NZ291479A - Contrast medium containing a manganese compound, an uptake promoter and carrier for use in mri - Google Patents

Description

New Zealand No 291479 international No. PCT/GB95/01969 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 18 08 1994,18 08 1994, Complete Specification Filed 18 08 1995 Classification (6) A61K49/00, A61K33/32 Publication date 29 April 1999 Journal No 1439 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Compositions Name, address and nationality of apphcant(s) as in international application form NYCOMED IMAGING AS, Nycoveien 2, N-0141 Oslo, Norway ?Q 1 A 7Q ^WO 96/05867 Cm O S ^ J7 PCT7GB9S/01969 COMPOSITIONS The present invention relates to improvements m and relating to magnetic resonance imaging (MRI) and m particular to compositions for use as or m the preparation of MRI contrast media for imaging of the stomach, intestine, liver, bile duct and gall bladder 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 m 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, m 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 relptive 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.

The majority of materials now being proposed as MRI contrast media achieve a contrast effect because they contain paramagnetic, superparamagnetic or ferromagnetic species PCT7GB95/01969 For ferromagnetic and superparamagnetic contrast agents, which are negative MRI contrast agents, the enhanced image contrast derives primarily from the reduction m the spin reeguilibration parameter known as T2 or as the spin-spin relaxation time, a reduction arising from the effect on the imaging nuc3ei of the fields generated by the ferromagnetic or superparamagnetic particles Paramagnetic contrast agents on the other hand 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 m the imaging routine. Generally, however, paramagnetic contrast agents are positive MRI contrast agents at low concentrations where their Tx lowering effect dominates and negative MRI contrast agents at higher concentrations where their T2 lowering effect is dominant In either event, the relaxation time reduction results from the effect on the imaging nuclei of the magnetic fields generated by the paramagnetic centres.

The use of paramagnetic, ferromagnetic and superparamagnetic materials as MRI contrast agents has been widely advocated and broad ranges of suitable materials have been suggested in the literature.

An example of a physiologically tolerable paramagnetic material known for use as an MRI contrast agent is manganese ion, which may conveniently be used m the form of its salts or chelates Indeed, even at very low i v dosages (about 5-10 jimol/kg bodyweight) manganese has been found to be particularly effective as a contrast agent for imaging of the liver.

However manganese, when administered intravenously as a contrast agent, may be teratogenic at clinical 28 1 479 dosages Administered intravenously, manganese is also known to interfere with the normal functioning of the heart by replacement of calcium m the calcium pump of the heart In order to reduce the direct effect on the heart, oral administration has been proposed. This ensures passage of the contrast, agent through the liver before going to the heart Oral administration of MnCl2 as a liver imaging MR contrast agent has been proposed and orally administered MnCl2 has not been found to be teratogenic. However, the absorption of MnCl, through the gut is poor, and as a result the dosage required for clinical efficacy is of the order of 100-1000 /zmol/kg bodyweight. In the event of damage to the gut resulting in increased uptake, such a high dosage level still has the potential for causing undesired adverse effects, eg. cardiac effects We have now surprisingly found that gastrointestinal tract manganese contrast agents suitable for imaging of the liver rray be produced by the incorporation of an uptake promoter capable of enhancing manganese transport across the membranes of the g i tract.

Compounds which have been found to be suitable for use as uptake promoters include reducing compounds containing an a-hydroxy ketone group (-C(OH)-CO-), as well as vitamin D, Thus, viewed from one aspect the present invention provides a contrast medium composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0 3mM, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, and wherein the molar ratio of manganese to uptake promoter is from 1 2 to 1 6 I INTELLECTUAL PROPERTY OI-HUt OF NZ - 7 JAN 1999 RECEIVED 29 1 479 Zf The contrast medium composition according to the invention may comprise a manganese compound together with a mixture of several uptake promoters The manganese compound, which preferably is soluble m gastrointestinal fluid may for example be a chelate or a salt, or may be a mixture of different salts and/or chelates Part]cularly preferred are metal chelates and salts m 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 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) Preferred compositions according to the invention are those m which the reducing compound further contains an oxygen atom m a heterocyclic ring structure.

Particularly preferred as an uptake promoter m the compositions of the invention is ascorbic acid which has been found to increase the uptake of manganese in the liver about 5-fold compared with oral administration of MnCl2 alone. This surprising increase is demonstrated m Figure 2 of the accompanying drawings Moreover ascorbic acid (vitamin C) is particularly preferred as an uptake promoter since it is cheap, readily available and particularly well tolerated by the body Yet more particularly preferred compositions m accordance with the invention are those an which the uptake promoter is kojic acid The dramatic increase m the uptake of manganese in the liver following administration of MnCl2 + kojic acid can be seen from Figure 5 of the accompanying drawings Other preferred compositions in accordance with the invention are those which comprise vitamin D as an uptake promoter Using the compositions of the mvont-inn i intellectual property office of m z - 7 JAN 1999 RECEIVED 29147 S can be effectively MR imaged with a significant reduction in the dosage of manganese otherwise required Thus, for example, a 5 0% enhancement of the liver can be obtained by oral administration of 100 /*mol manganese/kg body weight and 1 mmol ascorbic acid/kg. Such a dosage results m the same degree of enhancement of the liver as 5 /xmol Mn(II)/kg body weight (MnCl2, l v ) or as 500 Hmol Mn(Il)/kg body weight (MnCl2, p-o ) Figure 1 hereto demonstrates the effect of p o administration of MnCl2 and ascorbic acid on MR liver enhancement compared with p o. administration of MnCl2 alone.

Increase m the ratio of ascorbic acid to MnCl2 results m an increase in the enhancement effect obtained This dose-response relationship can be seen from Figure 2 hereto The gradual increase m enhancement of the liver with time following administration of a composition in accordance with the invention enables the dynamics of uptake of the contrast agent by the liver to be monitored (see for example Figure 2). This is of particular importance m enabling identification of areas of healthy tissue and areas of possible tumor growth In the compositions according to the invention, the preferred molar ratio of manganese to uptake promoter is from 1 3 to 1 6, particular preferably about 1 5 The uptake promoter may if desired be present m whole or in part as the counterion to the manganese ions. Thus m one embodiment the composition of the invention comprises as both manganese compound and uptake promoter a manganese salt of a reducing compound containing an a-hydroxy ketone group, eg manganese (II) ascorbcte.

The compositions according to the invention may be used to achieve a so-called "double contrast effect" by increasing the signal level from the liver whilst at the intellectual PROPERTY OFFICE OF NZ - 7 JAN 1999 2£1479 same time decreasing that from the surrounding tissues, in particular from the gut Such an effect enables yet further enhancement of the liver A double contrast effect and margin definition can be achieved with the compositions of the invention since the resulting manganese ion concentration within the g.i tract will generally be such as to create a signal suppressing effect there. In this case, to a-void image artefacts resulting from pockets of the gut being contrast agent free, it is desirable to incorporate m the compositions a viscosity enhancing agent and desirably also an osmoactive agent Examples of suitable viscosity enhancers and osmoactive agents are described m WO 91/01147 and WO 91/01148 In a particularly preferred embodiment, the compositions of the invention may be used m combination with a second contrast agent having an opposing contrast effect This results m a "double contrast effect" enabling visualisation and margin definition of the liver to be particularly enhanced.

In a further aspect the invention thus provides a contrast medium composition comprising: (a) a composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0 3mM or being m a dosage unit form containing at least 300 /mol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, together with (b) a second contrast agent having an opposing contrast effect to said first contrast agent 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 INTELLECTUAL PROPERTY OFFICE OF NZ - 7 JAN 1999 251479 site and the magnetic field strength used m the imaging procedure At the concentrations of manganese contemplated for use m the compositions of the invention, the manganese-containing contrast agent will, m general, 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 oral administration However, as indicated above, any MR contrast agent, negative or positive, may be used.

Examples of negative MRI contrast agents for use m combination with the compositions of the invention include known ferromagnetic and superparamagnetic species, such as for example magnetic iron oxide particles either free or enclosed within or bound to a non-magnetic matrix material such as a polysaccharide eg. LUMIREM and sulphonated polystyrene eg ABDOSCAN® Further examples of contrast agents for use in combination with the compositions of the invention include Gd and Dy ions bound to a polymeric matrix, for example LUMIREM or GADOLITE (Gadolinium alumina silicate oral suspension) When using the compositions of the invention to achieve a double contrast effect, it is particularly preferable to incorporate a viscosity enhancing agent which attains its full viscosity enhancing effect only after administration of the contrast medium The contrast medium is thus able to be ingested m a relatively tolerable form while yet developing the desired viscosity at or during passage towards the site which is to be imaged.

The compositions of the invention are particularly suited to use, if required after dispersion m aqueous media, for imaging of the liver. For such a purpose the compositions may be administered into the gastrointestinal tract orally, rectally or via a stomach tube ~TtLLECTUAL PROPERTY OFFICE or NZ - 7 JAN 1999 2S147E.

Thus, viewed from a further aspect the present 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 a contrast medium comprising a physiologically tolerable manganese compound and a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, and generating a magnetic resonance image of the liver and the gastro-intestinal tract of said body.

Viewed from a yet further aspect the invention also provides 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 an effective amount of a composition comprising (a) a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, preferably having a manganese concentration of at least 0.3mM or being m a dosage unit form containing at least 3 00 (imol manganese, together with (b) a second contrast agent having an opposing contrast effect to said first contrast agent and generating a magnetic resonance image of the liver and abdomen of said body It is possible to formulate the contrast medium immediately or shortly prior to administration by mixing the uptake promoter with the manganese species. Thus, m a further aspect the invention also provides an MRI contrast agent kit comprising m a first container a physiologically tolerable manganese compound, and m a second container a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, wherein said manganese compound and hptake promoter are present in an amount Intellectual property office OF NZ -7 JAN 1999 9ei479 sufficient to provide a molar i^^io of manganese to uptake promoter of from 1 1 to 1 6 Viewed from a further aspect the invention also provides an MRI contrast agent kit comprising m a first container a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, preferably having a manganese concentration of at least 0 3nM or being m a dosage unit form containing at least 3 00 /imol manganese, and m a second container a second contrast agent comprising a particulate ferromagnetic or superparamagnetic material.

The contrast agent compositions of the invention may of course include components other than the uptake promoter, the manganese compound, the viscosity enhancing and osmoactive agents, for example conventional pharmaceutical formulation aids such as wetting agents, buffers, dismtegrants, binders, fillers, flavouring agents and liquid carrier media such INTELLECTUAL PROPERTY OFFICE OF NZ - 7 JAN 1999 RECEIVED as sterile water, w,iter/ethanol etc For oral administration, the pH of the composition is preferably in the acid range, eg 2 to 7 and while the uptake promoter may itself serve to yield a composition with this pH, buffers or p'T 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 composition according to the present invention will vary according to a number of factors, such as the administration route, the age, weight and species of the subject and the particular uptake promoter used Conveniently, the dosage of manganese will be m the of from 5 to 500 /zmol/kg bodyweight, preferably froti' 5 to 150 /unol/kg bodywexght, more preferably from 10 to 100 /imol/kg bodyweight, while the dosage of the uptake promoter will be m the range of from 5 fimol to 1 mmol/kg bodyweight, preferably from 25 jimol to 0.5 mmol/kg bodyweight Preferred embodiments of the invention will now be described by reference to the following non-limiting Examples and the accompanying drawings, in which- Figure 1 is a graph illustrating the effect of p.o administration of different Mn2+ salts on liver enhancement, Figure 2 is a graph illustrating the effect of p.o administration of MnCl2 + ascorbic acid on liver enhancement at varying concentrations of ascorbic acid; and Figure 3 is a graph illustrating the effect of p.o administration of different doses of MnCl2 containing 0 1 mmol/kg ascorbic acid on liver enhancement Figure 4 is a graph illustrating the effect of the addition of ascorbic acid or ascorbic acid-palmitate to MnCl2 on enhancement of the liver Figure 5 is a graph illustrating the effect of the addition of ascorbic acid or kojic acid to MnCl2 on enhancement of the liver Figure 6 is a graph illustrating the results of a pharmacokinetic study to determine the variation in concentration of Mn(II) in the blood following administration of various Mn(II)-containing compositions Figure 7 is a graph comparing the effect on liver enhancement of i.v. administration of Mn DPDP (S-095) with that of p.o. administration of MnCl2 + ascorbic acid Figure 8 is a graph illustrating the effect of the addition of ascorbic and salicylic acids to MnCl2 on liver enhancement Figure 9 is a graph illustrating the effect of the addition of different amino acids to MnCl2 on liver enhancement.

Figure 10 illustrates transversal Tl-weighted (SE 57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 /xmol/kg MnCl2 + 1000 /imol/kg ascorbate The signal intensity of the liver is substantially increased after gavage administration of Mn2+ and ascorbate Figure 11 illustrates coronal T1-weighted (SE 90/17, 2.4 T) liver images from two rats 2 hours after oral administration of 200 jxmol/kg MnCl2 + 1000 /xmol/kg ascorbate The signal intensity in the gastrointestinal lumen is reduced after administration of Mn2+.

Figures 12 and 13 are graphs illustrating the effect of the addition of ABDOSCAN® to Mn-ascorbate on the enhancement of the liver.

Figure 14 illustrates transversal Tl-wejghted (SE 57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 /nnol/kg MnCl2 + 1000 /imol/kg ascorbate + ABDOSCAN® (21 12 /xmol/kg Fe) The addition of ABDOSCAN did not influence the signal intensity of the liver.

Figure 15 illustrates coronal Tl-weighted (SE 90/17, 2 4 T) liver images from a control rat and from a rat 2 hours after oral administration of 200 /zmol/kg MnCl2 + 1000 /imol/kg ascorbate + ABDOSCAN® (21 /imol/kg Fe) . The signal intensity m the gastrointestinal lumen is markedly reduced after co-administration of Mn2+ and ABDOSCAN For the measurement of the curves of Figures 1 to 9 the following materials were used: Figure 1 Mn-ascorbate MnCl2 x 2H20 Ascorbic acid Water ad 6.48 g 35.2 g 1000 ml Mn-gluconate Mn-gluconate Water ad 19.2 g 1000 ml Mn-citrate MnCl2 x 2H20 Na3-citrate x 2H20 Water ad 6.48 g 23 5 g 1000 ml Figure 2 Mn£l2 MnCl2 x 2H20 Water ad 6.48 g 1000 ml MnCl- +0.1 mrnol/ka ascorbic acid MnCl2 x 2H20 Ascorbic acid 6 48 g 3.52 g Water ad 1000 ml Mndl- + 0-4 mmol/ka ascorbic: acid MnCl2 x 2H20 Ascorbic acid Water ad 6 48 g 14 1 g 1000 ml MnHl. +1.0 mmol/ka ascorbic acid MnCl2 x 2H20 Ascorbic acid Water ad 6 48 g 35 2 g 1000 ml Figure 3 MnCl? (0-2 nimol/kal + ascorbic acid MnCl2 x 2H20 Ascorbic acid Water ad 6 48 g 3 52 g 1000 ml MnCl2 (0.5 mmol/Kg) MnCl2 x 2H20 Ascorbic acid Water + ascorbic acid ad 16.2 g 3.52 g 1000 ml MnCl. (2.0 mmol/ko) + ascorbic acid MnCl2 x 2HZ0 Ascorbic acid Water ad 64.8 g 3.52 g 1000 ml Figure 4 MUC1: MnCl2 X 2H20 Water ad 13 0 g 1000 ml MnCl. + ascorbic arid - palmitate (0.4 mmol/kg^ L-ascorbic acid 6-palmitate 66.4 g - 14 Polyethylene glycol 300 ad 1000 ml Figure 5 MnCl2 + kojic acid (0.4 mmol/kg) MnCl2 x 2HzO Kojic acid Water ad 6 48 g 11 4 g 100 0 ml Figure 8 MnC!!., (0.2 mmol/ka) MnCl2 x 2H20 Water ad 6 48 g 100 0 ml MnCl, (0-2 mmol/ka) + ascorbic acid (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Ascorbic acid 14.1 g Water ad 1000 ml MnCl-, (0.2 mmol/ka) + salicylic acid (0.4 mmol/ka) MnCl2 x 2H20 Salicyclic acid sodium salt Water ad 6 .48 g 12 8 g 1000 ml Figure 9 MnCl2 (0.2 mmol/kg) MnCl2 x 2H20 Water ad 6 .48 g 1000 ml MnCl7 (0-2 mmol /ka) + ascorbic acid (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Ascorbic acid 14.1 g Water ad 1000 ml -wo 96/05867 MnCl- (0.2 Tnmol/ka) + alvcine f0.4 mmol /kg) MnCl2 x 2H20 6 48 g Glycine 7 76 g Water ad 1000 ml MnCl-, (0.2 mmol/ka) + valine (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Valine 9 36 g Water ad 1000 ml MnCl. (0-2 mmol/ka) + crliir.amme (0.4 mmnl/ka) MnCl2 x 2H20 6 48 g Glutamine 11 7 g Water ad 1000 ml MnCl- (0.2 mmol/ka) + aspartic acid (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Aspartic acid 13 8 g Water ad 1000 ml MnCl- (0.2 mmol/ka) + glutamic acid (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Glutamic acid monosodium salt monohydrate 15.0 g Water ad 1000 ml MnCl- (0.2 mmol/ka) + lysine (0.4 mmol/ka) MnCl2 x 2H20 6.48 g Lysine monohydrochloride 14.6 g Water ad 1000 ml MnCl- (0.2 mmol/ka) + arginine (0.4 mmnl/ka) MnCl2 x 2H20 6.48 g Arginine monohydrochloride 16.9 g Water ad 1000 ml WO 96/05867 PCT/GB95/01969 MnCl-, (0.2 mmol/kg) + cysteine (0.4 mmol/ka) MnCl2 x 2H20 6 48 g Cysteine monohydrochloride monohydrate 14.0 g Water ad 1000 ml MnCl-, (0.2 mmol/ka) + methionine (0.4 mmol/ka) MnCl2 x 2H20 6.48 g Methionine 11.9 g Water S£i 1000 ml For the measurement of the curves of Figures 12 and 13 the following materials were used: MnCl2 x 2H20 Ascorbic acid ABDOSCAN® Water ad 0.567 g 3.08 g 23.4 mg Fe (one dose-package) 200 ml Example 1 Oral Cnmooffltinn MnCl2 x 2H20 Ascorbic acid Water ad 6.48 g 35.2 g 1000 ml The manganese chloride and ascorbic acid are dissolved m sterile deionised water. The dose for a 70 kg adult human would be 350 ml, taken orally.

Example 2 Oral Composition MnCl2 x 2H20 Kojic acid 6.48 g 11.4 g Water ad. 1000 ml The manganese chloride and kojic acid are dissolved in sterile deionised water The dose for a 70 kg adult human would be 350 ml, taken orally Example 3 Oral Composition MnCl2 x 2H20 13 0 g Water ad 1000 ml B L-ascorbic acid 6-palmitate 66 4 g Polyethylene glycol 300 ad 1000 ml The dose for a 70 kg adult human would be l^S ml of A and 175 ml of B, taken orally.

Example 4 Oral Composition MnCl2 x 2H20 Ascorbic acid ABDOSCAN® Water ad 0.567 g 3 08 g 23 4 mg Fe 200 ml The dose for a 70 kg adult human would be 4 x 200 ml, taken orally. example 5 Oral Composition - MnCl- (0.2 mmol/ka) + vitamin D (0.4 mmol/ka) A MnCl2 x 2H20 13.0 g Water asl 1000 ml B Vitamxn D 30.0 g Polyethylene glycol 300 adl 1000 ml

Claims (8)

Claims• - 19 - 2S 1 479

1. A contrast medium composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, said composition having a manganese concentration of at least 0 3mM, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, and wherein the molar ratio of manganese to uptake promoter is from 1.2 to 1 6

2. A composition as claimed m claim 1 wherein the molar ratio of manganese to uptake promoter is from 1 3 to 1.6.

3 A composition as claimed in claim 1 or claim 2 wherein the uptake promoter comprises one or more of the compounds defined m claim 1

4. A composition as claimed in any one of claims 1 to 3 wherein the manganese compound is a chelate or a salt m which the manganese is present as Win(II)

5 A composition as claimed m any one of claims 1 to 4 wherein the reducing compound further contains an oxygen atom in a heterocyclic ring structure.

6. A composition as claimed m any one of claims 1 to 5 wherein the uptake promoter is ascorbic acid.

7. A composition as claimed 5 wherein the uptake promoter

8. A composition as claimed 4 wherein the uptake promoter in any one of claims 1 to is kojic acid. in any one of claims 1 to is vitamin D INTELLECTUAL PROPERTY OFFICE OF NZ - 7 JAN 1999 RECEIVED 201479 - 20 - 9 A composition as claimed m any preceding claim wherein the uptake promoter is present in whole or in part as the counterion to the manganese ions. 10 Use of a physiologically tolerable manganese compound together with an uptake promoter m the manufacture of a diagnostic agent for use m a method of image generation practised on the human or non-human animal body, wherein said uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, and wherein the molar ratio of manganese to uptake promoter is from 1:1 to 1:6. 11 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 bodv a contrast medium comprising a physiologically tolerable manganese compound and a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, wherein the molar ratio of manganese to uptake promoter is from 1:1 to 1:b, and generating a magnetic resonance image of the liver and abdomen of said body 12 An MRI contrast agent kit comprising m a first container a physiologically tolerable manganese compound, and m a second container an uptake promoter comprising a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, and wherein sa±d manganese compound and uptake promoter are present in an amount sufficient to provide a molar ratio of manganese to uptake promoter of from 1:1 to 1 6 13 A contrast medium composition comprising INTELLECTUAL PROPERTY office OF NZ - 7 JAN 1999 2S1479 (a) a composition comprising a physiologically-tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3mM or being m a dosage unit form containing at least 3 00 /zmol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof, and/or vitamin D, together with (b) a second contrast agent having an opposing contrast effect to said first contrast agent. 14 A composition as claimed m claim 13 wherein the molar ratio of manganese to uptake promoter is from ll1 to 1 6 15 A composition as claimed m claim 13 or claim 14 wherein the second contrast agent has a negative contrast effect 16 A composition as claimed m claim 13 or claim 14 wherein the second contrast agent comprises a particulate ferromagnetic or superparamagnetic material 17 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 an effective amount of a composition as defined m claim 13 and generating a magnetic resonance image of the liver and abdomen of said body 18 An MRI contrast agent kit comprising in a first container a first contrast agent comprising a physiologically tolerable manganese compound together with an uptake promoter, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an a-hydroxy ketone group, or a salt thereof. . INTELLECTUAL PROPERTY OFFICE OF NZ -7 JAN 1999 RFHEIVED I - 22 - 291479 and/or vitamin D; and in a second container a second contrast agent as defined m claim 16. 19 A composition as claimed in claim 1 substantially as herein described with reference to any one of the Examples 1 to 5 END OF CLAIMS INTELLECTUAL PROPERTY OFFICE OF NZ -7 JAN 1999 RECEIVED