EP0930897A2

EP0930897A2 - Method

Info

Publication number: EP0930897A2
Application number: EP97934621A
Authority: EP
Inventors: Göran Pettersson; Klaes Golman; Anne Jacobsen; Liv-Ingrid Deg Rdstuen; Anne Kjersti Fahlvik
Original assignee: Nycomed Imaging AS
Current assignee: GE Healthcare AS
Priority date: 1996-09-23
Filing date: 1997-07-30
Publication date: 1999-07-28
Also published as: GB9619759D0; WO1998011921A3; WO1998011921A2; JP2001500870A; CN1238698A; AU3776697A; CA2265856A1

Abstract

The invention provides the use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn2+- chelating unit, in the manufacture of an enterally, e.g. orally or rectally, administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6, preferably at least 10, more preferably at least 12 hours before enteral administration of said composition. It has been found that diagnostically effective levels of uptake of orally or rectally administered manganese may be achieved using this method.

Description

Method

The present invention relates to improvements in and relating to magnetic resonance imaging (MRI) , in particular to the use of manganese compounds in the preparation of contrast media for imaging of the abdome .

MRI is now well established as a medical diagnostic tool . The ability of the technique to generate high quality images and to differentiate between soft tissues without requiring the patient to be exposed to ionizing radiation has contributed to this success.

Although MRI can be performed without using added contrast media, it has been found that substances which affect the nuclear spin reequilibration of the nuclei (hereinafter the "imaging nuclei" - generally water protons in body fluids and tissues) responsible for the magnetic resonance (*MR) signals from which the images are generated may be used to enhance image contrast and, accordingly, in recent years, many such materials have been suggested as MRI contrast agents .

The enhanced contrast obtained with the use of contrast agents enables particular organs or tissues to be visualized more clearly by increasing or by decreasing the signal level of the particular organ or tissue relative to that of its surroundings. Contrast agents raising the signal level of the target site relative to that of its surroundings are termed "positive" contrast agents whilst those lowering the signal level relative to surroundings are termed "negative" contrast agents.

Development of MRI as a technique for imaging the gastrointestinal (g.i.) tract, or indeed the abdomen in general, has been hindered by problems particular to the abdomen in which natural inter-tissue contrast is relatively poor and by the absence of a particularly effective contrast medium.

The majority of materials now being proposed as MRI contrast media achieve a contrast effect because they contain paramagnetic, superparamagnetic or ferromagnetic species.

Paramagnetic contrast agents may be either positive or negative MRI contrast agents. The effect of paramagnetic substances on magnetic resonance signal intensities is dependent on many factors, the most important of which are the concentration of the paramagnetic substance at the imaged site, the nature of the paramagnetic substance itself and the pulse sequence and magnetic field strength used in the imaging routine. Generally, however, paramagnetic contrast agents are positive MRI contrast agents at low concentrations where their Tj lowering effect dominates and negative MRI contrast agents at higher concentrations where their T₂ (or T₂*) lowering effect is dominant.

An example of a physiologically tolerable paramagnetic material known for use as an MRI contrast agent is manganese ion, which may conveniently be used in the form of its salts or chelates. However manganese, when administered intravenously as a contrast agent, may be teratogenic at clinical dosages. Administered intravenously, manganese is also known to interfere with the normal functioning of the heart by replacement of calcium in the calcium pump of the heart.

In order to reduce the direct effect on the heart, oral administration of manganese has been proposed. A result of the vascularisation of the upper g.i. tract is that orally administered material taken up into the blood from the gut passes to the liver before passing to the heart. In the case of manganese, absorption by the hepatocytes in the liver prevents cardiotoxic levels of manganese reaching the heart. This hepatocyte uptake of manganese thus means that orally administered manganese could be used as a liver imaging MR contrast agent . However, in early animal studies no diagnostically effective uptake of orally administered MnCl₂ through the gut wall was found when manganese was given in clinically relevant doses. Moreover, orally administered, manganese containing g.i. tract MR contrast media, such as the manganese/hydrophilic polymer composition Lumenhance, show no contrast enhancement other than in the content of the gut .

It was therefore considered that to achieve uptake from the gut of diagnostically effective, i.e. contrast effective, quantities of manganese, the use of materials which positively promote manganese uptake was required and WO-A- 96/05867 proposed as a solution to this problem of inadequate uptake of manganese in the gut the use of manganese contrast agents in combination with one or more uptake promoters capable of enhancing manganese transport across the membranes of the g.i. tract. Examples of such uptake promoters include ascorbic and kojic acids.

However, there still exists the need for improved methods of MR imaging using manganese contrast agents, in particular for imaging of the abdomen, e.g. the liver and the g.i. tract.

We have now surprisingly found that diagnostically effective levels of uptake of orally or rectally administered manganese may be achieved simply by ensuring that no food or no hydrophilic polymer components containing a significant amount of a Mn^2t- chelating unit are simultaneously present in the gut, e.g. by administering manganese chloride following a period of fasting. By "significant amount" is meant that the amount of Mn²⁺- chelating unit is sufficiently high so as to influence the uptake of manganese.

Whilst not wishing to be bound by theoretical considerations, it is believed that food present in the gut, and in particular constituents of food containing hydrophilic polymer components containing a significant amount of a Mn²'- chelating unit, form tight complexes with the manganese ions thereby hindering manganese transport across the membranes of the g.i. tract.

Thus viewed from one aspect the invention provides the use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, in the manufacture of an enterally, e.g. orally or rectally, administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6, preferably at least 10, more preferably at least 12 hours before enteral administration of said composition.

By fasting it is meant that no solid food which may contain hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, in particular soluble or fibrous hydrophilic polymers, has been consumed within the stated period. Water or sugar containing fluids may be taken during the fasting period.

In a particularly preferred embodiment of the invention, the manganese contrast agent is administered substantially in the absence of any uptake promoter, e.g. ascorbic acid.

In an alternative embodiment the invention provides a method of obtaining enhanced images of the liver and the lower gut by means of rectal administration of the contrast medium. Due to the special vascularisation of the lower gut, a proportion of the rectally administered manganese passes directly to the heart following absorption, without first passing through the liver. We have, however, surprisingly found that effective uptake of manganese in the lower gut can be achieved using much lower doses of rectally administered manganese, resulting in particularly enhanced images of the liver and lower gut. This is of particular value in detecting tumors in the lower gut, e.g. in the diagnosis of colorectal cancer.

Viewed from a further aspect the invention thus provides the use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, in the manufacture of a rectally administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body wherein the g.i. tract of said body is substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit at the time of imaging. Conveniently, the contrast medium composition is administered to a human or non-human animal body which has fasted for a period of at least 6, preferably at least 10, more preferably at least 12 hours.

Maximum uptake of rectally administered manganese may, however, be achieved by prior irrigation of the colon, thereby ensuring that this is substantially free from any hydrophilic polymer components containing a significant amount of a Mn⁺- chelating unit. As soon as the gut is cleared of any undesirable hydrophilic polymer components, manganese uptake in the gut occurs and images can be produced.

Rectal administration may be via rectally inserted tubes which enable administration of the contrast medium to a selected region of the gut.

Conveniently, the manganese compound may be present in the contrast medium composition at a concentration of at least 0.3mM or, alternatively, may be present in a dosage unit form containing at least 300μmol manganese.

The manganese compound, which for oral administration is preferably soluble in gastrointestinal fluid, may for example be a chelate or a salt, or may be a mixture of different salts and/or chelates. Particularly preferred are metal chelates and salts in which the manganese is present as Mn(II) rather than Mn(III) since the former has a higher magnetic moment and thus is more effective as an MR contrast agent.

Examples of manganese compounds particularly suitable for use in accordance with the invention include manganese chloride, ascorbate and kojate.

The manganese compounds may conveniently be used in combination with one or more uptake promoters, such as those described in WO-A-96/05867. In this regard, the contrast media compositions may be administered as a combined preparation with the uptake promoter or, alternatively, may be administered separately, prior to, during or subsequent to administration of the uptake promoter. Alternatively, the manganese compound is administered substantially free from such uptake promoter .

Suitable uptake promoters include reducing compounds containing an -hydroxy ketone group (-CH (OH) -CO-) , acids containing - and/or β-hydroxy or amino groups, vitamin D and mixtures thereof. The reducing nature of the uptake promoter is important since normal uptake of manganese by the gut tends to favour Mn(II) rather than Mn(III) .

As used herein, the expression "acids containing α- and/or β-hydroxy or amino groups" is intended to include aromatic acids containing ortho-hydroxy or ortho-amino groups .

Preferred uptake promoters include those in which the reducing compound further contains an oxygen atom in a heterocyclic ring structure.

Particularly preferred as an uptake promoter is ascorbic acid which has been found to increase the uptake of manganese in the g.i. tract about 5 -fold compared with oral administration of MnCl_? alone. Moreover, ascorbic acid (vitamin C) is cheap, readily available and particularly well tolerated by the body. When administered orally, it also serves to mask the metallic taste of the manganese, thus improving the taste of the contrast medium.

Also preferred as an uptake promoter is kojic acid.

Examples of acids which have been found to be particularly effective as uptake promoters include carboxylic acids, e.g. gluconic and salicylic acid. - and β-amino acids have also been found to be useful as uptake promoters, in particular -amino acids, e.g. alanine, glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine, especially arginine, lysine and aspartic acid.

Conveniently, the molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50, e.g. 1:1 to 1:20, particularly 1:1 to 1:10, more preferably 1:1 to 1:8, yet more preferably 1:1 to 1:6, especially 1:2 to 1:6, particularly preferably about 1:5.

Alternatively, the molar ratio of manganese to uptake promoter may be in the range of from 1:1.5 to 1:5, e.g. 1:1'.5 to 1:4, particularly 1:2 to 1:4, especially 1:2 to 1:3, particularly preferably about 1:2.

The uptake promoter may if desired be present in whole or in part as the counterion to the manganese ions . Thus in one embodiment the manganese compound for use in accordance with the invention comprises a manganese salt of a reducing compound containing an α- hydroxy ketone group, or a manganese salt of an acid containing - and/or β- hydroxy or amino groups, e.g. manganese (II) ascorbate or manganese salicylate.

As mentioned above, paramagnetic materials such as manganese ions may act as either positive or negative MRI contrast agents depending upon a number of factors, including the concentration of the ions at the imaging site and the magnetic field strength used in the imaging procedure. Depending upon the resulting manganese ion concentration within the g.i. tract, this may be such as to create a signal suppressing or enhancing effect there. In this way a "double contrast effect" and margin definition can thus be achieved with varying concentrations of manganese.

Whilst a broad range of manganese concentrations is deemed to fall within the scope of the invention, there will generally be two preferred concentration ranges - one enabling strong negative contrast to be obtained between the stomach and the surrounding muscle tissue and the other providing strong positive contrast. For negative contrast the concentration of manganese is conveniently greater than lO M, preferably in the range of from lOmM to 50mM. For positive contrast the manganese concentration is conveniently in the range of from O.lmM to lOmM, preferably from lmM to 6mM.

When using the contrast media to obtain a double contrast effect, in order to avoid image artefacts resulting from pockets of the gut being contrast agent free, it is desirable to incorporate in the contrast media a viscosity enhancing agent and/or an osmoactive agent, these being other than a hydrophilic polymer component containing a significant amount of a Mn⁺- chelating unit. Examples of suitable viscosity enhancers and osmoactive agents are described in WO-A- 91/01147 and WO-A- 91/01148.

The contrast media compositions may also be used in combination with a second contrast agent, preferably one which is retained within the gut and there exhibits a negative contrast effect. This results in a double contrast effect enabling visualisation and margin definition of the abdomen to be particularly enhanced. In this regard, the contrast media may be administered as a combined preparation with a second contrast agent. Alternatively, the second contrast agent may be administered separately, prior to, during or subsequent to administration of the manganese-containing contrast medium. Viewed from a further aspect the invention thus provides the use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, together with a second contrast agent having a negative contrast effect in the gut, in the manufacture of MRI contrast medium compositions for simultaneous, separate or sequential administration in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6, preferably at least 10, more preferably at least 12 hours before enteral administration of said compositions.

Depending upon the concentration of manganese present, the manganese-containing contrast agent may function either as a positive or a negative contrast agent. In general, at the concentrations contemplated for use in accordance with the ^"invention the manganese- containing contrast agent will function as a positive contrast agent . The second contrast agent is therefore conveniently a negative contrast agent and may be any negative MRI contrast agent suitable for enteral administration.

Conveniently, the second contrast agent is substantially free from hydrophilic polymers containing a significant amount of a Mn²⁺- chelating unit.

Examples of negative MRI contrast agents for use in accordance with the method of the invention include known ferromagnetic and superparamagnetic species, e.g. AMI 227, SINEREM from Advanced Magnetics, and for example magnetic iron oxide particles either free or enclosed within or bound to a non-magnetic matrix material such as the magnetic polymer particles available under the trade names LUMIREM (Guerbet SA) and ABDOSCAN (Nycorned Imaging AS) .

Further examples of a second contrast agent for use in accordance with the method of the invention include Gd and Dy ions bound to a polymeric matrix, for example the materials available under the trade name GADOLITE (Gadolinium alumina silicate oral suspension) , available from Pharmacyclics . Yet further examples include known susceptibility agents such as insoluble barium compounds, e.g. barium sulphate, and other agents commonly used in barium meals or barium enemas in X-ray investigations of the gut.

Since the manganese is also present in the g.i. tract, the quantity of the second contrast agent necessary to achieve negative contrast within the gut may be significantly lower, e.g. 1/10 to 1/2 the quantity required in the absence of the manganese.

When using the manganese compositions in accordance with the invention to achieve a double contrast effect, it is particularly preferable to incorporate into the contrast medium a viscosity enhancing agent, other than a hydrophilic polymer component containing a significant amount of a Mn²⁺- chelating unit, which attains its full viscosity enhancing effect only after administration of the contrast medium. The contrast medium is thus able to be ingested in a relatively tolerable form while yet developing the desired viscosity at or during passage towards the site which is to be imaged.

Other examples of negative contrast agents suitable for use in accordance with the invention include gases, gas generating agents or gas filled particles. Thus, the second contrast agent may comprise a gas generating agent capable of releasing a gas, such as C0₂ or N₂, following oral administration. Preferred gas generating agents are those capable of releasing C0₂ or N₂ on contact with the gastric juices in the stomach. Alternatively, if delayed release of the gas is desirable, this can be achieved by providing the gas generating agent with a coating which does not dissolve on contact with the gastric juices. Examples of suitable gas generating agents for use in accordance with the invention include MnC0₃, Na₂C0₃ and NaHC0₃.

In a preferred embodiment of the invention, rectal administration of the contrast medium may be combined with insufflation of the lower g.i. tract to obtain a particularly enhanced double contrast effect. Insufflation may conveniently be achieved by blowing a gas, such as air, preferably C0₂ or N₂, into the lower colon either simultaneously or subsequent to administration of the manganese contrast agent . In this way, the bulk of the lower colon is filled with gas and the manganese contrast agent coats the walls of the gut . In the resulting MR images, the bulk of the colon is blackened out and the gut walls and liver are highlighted.

One of the problems encountered in imaging of the abdomen, in particular the g.i. tract, is that the MR signal intensity has a tendency to vary due to physical movements in the region being imaged. This problem can to some extent be overcome by the use of fast imaging procedures. Techniques capable of generating images with time intervals of less than 20 seconds (thus enabling imaging during one single "breath hold") are preferred for use in accordance with the method of the invention. Particularly suitable techniques include spin echo procedures (TR = 80-150ms, TE = 10-14ms) and gradient echo procedures (TR ~ 50ms, TE = 4ms, flip angle = 80-90°) . The gradient echo sequence should preferably be spoiled.

The contrast agent compositions for use in the invention are particularly suited to use, if required after dispersion in aqueous media, for imaging of the abdomen, in particular the stomach, intestine, liver, bile duct and gall bladder. For such a purpose the contrast media may be administered into the gastrointestinal tract orally, rectally or via a stomach tube. The method of the invention is capable of generating high quality 3D images of the abdomen, in particular of the liver. The method is also of particular value in providing clear images showing the structure of the gut wall, thus enabling detection of any abnormalities in the gut wall.

Viewed from another aspect the invention thus provides a method of generating a magnetic resonance image of a human or non-human, preferably mammalian, animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6, preferably at least 10, more preferably at least 12 hours prior to enteral administration, a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, and generating an image of a part of said body.

Viewed from a yet further aspect the invention provides a method of generating a magnetic resonance image of a human or non-human, preferably mammalian, animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6, preferably at least 10, more preferably at least 12 hours prior to enteral administration, an effective amount of a composition comprising (a) a first contrast agent comprising a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, together with (b) a second contrast agent, preferably one capable with said first agent of achieving negative contrast in the gastrointestinal tract, and generating an image of a part of said body, e.g. the gut, liver or the whole of the abdomen. Such a method may conveniently be used to generate a series of images through the part of the body being imaged, resulting in the production of 3D images .

The contrast medium compositions for use in accordance with the invention may include other components, for example conventional pharmaceutical formulation aids such as wetting agents, buffers, disintegrants, binders, fillers, flavouring agents and liquid carrier media such as sterile water, water/ethanol etc.

For oral administration, the pH of the composition is preferably in the acid range, eg. 2 to 7 and while any uptake promoter present may itself serve to yield a composition with this pH, buffers or pH adjusting agents may be used.

The contrast media may be formulated in conventional pharmaceutical administration forms, such as tablets, capsules, powders, solutions, dispersions, syrups, suppositories etc.

The preferred dosage of the contrast media will vary according to a number of factors, such as the administration route, the age, weight and species of the subject and, if present, the particular uptake promoter used. Conveniently, the dosage of manganese may be in the range of from 2-400 times the normal recommended daily dose of manganese, e.g. from 5 to 500 μmol/kg bodyweight, preferably from 5 to 150 μmol/kg bodyweight, more preferably from 10 to 100 μmol/kg bodyweight, while the dosage of the uptake promoter, if present, may be in the range of from 5 μmol to 1 mol/kg bodyweight, preferably from 25 μmol to 0.5 mmol/kg bodyweight.

Embodiments of the invention will now be further described by way of illustration and with reference to the accompanying figures, in which:

Figure 1 illustrates the effect of orally administered MnCl (100 μmol/kg) on signal intensity of transversal T, -weighted spin-echo images (TR/TE = 57/13 ms) in rat liver 2 hours after administration in non- fasted and fasted (18 hours) rats.

Figure 2 illustrates the effect of orally administered MnCl^ (25 μmol/kg) on signal intensity of a transversal T_α-weighted gradient-echo image (TR/TE = 52.5/4.8 ms, flip angle = 80°) in human liver 4 hours after administration in a non-fasted healthy volunteer.

Figure 3 illustrates the effect of orally administered MnCl₂ (25 μmol/kg) on signal intensity of a transversal T_x-weighted gradient-echo image (TR/TE = 52.5/4.8 ms, flip angle = 80°) in human liver 4 hours after administration in a fasted (12 hours) healthy volunteer.

Figure 4 illustrates the effect of rectally administered MnCl₂ (100 μmol/kg) + Abdoscan^® (80 μmol Fe/kg) on signal intensity of coronal T- -weighted spin- echo images (TR/TE = 120/12 ms) 25** hours after administration in fasted (24 hours) rats. The strong enhancement of the signal intensity of the colon wall is to be noted.

Figure 5 illustrates the effect of orally administered MnCl₂ (200 μmol/kg) , both with and without co-administration of alanine (400 μmol/kg) , on signal intensity of T_α-weighted spin-echo images (TR/TE = 57/13 ms) in rat liver following administration in fasted (12 hours) rats. Signal enhancement is expressed as a % increase of signal :noise ratio compared to a corresponding control .

Claims

Claims :

1. Use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, in the manufacture of an enterally administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6 hours before enteral administration of said composition.

2. Use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, in the manufacture of a rectally administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body wherein the gastrointestinal tract of said body is substantially free from hydrophilic polymer components containing a significant amount of a Mn^2t- chelating unit at the time of imaging.

3. Use as claimed in claim 2 wherein said body has fasted for a period of at least 6 hours prior to administration of said composition.

4. Use as claimed in claim 1 or claim 2 wherein said body has fasted for a period of at least 10 hours prior to administration of said composition.

5. Use as claimed in any one of claims 1 to 4 wherein said contrast medium composition has a manganese concentration greater than lOmM.

6. Use as claimed in any one of claims 1 to 4 wherein said contrast medium composition has a manganese concentration of from 0. ImM to lOmM.

7. Use as claimed in any preceding claim wherein said manganese compound is a chelate or a salt in which the manganese is present as Mn(II) .

8. Use as claimed in any preceding claim wherein said manganese compound is manganese chloride, manganese ascorbate or manganese kojate.

9. Use as claimed in any preceding claim wherein said contrast medium composition is administered separately, prior to, during or subsequent to administration of a second contrast agent and/or an uptake promoter capable of enhancing manganese transport across the membranes of the gastrointestinal tract.

10. Use as claimed in claim 9 ^"wherein said contrast medium composition is administered as a combined preparation with said second contrast agent and/or said uptake promoter .

11. Use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn^2*- chelating unit, together with a second contrast agent and/or an uptake promoter, in the manufacture of MRI contrast medium compositions for simultaneous, separate or sequential administration in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6 hours before enteral administration of said compositions.

12. Use as claimed in any one of claims 9 to 11 wherein said uptake promoter comprises a physiologically tolerable reducing compound containing an α-hydroxy ketone group, a physiologically tolerable acid containing - and/or β-hydroxy or amino groups, vitamin D, or a mixture thereof.

13. Use as claimed in any one- of claims 9 to 12 wherein said uptake promoter is selected from ascorbic acid, kojic acid, gluconic acid and salicylic acid.

1 . Use as claimed in any one of claims 9 to 12 wherein said uptake promoter comprises an - or β-amino acid.

15. Use as claimed in claim 14 wherein said acid is selected from alanine, glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine.

16. Use as claimed in any one of claims 9 to 15 wherein the molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50.

17. Use as claimed in any one of claims 10 to 15 wherein said uptake promoter is present in whole or in part as the counterion to the manganese ions .

18. Use as claimed in any one of claims 9 to 17 wherein said second contrast agent has a negative contrast effec .

19. Use as claimed in any one of claims 9 to 18 wherein said second contrast agent is substantially free from hydrophilic polymers containing a significant amount of a Mn²⁺- chelating unit.

20. Use as claimed in any one of claims 9 to 19 wherein said second contrast agent is selected from:

(a) a particulate ferromagnetic or superparamagnetic material;

(b) Gd or Dy ions bound to a polymeric matrix; (c) a gas, a gas generating agent or gas filled particles; and

(d) insoluble barium compounds.

21. Use as claimed in any preceding claim wherein said method of imaging is capable of generating a series of images with time intervals of less than 20 seconds.

22. Use as claimed in any preceding claim wherein said method of imaging is a spin echo or gradient echo imaging procedure .

23. Use as claimed in any preceding claim wherein said method of imaging provides an image of the stomach, intestine, liver, bile duct or gall bladder of said body.

24. Use as claimed in any one of claims 1 to 22 wherein said method of imaging provides a series of images of the whole abdomen of said body.

25. A method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6 hours prior to enteral administration, a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, and generating an image of a part of said body.

26. A method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6 hours prior to enteral administration, an effective amount of a composition comprising (a) a first contrast agent comprising a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn²⁺- chelating unit, together with (b) a second contrast agent, and generating an image of a part of said body,