filtration with a half-time of approx. 20 min. from the rat. The proportion that is eliminated with faeces is less than 5% of the applied dose.

After oral administration, no resorption of the substance is observed. The pharmacokinetic relationship is similar to that of the classical X-ray contrast agents for uroangiography.

Illust. 1: Recording in the sagittal plane of a living rat, which had a Novikoff nepatoma transplanted 8 days before the examination. Illust. 3: Recording in the sagittal plane 2 2 min. after intravenous administration of 1 mmol/kg of the N-methylglucamine salt of the gadolinium complex of diethylenetriaminepentaacetic acid. The strong clarification of the ascites fluid can be clearly felt. Illust. 2; Recording in the horizontal plane of the same animal at the height of the abdomen. In llust. 4: Recording in the horizontal plane of the same animal at the height of the abdomen. illus. 5: Recording of a living rat before administration of a contrast agent. Illust. 6: Recording of the same animal 10 min. after oral administration of 5 ml of a solution (1 mmol/1) of the N-methylglucamine salt of the gadolinium complex of diethylenetriaminepentaacetic acid.

Illust. 7; Horizontal section through the abdomen of the same animal at the level of the stomach 30 min. after oral administration of the contrast agent. The stomach is clearly delineable with the help of the contrast agent.

The preparation of the paramagnetic complex salts

takes place according to methods known to those skilled in the art, whereby the paramagnetic metal salt of the lanthanide elements with atomic numbers 57 to 70 or the transition metals with atomic numbers 21 to 29, 42 and 44 is dissolved in water and/or alcohol and a solution of the equivalent amounts of the complex formers in water is added and/or alcohol and stirred, if necessary while heating to 50°C to 120°C until the

ning has ended. If alcohol is used as solvent, methanol or ethanol is used. When the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off. Is it soluble,

can be isolated by evaporating the solution to dryness.

The procedure shall be explained in more detail by means of

the following work regulations:

Preparation of the manganese-II complex from ethylenediamine-tetraacetic acid:

The suspension of 6.17 g of manganese II carbonate in 500 ml

water, 14.6 g of ethylenediaminetetraacetic acid is added and up-

is heated while stirring in a steam bath, whereby a gas evolution occurs. The initially pink color disappears after approx. 20 min. and all but a small remnant goes up-

solution. After stirring for 1 hour at 110°C, the undissolved material is filtered off and the filtrate is cooled. After standing for 15 hours, the crystallisate is suctioned off and dried: = 14.1 g (mol weight 345.17) m.p. 256°/258-259°C. Preparation of the gadolinium-III complex of diethylenetriamine-pentaacetic acid: Preparation of the suspension of _435 g of gladolinium oxide (Gd20.j) and 944 g of diethylenetriamine-penta-acetic acid in 12 1 of water is heated with stirring at 90°C to 100°C and stirred in 48 hours at this temperature. The undissolved material is then filtered off and the filtrate is evaporated to dryness. The amorphous residue is pulverized.

Yield 144 g: (molecular weight 547.58)

Melting point: melts from 235° and remains undecomposed up to 320°C.

If the obtained paramagnetic complex compound still contains one or more acidic or basic groups, then the obtained complex compound can, if desired, then be dissolved or suspended in water and added to the inorganic or organic base or acid, until the neutral point is reached. After filtering off undissolved parts, the solution is evaporated and the desired complex salt is obtained as a residue.

These connections are new.

The following examples shall explain the invention in more detail.

Example 1

Preparation of the di-N-methylglucamine salt of the manganese(II) complex of ethylenediamine-tetraacetic acid<e,><C>2^<H>^<gN>^0^gMn.

7.4 g (= 20 mmol) of the manganese(II) complex of ethylenediamine-tetraacetic acid (water content 6.9%) are suspended in 30 ml of water and dissolved by the addition of approximately 7.8 g (= 40

mmol) N-methylglucamine at pH 7.5. After filtering off some insoluble material, the solution is evaporated to dryness in a vacuum. A solid foam is formed in quantitative yield, which melts from 95°C and becomes viscous at 170°C.

Analysis: Calculated dry substance C 39.19% H 6.58% N 7.61%

Mn 7.47%

Found; C 39.23 H 7.10% N 7.26%

Mn 7.53% H20 3.26% Equivalent weight calculated 367.8

found 369 (filtration with tetramethylammonium hydroxide in aqueous acetone).

By dissolving in hot methanol and evaporating in a vacuum to dryness, the substance is obtained as a white, hygroscopic powder.

Analogously, this is achieved:

Di-N-methylglucamine salt of the nickel(II) complex of ethylenediaminetetraacetic acid, C24H4gN40lgNi, as a blue powder with a decomposition point at 220-223°C.

Elemental analysis (calculated on dry matter):

Di-ethanolamine salt of the cobalt(II) complex of ethylenediaminetetraacetic acid, C^H^N^jO^Co, as pink powder which sinters at 105°C and melts at 180-185°C. Elemental analysis (calculated on dry matter): C 35.67% H 5.98% N 11.88% Co 12.50% (calculated)

C 35.78% H 6.03% N 11.70%' Co 12.40% (found)

Dimorpholine salt of the manganese(II) complex of ethylenediaminetetraacetic acid, ClgH32N401C)Mn, as white powder with decomposition point 270-275 C.

Elemental analysis (calculated on dry matter):

C 41.62% H 6.21% N 10.78% Mn 10.57% (calculated)

C 41.52% H 6.40% N 10.58% Mn 10.32% (found)

Di-diethanolamine salt of the copper(II) complex of ethylenediaminetetraacetic acid, ci8H36N4°12Cu' as clinched Powder with decomposition point at 212-215°C.

Elemental analysis (calculated on dry matter):

C 38.33% H 6.43% N 9.93% Cu 11.26% (calculated)

C 38.50% H 6.55% N 9.83% Cu 11.10% (found)

Tri-diethanolamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid<e,> C-jgHj-^NgO-^Mn, as a yellow powder which sinters at 90°C and melts at 185-188°C. Elemental analysis (calculated on dry matter): C 41.00% H 7.14% N 11.03% Mn 7.21% (calculated)

C 41.18% H 7.30% N 11.15% Mn 7.33S (found)

Tri-N-methylglucamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid<e,> C^H^Ng^S*11' as a white powder which sinters at 92°C and melts at 202-205°C. Elemental analysis (calculated on dry matter): ;C 40.73% H 7.03% N 8.14% Mn 5.32% (calculated) ;C 40.55% H 7.22% N 8.32% Mn 5, 11% (found) ;Example 2 ;Preparation of the N-methylglucamine salt of the gadolinium (III) complex from ethylenediamine-tetraacetic acid, ;<C>17<H>30<N>3°13<Gd>- ;4.58 g (= 10 mmol) of the gadolinium (III) complex of ethylenediamine-tetraacetic acid (water content 2.7%) is suspended in 15 ml of water and dissolved by the addition of 1.95 g (= 10 mmol) of N-methylglucamine at pH 7.4 . The solution is filtered and then evaporated to dryness in a vacuum, whereby a solid foam is formed. Taking into account the water content of 8.5%, the yield is practically quantitative. The substance sinters from 90°C, from 140°C until foam develops. ;Analysis: Calculated C 26.90% H 2.44% N 6.27% Gd 35.22% Found in dry substance: C 26.78% H 2.96% N 5.77% Gd 34.99 % ;Equivalent weight calculated 6 41.7 ;Found 634 (titration with tetramethylammonium hydroxide in aqueous acetone). By dissolving in hot ethanol and evaporating in a vacuum to dryness, the substance is obtained as a white powder. ;In an analogous way, the following is obtained: ;N-methylglucamine salt of the dysprosium(III) complex ;of ethylenediaminetetraacetic acid, C-^H^^O-^Dy, as a white powder with a melting point at 180-185°C. ;Elementary analysis (calculated on dry matter): ;;Di-N-methylglucamine salt of the holmium(III) complex of diethylenetriaminepentaacetic acid<e,> C"2gH54N5020Ho, as white powder which sinters at 88°C and melts at 187-190°C. Elemental analysis (calculated on dry matter): ;Di-lysine salt of the gadolinium(III) complex of diethylenetriamine-pentaacetic acid, C — H, oN-,0, .Gd: ;Z o ho I 14 Elemental analysis: ;Di-N-methylglucamine salt of the gadolinium(III) complex of diethylenetriamine-pentaacetic acid, C28<H>5<4>N5<0>2QGd.Elementary analysis: ;Example 3 ;Preparation of a solution of the di-N-methylglucamine salt of the manganese (II) complex of ethylenediamine- tetraacetic acid. ; 3.68 g (= 5 mmol) of the substance described in example 1 is dissolved in 70 ml of water pro injectione (p.i.) and the solution is added to 0.4 g of sodium chloride. It is then filled to 100 ml with water p.i. and the solution is filled in ampoules through a sterile filter. The solution is isotonic at 280 mOsm. ;Example 4 ;Preparation of a solution of the N-methylglucamine salt ;of g the adolinium (III) complex of ethylenediaminetetraacetic acid. ;9.6 3 g (= 15 mmol) of the substance described in example 2 is dissolved in 100 ml of water o.i. the nearly blood isotonic solution is filled into ampoules over a sterile filter. ;Example 5 ;Preparation of a solution of the di-N-methylglucamine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid. ;5.35 g (= 9 mmol) of the gadolinium (III) complex of diethylenetriaminepentaacetic acid (water content 8%) is dissolved in 50 ml of water p.i. and neutralized by adding approx. 3.2 g (equivalent to approx. 18 mmol) N-methylglucamine to pH 7.5. The solution is then filled up to 100 ml with water p.i., filled into ampoules and heat sterilized. The concentration of the solution is set to blood isotonicity (approx. 280 mOsm). ;Example 6 ;Preparation of a solution of the di-N-methylglucamine salt of the dysprosium (III) complex of diethylenetriaminepentaacetic acid^^ ;8.0 g (= 15 mmol) of the dysprosium (III) complex of diethylenetriaminepentaacetic acid are dissolved in 80 ml of water p.i. while adding approx. 5.3 g (equivalent to approx. 30 mmol) N-methylglucamine at pH 7.5. The solution is then filled up to 170 ml with water p.i. The nearly blood isotonic solution is filled into ampoules and heat sterilized. ;Example 7 ;Preparation of a solution of the di-N-methylglucamine salt of the holmium (III) complex of diethylenetriaminepentaacetic acid. ;8.02 g (= 15 mmol) of the holmium (III) complex of diethylenetriaminepentaacetic acid are dissolved in 80 ml of water p.i. while adding approx. 5.3 g (equivalent to approx. 30 mmol) N-methylglucamine at pH 7.2. The solution is then filled with water p.i. to 170 ml. The approximate blood isotonic solution is filled into ampoules and heat sterilized. The solution can also be prepared by dissolving the complex salt isolated according to example 2. in water p.i. ;Example 8 ;Preparation of a solution of the disodium salt of the manganese (II) complex of ethylenediamine-tetraacetic acid. ;5.55 g (15 mmol) of the manganese (II) complex of ethylenediaminetetraacetic acid (water content: 6.9%) is dissolved in 80 ml of water p.i. while adding dilute caustic soda at pH 7.5. The solution is then filled up with water p.i. to 170 ml, filter into ampoules and heat sterilize. *

Claims (14)

1. Physiologically compatible, paramagnetic complex salts for use in NMR diagnostics, characterized in that they consist of aminopolycarboxylic acids with the formulas I - II N,N,N<1>,N",N"-diethylenetriaminepentaacetic acid (DTPA), where m is 1 - 4. and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metals with atomic numbers 21 - 29, 42 and 44, and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine. 2.. Physiologically compatible, paramagnetic complex salts according to claim 1, characterized in that they are the di-N-methylglucamine salt of the manganese(II) complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the nickel(II) complex of ethylenediaminetetraacetic acid, the tri-N-methylglucamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolirium(III) complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of dysprosium(III)- the complex of ethylenediaminetetraacetic acid and the di-N-methylglucamine salt of the holmium(III) complex of diethylenetriaminepentaacetic acid. 3. Physiologically compatible, paramagnetic complex salt according to claim 1, characterized in that it is the di-N-methylIglucamine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid. 4. Physiologically compatible, paramagnetic complex salts according to claim 1, characterized in that they are the diethanolamine salt of the cobalt(II) complex of ethylenediaminetetraacetic acid, the di-diethanolamine salt of the copper(II) complex of ethylenediaminetetraacetic acid and the tri-diethanolamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid. 5. Physiologically compatible, paramagnetic complex salt according to claim 1, characterized in that it is the dimorpholine salt of the manganese(II) complex of ethylenediaminetetraacetic acid. 6. Physiologically compatible, paramagnetic complex salt according to claim 1, characterized in that it is the dilysine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid. 7. Means for use in NMR diagnostics, characterized in that it contains at least one paramagnetic, physiologically compatible complex salt of aminopolycarboxylic acids with the formulas I - II N,N,N<1>,N",N"-diethylenetriaminepentaacetic acid (DTPA), where m is 1 - 4, and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metals with atomic numbers 21 - 29, 42 and 44, and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine, possibly together with common additives in the art, such as physiologically compatible buffer solutions, surfactants and/or aromatic substances, dissolved or suspended in water or physiological salt solution, the agent containing 5 - 250 mmol/1, preferably 50 - 200 mmol/1, paramagnetic complex salt and has a pH in the range 6.5 - 8.0, preferably 6.5 - 7.5. 8. Means for use in NMR diagnostics according to claim 7, characterized in that it contains the di-N-methylglucamine salt of the manganese (II) complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the nickel (II) complex of ethylenediaminetetraacetic acid, tri- The N-methylglucamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium(III) complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of the dysprosium(III) complex of ethylenediaminetetraacetic acid and the di-N-methylglucamine salt of holmium(III)- the complex of diethylenetriaminepentaacetic acid. 9» Agent for use in NMR diagnostics according to claim .7, characterized in that it contains the di-N-methylglucamine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid. 10. Agent for use in NMR diagnostics according to claim 7, characterized in that it contains the diethanolamine salt of the cobalt (II) complex of ethylenediaminetetraacetic acid, the di-diethanol salt of the copper (II) complex of ethylenediaminetetraacetic acid and the triethanolamine salt of manganese (II) -the complex of diethylenetriaminepentaacetic acid. 11. Agent for use in NMR diagnostics according to claim 7, characterized in that it contains the dimorpholine salt of the manganese(II) complex of ethylenediaminetetraacetic acid. 12. Agent for use in NMR diagnostics according to claim 7, characterized in that it contains the dilysine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid. 13. Means for use in NMR diagnostics, characterized in that it contains at least one physiologically compatible, paramagnetic complex salt of aminopolycarboxylic acids with the formulas I - II N,N,N' ,N",N"-diethylenetriaminepentaacetic acid (DTPA), where m is 1 - 4, and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metals with atomic numbers 21 - 29, 42 and 44, and optionally an inorganic base. 14. Means for use in NMR diagnostics according to claim 13, characterized in that it contains at least one physiologically compatible, paramagnetic complex salt where sodium hydroxide is used as the inorganic base.