WO1996003155A1

WO1996003155A1 - Contrast mediums for use in imaging the liver

Info

Publication number: WO1996003155A1
Application number: PCT/EP1995/002902
Authority: WO
Inventors: Werner Krause; Ulrich Speck
Original assignee: Schering Aktiengesellschaft
Priority date: 1994-07-26
Filing date: 1995-07-21
Publication date: 1996-02-08
Also published as: ZA956226B; AU3116395A; DE4426439C1; IL114711A0; EP0773798A1; JPH10502936A

Abstract

The invention concerns the use of a compound comprising at least one halogenated, preferably iodated and most preferably tri-iodated, aromatic compound, for use in imaging the liver with synchrotron radiation, approximately monochromatic X-rays, or X-rays of below a certain wavelength.

Description

Contrast agent to show the liver

description

The invention relates to the object characterized in the claims.

X-ray diagnosis, for example of lesions of the liver, is currently only possible with contrast media that are not very suitable for this purpose. They are the same compounds used for uro / angiography and computed tomography. Examples of this are Amidotrizoaf », Iohexol *. Iopamidol *. Iopromide *, iopentol *. Ioversol *, Ioxaglaf », Iotrolan * and Iodixanol ⁹ . Tumors and metastases can only be visualized with these contrast media if they are either hyper- or hypovascularized. Lesions with the same vascular density as healthy tissue are not recognizable. The principle of diagnostics with these "classic" contrast media is based on the fact that with hyper- or hypovascularization the density of the lesion briefly becomes larger or smaller than that of the surrounding healthy liver tissue and a differentiation is possible. Because of the very fast extravascularization of the contrast medium, this difference disappears within a few minutes. One way out is the selective application of the contrast medium in the hepatic arteries (KA Miles, MP Hayball, AK Dixon: Functional images of hepatic perfusion obtained with dynamic CT. Radiology 188: 405-11 (1993); K. Minakuchi, K. Tamaoka, et al. Intra-arterial digital subtraction portography with a blood-isotonic, non ionic, dimeric contrast medium. Radiat. Med. 11: 43-8 (1993); D. Merine, K. Takayasu, F. Wakao: Detection of hepatocellular carcinoma: comparison of CT during arterial portography with CT after intτaarτerial injection of iodized oil. Radiology 175 (3): 707-10 (1990)). However, this is a very invasive procedure.

As a further alternative, it was examined to use the copper stem cells with their phagocytic properties. There are different approaches for this. On the one hand, attempts have been made to use iodine-containing emulsions, for example EOE-13, perfluorooctyl bromide (PFOB) or lipiodol, which are absorbed by the liver and thus lead to an increase in density in computer tomography (DL Miller, AA Rayner, M. Girton, JL Doppman: CT evaluation of hepatic and splenic trauma with EOE-13. An experimental study in monkeys. Invest. Radiol. 20: 68-72 (1985); K. Ivancev, A. Lunderquist et al. : Effect of intravenously injected iodinated lipid emulsion on the liver. An experimental study correlating computed tomography findings with in vivo microscopy and electron microscopy findings. Acta Radiol. 30 (3): 291-8 (1989); WP Reed, PJ Haney et al .: Ethiodized oil emulsion enhanced computerized tomography in the preoperative assessment of metastases to the liver from the colon and rectum. Surg. Gynecol. Obstet. 162 (2): 131-6 (1986); G. Adam, RW Günther et al .: Computed tomographic enhancement of the liver, liver abscesses, spieen, and major vessels with perfluorooctylbromide emulsion. Influence of dosage and iηjection velocity in an animal model. Invest Radiol. 27 (9): 698-705 (1992)). However, these emulsions were not very compatible.

On the other hand, the use of suspensions was examined. The particles examined encompassed liposomes, in which iodinated contrast agents are included (W. Krause, A. Sachse et al.: Preclinical characterization of iopromide-carrying liposomes. Invest. Radiol. 26: 172-4 (1991)) and poorly soluble derivatives of triiodinated Aromatics, e.g. Metrizoe or diatrizoic acid (MR Violante: Potential of microparticles for diagnostic tracer imaging. Acta Radiol. Suppl. 374: 153-6 (1990); P. Leander, K. Golman, P. Strande et al .: A comparison between IEEC , a new biodegradable particulate contrast medium, and iohexol in a tumor model of computed tomography imaging of the liver. Invest. Radiol. 28 (6): 513-9 (1993)). The disadvantage of this approach lies in the particle structure, which is very difficult to handle pharmaceutically. This problem has not yet been satisfactorily resolved. Human studies were therefore not carried out with these two approaches.

Water-soluble X-ray contrast media for the imaging of the liver are not known, although the need for these compounds is very high. In addition, it could be shown (W. Mützel, OH Wegener, R. Souchon, H.-J. Weinmann, in: Amiel M. (ed), Springer-Verlag, Berlin, 1982, pp. 320-3) that so far it was not possible to use water-soluble contrast agents in conventional X-ray diagnostics of the liver to be used because the saturation processes of the transport prevent a sufficiently high concentration in the liver.

For example, the absorption of bile contrast agents in the liver is a saturable process that competes with many other substances. The concentrations reached in the liver are therefore not sufficiently high for imaging in computer tomography (VG Urich, U. Speck: Biliary exeretion of contrast media. Progress in Pharmacology and Clinical Phaπnacology 8: 167-177 (1991); T. Fritzsch , W. Krause, HJ. Weinmann: Status of contrast media research in MRI, ultrasound and X-ray. Eur. Radiol. 2: 2-13 (1992)).

On the basis of the prior art, it was an object of the invention to provide contrast media which are well tolerated, which are easy to handle pharmaceutically and are easy to use on the patient, i.e. no major interventions such as require direct application into the hepatic arteries to display the liver using a method which allows a sensitive measurement despite the lowest possible concentration of contrast medium.

This object is achieved according to the invention in that a compound with at least one halogenated aromatic is used as a contrast medium for imaging the liver using synchrotron radiation, approximately monochromatic X-rays or X-rays below a certain wavelength.

As a compound with at least one halogenated aromatic compound, compounds with at least one iodinated aromatic compound are preferably used. In a particularly preferred embodiment, compounds with at least one triiodinated aromatic are used.

Surprisingly, studies have shown that compounds with at least one halogenated aromatic can be used as a contrast agent for imaging the liver if synchrotron radiation is used instead of the X-rays used in conventional X-ray devices or computer tomographs. In the Synchrotron radiation can be obtained monochromatic light, which allows a more sensitive measurement. The contrast agents used according to the invention show a distribution pattern in the liver which is of great use for the diagnosis of a wide variety of pathological processes. The differentiation of diseases is possible the better, the more sensitive the X-ray procedure and the lower the dosage of the contrast agents. Furthermore, different diagnostic information results over time.

Instead of synchrotron radiation, which is monochromatic X-ray radiation, it is also possible to use approximately monochromatic X-ray radiation or X-radiation below a certain wavelength, i.e. above a certain energy range. Radiation above a certain energy means radiation above the K-edge of iodine (33keV). In the following, however, the invention is only described on the basis of synchrotron radiation.

The synchrotron radiation used in accordance with the invention can be, for example, high-energy monochromatic synchrotron radiation (2.5 GeV storage ring, 280 mA, 5 T Wiggler), as is e.g. at the electron synchrotron at the University of Tsukuba in Ibaraki / Japan. However, the synchrotron radiation is in no way limited to the example described.

Generally, this procedure involves taking two x-rays of the liver, one without a filter and the other with a filter. After subtraction processes with an iodine filter (corresponding to the X-rays below the K-edge) and without an iodine filter (X-rays above the K-edge), an image of the ber is obtained. The images can be taken at intervals of 32 msec, for example, so that the entire liver can be displayed in one pass without movement artifacts occurring.

Preferred compounds which can be used as contrast agents for imaging the liver using synchrotron radiation are disclosed in claim 4. In further preferred embodiments, the compounds used according to the invention as a contrast medium to represent the liver have the following structural features:

The molecular weight of the compound should be in the range of 300 to 1000 regardless of the halogen atom (s). The lower limit is determined by the molecular weight that is at least necessary for hepatobiliary excretion. Furthermore, the transport mechanisms of the liver or bile also play a role for the molecular weight limits.

The compound should have at least one functional group with at least one negative charge, which is bound aromatically or aliphatically. A preferred functional group with a negative charge is the carboxyl group. It is a carrier of a negative charge because the COOH group dissociates into COO ^' and H ⁺ in aqueous medium.

In addition to the COOH group as a functional group with at least one negative charge, other functional groups such as the SO ₃ H or PO _j H ₂ group are also conceivable.

In addition to the functional group (s), each with at least one negative charge, which increases the anion transport for transfer to the liver / bile, the compound should also have lipophilic regions in the molecule which enable sufficiently high protein binding.

Structural features that increase lipophilicity are those atoms / groups in a molecule that do not contain oxygen or nitrogen, e.g. pure hydrocarbon residues or the iodine atom itself.

Overall, the hydrophilic and lipophilic areas in the compound used according to the invention should be selected such that the compound in the n-butanol / water system has a distribution coefficient P> 0.2. The determination of the Distribution coefficients P are described, for example, by W. Mützel, WR. Press, H.-J. Weinmann: Physicochemical Properties and General Phaπnacology of the Nonionic Iotrolan, described in advances in the field of X-rays and nuclear medicine, Frommhold W. and Thurn P. (Ed.), Georg Thieme Verlag Stuttgart, 1989, pp. 28-32.

The invention is described in more detail below by means of exemplary embodiments. In the individual exemplary embodiments, compounds are disclosed which, according to the invention, can be used, for example, using synchrotron radiation as a contrast medium for representing the liver.

Examples

example 1

Biligrafin * (formula I) is administered intravenously in the formulation customary for cholegraphy (representation of the bile).

The area of the liver is scanned using synchrotron radiation. In addition to the bile ducts, the density of the healthy liver parenchyma is now also increased. Metastases are largely left out. Other lesions (hemangiomas, areas with cirrhotic changes) show typical changes in density over time after the injection. This is not the case with conventional X-rays. Example 2

Biliscopin * (Formula II) is slowly infused in a dose of only 2g iodine.

- & (II)

The entire liver is scanned before and after the infusion and after a further 5 and 30 minutes. Metastases, abscesses, necroses and cysts show practically no change in density over the entire course of time, while the healthy liver parenchyma increases very rapidly, adenomas, focal nodular hyperplasias and fatty cirrhotic areas of the liver slowly increase in density.

Example 3

Biloptin * (formula HI) is administered orally in the formulation customary for cholegraphy.

The area of the liver is scanned using synchrotron radiation. In addition to the bile ducts, the liver parenchyma can now be displayed. This is not the case with conventional X-rays.

In the further exemplary embodiments, only those compounds are listed which, like the compounds of Examples 1 to 3, are already known per se, their use as contrast agents for imaging the liver using synchrotron radiation, approximately monochromatic X-rays or However, X-rays below a certain wavelength are not known. In most cases, reference is only made to the patents in which these compounds are disclosed.

Example 4

Formula IV (disclosed in DE-A 20 50 217)

Example 5

Formula V (disclosed in DE-A 11 80 896)

Example 6

Foπnel VI (disclosed in DE-A 30 44 814 and EP-A-0 079 397)

Example 7

Formula VII (disclosed in DE-A 25 58 572, DE-A 9 62 698, DE-A 25 58 573)

Example 8

Formula VIH (disclosed in DE-A 9 62 698)

Example 9

Formula IX (disclosed in DE-A 9 07 529)

Example 10

Formula X (disclosed in DE-A 19 56 844)

Example 11

Formula XI (disclosed in DE-A 25 58 572, DE-A 19 37 211, DE-A 25 58 573)

Example 12

Formula XH (disclosed in DE-A 21 41 803)

^ & y- ^ yχ ° ^<xπ)

Example 13

Formula XUI (disclosed in DE-A

Example 14

Formula XIV (disclosed in DE-A 22 19 707)

Example 15

Formula XV (disclosed in DE-A 15 18 047)

(VX)

Example 16

Formula XVI (disclosed in DE-A 14 67 996)

Example 17

Formula XVII (disclosed in DE-A 12 29 679)

Example 18

Formula XVffl (disclosed in DE-A 12 12 682)

i

- "# (XVffl)

Example 19

Foπnel XDC (disclosed in DE-A 11 17 135)

(XIX)

«^ ^ ^Β Example 20

Formula XX (disclosed in DE-A 10 85 648, DE-A 11 17 135)

Example 21

Formula XXI (disclosed in DE-A 11 02 345)

Example 22

Formula XXII (disclosed in DE-A 10 99 696)

Example 23

Formula XXIII, (disclosed in DE-A 10 97 085)

(XXffl)

Example 24

Formula XXTV (disclosed in DE-A 10 94 931)

Example 25

Formula XXV (disclosed in DE-A 10 85 648)

Example 26

Formula XXVI (disclosed in DE-A 10 82 368)

Example 27

Formula XXVÜ (disclosed in DE-A 10 06 124)

(xxvπ)

14

Example 28

Formula XXVffl (disclosed in DE-A

(XXVffl)

Example 29

Foπnel XXDC (disclosed in DE-A 9 36 928)

Example 30

Formula XXX (disclosed in DE-A 9 07 529)

Example 31

Formula XXXI (disclosed in DE-A 16 43 493)

(XXXI)

y?. * Example 32

Foπnel XXXH (disclosed in DE-A 17 70 112)

Example 33

Formula XXXffl (disclosed in DE-A 19 56 844)

(XXXffl)

Example 34

Foπnel XXXIV (disclosed in DE-A 19 22 613)

(XXXTV)

Example 35

Formula XXXV (disclosed in DE-A 19 22 578)

(XXXV) 16

Example 36

Foπnel XXXVI (disclosed in DE-A 19 15 196)

(XXXVI)

Example 37

Foπnel XXXVII (disclosed in DE-A 20 50 217)

(xxxvπ)

Example 38

Formula XXXVffl (disclosed in DE-A 21 41 803, DE-A 20 50 217)

(XXXVffl)

Example 39

Formula XXXDC (disclosed in DE-A 22 35 915)

(XXXDC)

Example 40

Formula XXXX (disclosed in DE-A 25 23 567)

Example 41

Formula XXXXI (disclosed in DE-A 25 24 059)

(XXXXI)

Example 42

Formula XXXXII (disclosed in DE-A 27 15 382)

(XXXXII)

Example 43

Formula XXXXffl (disclosed in DE-A 27 32 599)

(XXXXffl)

Example 44

Formula XXXXTV (disclosed in DE-A 30 00 215, EP-A 0 032 540)

(XXXXTV)

Example 45

Foπnel XXXXV (disclosed in DE-A 29 21 467)

(XXXXV)

Claims

claims

1. Use of a compound with at least one halogenated aromatic as a contrast agent for imaging the liver using synchrotron radiation, approximately monochromatic X-rays or X-rays below a certain wavelength.

2. Use of a compound according to claim 1, characterized in that this compound has at least one iodinated aromatic.

3. Use of a compound according to claim 1 or 2, characterized in that this compound has at least one triiodinated aromatic.

4. Use of a compound according to claim 3, characterized in that it has the general formula I,

where R ,: -COOR ₃ , - (CH ^ -COORs, -CH-COOR ₃ ,

CH ₃ -CH ₂ -CH-COOR ₃ , CH ₂ -CH ₃ O,, O // /

Is -CH ₂ -CH-COOR ₃ , -CN or -CH ₂ -NH-C, O-CH ₂ -CH ₃ R ₅ CH ₃

where R ₃ : -H, -CH ₃ , -CH ₂ -CH ₃ - (CH ^ -OH, -CH ₂ -COOCH ₃ , -CH _j -COO H _j

CH ₃ or -C-COOH; I CH ₃

R,: -H, -CH ₂ -CH ₃ , - (CH ₂ ) ₃ -O-CH ₃ ,

and R * is -CH ₂ -COOH, - (Α ^ -COOH. or -CH ₂ -CH-COOH;

CH ₃

or

where R *: -H, -CH ₃ or -CH ₂ -CH ₃ ; R ₇ : -H, -CH ₃ or

and Rg is -NH ₂ , - ^ CH ^ ₂ , -N (C ₂ H ₅ ) ₂ or -NO;

with R *: -CH ₃ , - (CH2) ₅ -NH ₂ ,

-O-CH ₂ -COOH, - (CH ₂ ) ₃ -COOH, -CH ₂ -O-CH ₂ -COOH or -C ^ -O- ^ H ^ -O- ^ H ^ zO-CHa;

or has the general formula π,

OOO woπn X and Y each independently -NH-C-, -C-NH-, -N (CH ₃ ) -C-,

R ₁₀ : -COOH, -COOCHj or -N (CH ₃ ) -CO-CH ₃ ;

R ": -H or -CH ₂ OH;

R, ₂ : - (CH ₂ ) _n - with n = 0-6, -CH ₂ -O-CH ₂ -, -CH ₂ -S-CH ₂ -,

-CH ₂ -O- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ -, 22

- ((CH ₂ ) ₂ -O) ₂ - (CH ₂ ) ₂ -,

- ((CH ₂ ) ₂ -O) ₃ - (CH ₂ ) ₂ -,

- ((CH ₂ ) ₂ -0) ₄ - (CH ₂ ) ₂ -,

OH OH

-CH, -CH- CHrO-CH ₂ -CH-CH ₂ -

COOH I -CH- (CH ₂ ) ₄ -

R ₁₃ : -H or R _I0 and

R _{14 is} -H, -N (CH ₃ ) -CO-CH ₃ or R ".

5. Use of a compound according to one of the preceding claims, characterized in that the compound has a molecular weight in the range from 300 to 1000 without taking into account the halogen atoms.

6. Use of a compound according to any one of the preceding claims, characterized in that the compound has at least one functional group with at least one negative charge which is bound aromatically or aliphatically.

7. Use of a compound according to claim 6, characterized in that the functional group is a carboxyl group.

8. Use of a compound according to any one of the preceding claims, characterized in that the compound in the n-butanol / water system has a distribution coefficient P> 0.2.