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Page 1 Note: Within Nine Months from the Publication of the Mention Europäisches Patentamt (19) European Patent Office & Office européen des brevets (11) EP 1 411 992 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 49/04 (2006.01) A61K 49/18 (2006.01) 13.12.2006 Bulletin 2006/50 (86) International application number: (21) Application number: 02758379.8 PCT/EP2002/008183 (22) Date of filing: 23.07.2002 (87) International publication number: WO 2003/013616 (20.02.2003 Gazette 2003/08) (54) IONIC AND NON-IONIC RADIOGRAPHIC CONTRAST AGENTS FOR USE IN COMBINED X-RAY AND NUCLEAR MAGNETIC RESONANCE DIAGNOSTICS IONISCHES UND NICHT-IONISCHES RADIOGRAPHISCHES KONTRASTMITTEL ZUR VERWENDUNG IN DER KOMBINIERTEN ROENTGEN- UND KERNSPINTOMOGRAPHIEDIAGNOSTIK SUBSTANCES IONIQUES ET NON-IONIQUES DE CONTRASTE RADIOGRAPHIQUE UTILISEES POUR ETABLIR DES DIAGNOSTICS FAISANT APPEL AUX RAYONS X ET A L’IMAGERIE PAR RESONANCE MAGNETIQUE (84) Designated Contracting States: (74) Representative: Minoja, Fabrizio AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Bianchetti Bracco Minoja S.r.l. IE IT LI LU MC NL PT SE SK TR Via Plinio, 63 20129 Milano (IT) (30) Priority: 03.08.2001 IT MI20011706 (56) References cited: (43) Date of publication of application: EP-A- 0 759 785 WO-A-00/75141 28.04.2004 Bulletin 2004/18 US-A- 5 648 536 (73) Proprietor: BRACCO IMAGING S.p.A. • K HERGAN, W. DORINGER, M. LÄNGLE W.OSER: 20134 Milano (IT) "Effects of iodinated contrast agents in MR imaging" EUROPEAN JOURNAL OF (72) Inventors: RADIOLOGY, vol. 21, 1995, pages 11-17, • AIME, Silvio XP002227102 20134 Milano (IT) • K.M. WARD, A.H. ALETRAS, AND RS BALABAN: • BARGE, Alessandro "A new class of contrast agents for MRI based on 20134 Milano (IT) proton chemical exchange dependent saturation • MAINERO, Valentina transfert (CEST)" JOURNAL OF MAGNETIC 20134 Milano (IT) RESONANCE, vol. 143, 2000, pages 79-87, XP002227103 cited in the application Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 992 1 411 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 411 992 B1 Description [0001] The present invention discloses the use of radiographic contrast agents for the preparation of diagnostic for- mulations for the sequential or simultaneous X ray and nuclear magnetic resonance (MRI) diagnostics. 5 [0002] X-ray contrast agents used in in vivo diagnostics are usually characterized by high water solubility, low viscosity, low osmotic pressure, high contrast density, low toxicity and good tolerability. [0003] The clinical use of non-ionic contrast agents has gradually replaced that of ionic contrast agents which, on the other hand, are still being used (see e.g. Renografin) in some diagnostic applications. [0004] Examples of non-ionic contrastographic agents comprise Ioexol, Iomeprol, Iopentol, Iopromide, Ioversol, Ioxilan, 10 Iodixanol and Iopamidol. [0005] Magnetic Resonance Imaging diagnostic procedures mainly use paramagnetic compounds, preferably chelated complexes of bi- or trivalent paramagnetic metal ions with polyaminopolycarboxylic acids and/or their derivatives or analogues. [0006] Currently available MRI contrast agents comprise: Gd-DTPA, MAGNEVIST®; Gd-DOTA, DOTAREM®; Gd- 15 HPDO3A PROHANCE®; Gd-DTPA-BMA, OMNISCAN®. [0007] The contrast agents listed above are designed for a wholly general use. In fact, after intravenous administration, the MRI contrast agent is distributed in the extracellular spaces in different parts of the body prior to being excreted. In this sense they are similar to iodine compounds used in X ray medical diagnosis. [0008] A recently proposed technique for MRI diagnostic is the magnetization transfer technique (see e.g. J. Chem. 20 Phys. 39 (11), 2892-2901, 1963), in which the proton signal of a molecule, present in the medium or added thereto, is suitably irradiated with a radiofrequency signal generated by the apparatus magnetic field, and transferred through magnetization to the water molecules surrounding the compound, i.e. the so-called "bulk water" of the medium. [0009] The parameters affecting this process are related to different factors such as the nature of the chemical group involved in the proton transfer, the pH of the solution, the temperature of the medium and the intensity of the applied 25 magnetic field. [0010] US 5 050 609 discloses the use of the saturation transfer technique in magnetic resonance, which consists in the magnetization transfer in the presence of an irradiating field able to saturate the protons involved in the exchange process, which procedure is used in vitro and provides further information from the analyzed samples, e.g. biological tissues, polymeric compounds or samples of solid compounds of geologic interest. 30 [0011] Mag. Res. In Medicine, 44, 799-802, 2000, describes a procedure for the determination of the pH in solution using the magnetization signal transfer technique in MRI, in the presence of 5-hydroxy trypthophan or 5,6-dihydrouracil. [0012] J. Mag. Res., 133, 36-45, 1998 and J. Mag. Resonance Imag., 12, 745-748, 2000 describe in vivo and in vitro MRI imaging procedures involving the determination of the proton exchange between metabolites such as urea and water. [0013] Investigative Radiology, 23, S267-270, 1988, describes the effect of some compounds, such as arginine, 35 glycine, Iopamidol, ornithine, serine and serinol, in MRI, in inducing a contrast increase by decreasing T2 relaxation time, i.e. transversal relaxation time of water protons. The decrease of T2, which is experimentally observed, causes a decrease in the intensity of the resulting imaging signal, and this is mainly ascribed to the chemical exchange between the mobile proton of the molecule and bulk water. [0014] Mag. Res. Med. 35, 30-42, 1996 reports an interesting study on the effect of proton exchange between amino 40 acids and water surrounding the compound in MRI, as a function of pH, temperature and presence of some compounds acting as exchange catalysts in the medium. [0015] Furthermore, both J. of Mag. Res., 143, 79-87, 2000 and WO00/66180 disclose the use of some compounds in MRI with saturation transfer techniques of the proton signal. [0016] The compounds used for this purpose belong to different chemical classes, consisting of sugars (e.g. mannitol, 45 sorbitol, fructose, maltose, lactose and dextran), amino acids (e.g. L-Ala, L-Arg, L-Lys), nucleosides, purine and pyrimidine bases, barbituric acid, imidazole compounds and other heterocyclic compounds. [0017] A large number of compounds have been suggested as contrast agents for imaging of the vascular system and of the extra-vasal space, but the parenteral use thereof can involve unwanted side-effects which make their clinical use in vivo troublesome, although their enteral toxicity is not particularly high (see, for instance, Merck Index 12th ed.: 50 972. Barbital LD orally in mice: 600 mg/Kg; 973. Barbituric Acid LD50 orally in male rats: > 5000 mg/kg; 4475. Guanidine LD orally in rabbits: 500 mg/kg RTECS Vol. 5 and. 1985-86: 82776. Thymidine LD50 intraperitoneal mouse 2512 mg/kg; 60194. Pipecolinic Acid LD50 intravenous mouse 2200 mg/kg; 9721. L-Arginine LD50 intravenous mouse 2030 mg/kg; 41867. 2-Imidazolidinone LD50 intraperitoneal mouse 500 mg/kg; 41826. 2-Imidazolidinetione LD50 intraperitoneal mouse 200 mg/kg). 55 [0018] Nowadays, one of the most pressing requests by the medical class concerns the availability of innovative contrast media for specific organs or disorders, which usually are not effectively evidenced with the known techniques. [0019] X ray diagnostic contrast agents are an extremely versatile and interesting class of compounds widely used in clinics thanks to their effectiveness, low toxicity and safety of use in diagnosis concerning different districts of the human 2 EP 1 411 992 B1 body, such as in urography, angiography, ventriculography and myelography. [0020] The use of the same contrast medium for both X ray radiology and MRI diagnostics would remarkably widen the diagnostic potentialities of the compound used and provide diagnostic results so far unexpected. [0021] The availability of a single contrast agent providing diagnostic results through different techniques, which 5 previously required the use of different contrast agents, is an important innovative aspect of the diagnostic technique, particularly in clinics, where diagnostic procedures based on both the usual radiographic procedures, computerized axial tomography (CAT) and magnetic resonance imaging are nowadays employed. [0022] In case of iodinated contrast agents, the use of a single compound for a number of diagnostic procedures would be advantageous also since the total amount of the administered product is by far higher than that of other medicaments. 10 [0023] By way of example, the dose of opacifying agent being injected can reach and even exceed 150 g and the combination of two diagnostic techniques would be cost-saving. [0024] Therefore, the object of the present invention is the use of a iodinated contrast agent comprising at least one amido function for the preparation of a diagnostic formulation to obtain in vitro or in vivo images using magnetization transfer MRI techniques. 15 [0025] "Iodinated contrast agents comprising at least one amido function" herein means iodinated aromatic compounds having a triiodinated aromatic ring bearing at the remaining positions straight or branched, functionally substituted organic residues or an organic compound comprising at least two triiodinated aromatic residues mutually covalently linked at one of the positions, either directly or through a straight or branched, functionally substituted organic residue, said aromatic ring being further substituted at the remaining positions by straight or branched, functionally substituted organic 20 residues and in which the organic residues and the triiodinated aromatic ring are linked by amido functions.
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