EP0758907A1 - Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus - Google Patents

Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus

Info

Publication number
EP0758907A1
EP0758907A1 EP95920012A EP95920012A EP0758907A1 EP 0758907 A1 EP0758907 A1 EP 0758907A1 EP 95920012 A EP95920012 A EP 95920012A EP 95920012 A EP95920012 A EP 95920012A EP 0758907 A1 EP0758907 A1 EP 0758907A1
Authority
EP
European Patent Office
Prior art keywords
porphyrin
infarction
necrosis
complex
diagnosticum
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95920012A
Other languages
German (de)
English (en)
Inventor
Guy Jacques Felix Marchal
Yicheng Ni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to EP95920012A priority Critical patent/EP0758907A1/fr
Publication of EP0758907A1 publication Critical patent/EP0758907A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • porphyrin-complex or expanded porphyrin-complex compounds as localisation diagnosticum for Infarction or necrosis
  • the present invention relates to the use of porphyrin- complex and expanded porphyrin-complex compounds for use as a diagnosticum, in particular for use as a diagnosticum for the detection, localization, and monitoring of an infarction, and of a necrosis .
  • Suitable porphyrin-complex compounds are subject of DE-A-4,232, 925, DE-A-4, 305, 523, EP-A-336, 879, and EP-A-355, 041. The subject matter of these applications are included by cross reference. These porphyrin-complex compounds are used as a pharmaceutical preparation for the diagnosis and therapy of tumours .
  • porphyrin-complex compounds are expanded prophyrin-complex compounds (17) .
  • the present invention is based on the inside that these porphyrin-complex compounds can be used for the detection, localization, and monitoring of an infarction, and of a necrosis, such as ischemic, alcohol, and biliary obstruction, induced necrosis, and further laser induced hepatic, renal and muscular necrosis.
  • a necrosis such as ischemic, alcohol, and biliary obstruction, induced necrosis, and further laser induced hepatic, renal and muscular necrosis.
  • infarction localization diagnosticum is primarily exemplified for a myocardial infarction and for a renal infarction, but it will be obvious for a skilled person that due to similar pathophysiological situations the same experimental findings apply to other infarction such as those of the intestines, lung, brain and the like.
  • Myocardial infarction is not a stable pathophysiological situation, but instead progresses to its definite form over several weeks to months. This process can be subdivided, although overlapping, in at least three periods.
  • the first 24 hours after the start of ischemia (acute evolving myocardial infarction) damage progresses as a wavefront phenomenon from the subendocardium to include the myocardium transmurally.
  • this area stabilizes and fibrosis is formed as a healing process.
  • the third phase (healed infarction) starts after all the damaged tissue is replaced by a fibrotic scar. During this phase, considerable remodelling takes place. So far no accurate and reliable technique exists that can determine the evolution phase of the myocardial infarction antemortem.
  • nuclear scintigraphy with perfusion and infarct avid tracers (3-5) and magnetic resonance imaging (MRI) without and with different contrast media (6-9) are still far from optimal in terms of sensitivity, specificity, spatial resolution, contrast and reliability (1) .
  • Necrosis is a status of local tissue death, and results from the effects of diseases resulting in an adverse and detrimental effect on body tissue. Necrosis may be caused by radiation, injury, chemicals, local oxygen deficiency, infections, cancer, and the like. Monitoring, localization and detection of necrosis allowes the follow up and effectiveness determination of all kinds of diagnostic and therapeutic therapies and treatments.
  • the present invention relates to the use of these porphyrin-complex compounds or metalloporphyrins, for the localization, visualization of an infarction and of a necrosis.
  • This invention is based on experimental results with myocardial and renal infarctions, and with hepatic, renal and muscle necrosis demonstrating an extraordinary effect with one-to-one correlation between magnetic resonance images (MRI) and histochemical preparations. This preclinical result open new horizons for especially the cardiac and necrotic imaging.
  • MRI magnetic resonance images
  • porphyrin-complex compounds comprise a ligand having the general formula I
  • R 1 represents a hydrogen atom, a straight or branched C ⁇ -C,. alkyl group, a C_-C 12 aralkyl group or a OR' group wherein R' is a hydrogen atom or a C ⁇ C. alkyl group,
  • R 2 and R 3 represent a group CO-Z or a group (NH) o -(A) -NH-D, wherein Z is a group OL with L is an inorganic or organic cation or a C 1 -C 4 alkyl group, A is a phenylenoxy group, a C,-C 12 alkylene group possibly interrupted by one or more oxygen atoms, or a C 7 -C 12 aralkylene group, o and q independently represent an integer 0 or 1, and D represents an hydrogen atom or a group CO-A (COOL) o - (H) m with m equals 0 or 1 under the provisio that the sum of m and o equals 1;
  • R 5 when K is formula Ila has the same meaning as R 4 and when K has the formula lib has the same meaning as D, under the proviso that a direct oxygen-nitrogen bond is not allowed, wherein L 1 has the meaning of a C 1 -C 6 alkyl group or an inorganic or organic cation and wherein
  • L 2 , L 3 and L 4 independently have the same meaning as L 1 or are an hydrogen atom, under the proviso that the complex former comprises at least two free carbon acid groups, and optionally for charge mutualization of the metalloporphyrin other anions, and pharmaceutically acceptable addition salts and carriers and diluants.
  • the porphyrin-complex compounds comprises at least one paramagnetic metal ion, preferably di- or trivalent ions of the metal elements having the atomic number 21-29, 42, 44 and 57-70.
  • Suitable metal ions are for instance chromium (III) , manganese (II) , manganese (III) , iron (III), cobalt (II), cobalt (III), nickel (II), copper (II) , praseodymium (II) , neodymium (III) , samarium (III) and ytterbium (III) .
  • chromium (III) chromium
  • manganese (II) manganese (III)
  • iron (III) iron
  • cobalt (II) cobalt
  • cobalt (III) nickel
  • nickel (II) copper
  • praseodymium (II) neodymium (III)
  • radioisotopes of the elements having the atomic number 27, 29-32, 37-39, 42-51, 62, 64, 70, 75, 77, 82 or 83 are preferred. It is noted that when the complex compounds comprises various metal ions these metal ions may originate from the group for MR visualization and radioscintigraphic visualization.
  • the metal ion may be complexed in the porphyrin skeleton, in the so called expanded porhyrin skeleton, and/or in the complex former.
  • porphyrin-complex compounds are the disodium salt of the digadolinium complex of N,N' -Bis [9- carboxylato-2 , 5, 8-tris (carboxylatomethyl ) -2,5, 8-triazanonyi- carbamoyl] -mesoporphyrin-IX-13 , 17-diamides (Gd-MP) .
  • the diagnosticum has the form of a pharmaceutical formulation suitable for intra-veneou ⁇ or intra-arterial injection in the form of a solution or suspension.
  • the diagnosticum may comprise suitable additives, such as a buffer (tromethamine) , complex formers such as diethylenetriaminpenta-acetic acid, electrolyte such as sodium chloride, antioxydantia such as ascorbinic acid.
  • the diagnosticum may comprise the porphyrin or expanded porphyrin complex compound in an amount of 0.0001 - 10.0 mmol/kg body weight. Preferred is an amount of 0.005 - 2 mmol/kg body weight, more preferred 0.01 - 1.0 mmol/kg body weight.
  • the actual dose is also dependent on the infarction to be localized, on the patient and on the localization technique to be used.
  • Gadolinium mesoporphyrin (Gd-MP) and manganese tetraphenylporphyrin (Mn-TPP) have been used.
  • the model of myocardial infarction was produced in rats by ligation of the left coronary artery according to an established technique (15) .
  • Two groups of rats (12 in each) with myocardial infarction aging 2 to 24 hours received intravenously either Gd-MP (IDF GmbH, Berlin) or Mn-TPP (IDF GmbH, Berlin) at doses of 0.1, 0.05 and 0.01 mmol/kg (4 rats each) .
  • Gd-MP IDF GmbH, Berlin
  • Mn-TPP IDF GmbH, Berlin
  • the excised heart was incubated with triphenyl tetrazolium chloride (TTC) , which is a reliable histochemical staining to distinguish the infarcted from the non-infarcted myocardium (16) .
  • TTC triphenyl tetrazolium chloride
  • two groups of rats (6 in each) were used as controls and underwent the same imaging and histochemical procedures, i.e. one group with infarction but without contrast agent injection, the other group with injection (3 with Gd-MP, 3 with Mn-TPP) but without infarction.
  • SI signal intensities
  • the MRI was performed 10 hours after Mn-TPP (0.05 mmol/kg body weight) intervenou ⁇ injection.
  • the technique is so sensitive that even lesions between 1 to ? mm in size were easily detectable (Fig.2) .
  • a rat with partial renal infarction of the right kidney was injected with Gd-MP (0.1 mmol/kg body weight by intervenous injection) . 24 Hours after Gd-MP injection, the Gd-content
  • the contrast agents used were Mn-TPPS4 (Mn-meso-tetra- (4-sulfonato-phenyl) -porphyrine (available from Porphyrin Products Inc., Logan, Utah, USA), in an amount of 0.05 mmol/kg, and Gd-Mn-porphyrin (Mn(III) - ⁇ N-Bis- [11- carboxylato-2-oxo-4,7,10-tris- (carboxylatomethyl) -1,4,7,10- tetraazaundecyl] -methylpyrroporphyrin-XXI-amide ⁇ -acetate, Gd- complex, sodium salt can be prepared according to example 1/14 in WO84/07894) .
  • Methylpyrroporphyrinethylester (Aldrich Chemicals) is reacted with hydrazine in pyridine and subsequently with manganese acetate in acetic acid.
  • the obtained intermediate is reacted with DTPA-monoanhydride-monoethylester in absolute N,N-dimethylformamide and addition of triethylamine.
  • hydrolysis and neutralisation complexation is carried out with the use of gadolinium acetate in an amount of 0.05 mmol/kg.
  • the experimental results are summarized in tables 3 and 4.
  • Gd content and signal intensity in a rat with partial renal infarction measured 24 hours after Gd-MP (0.1 mmol/kg) .
  • Fig. 1 (A-C). MRI and macroscopic photographs of a rodent heart with myocardial infarction. The MRI was performed 24 hours after Gd-MP
  • NEX 6
  • the graduation near the frame on the right side represents 1 cm.
  • TTC triphenyl tetrazolium chloride
  • Fig. 2 (A-C). MRI and macroscopic photographs of a rodent heart with local injury caused by ligation. Such minute necrotic lesions were found at the ligation sites in two rats who failed to form real infarction and were excluded as successful models from the study. The MRI was performed 10 hours after Mn-TPP (0.05 mmol/kg) intravenous injection and immediately after sacrificing the animal.
  • Mn-TPP 0.05 mmol/kg
  • A, B On both the coronal (A) and axial (B) MR images (the same parameters as in fig. 1), an hyperintense lesion(arrow) of approximately 1 mm in size can be clearly seen in the left ventricular wall, despite a partial volume effect (i.e. the diameter of the lesion is smaller than the thickness of the MR slice; otherwise the lesion would appear brighter).
  • the graduation near the frame on the right side represents 1 cm.
  • C TTC stained axial section of the heart on a similar plane to the MR image (B) displays the ligature and adjacent minute unstained necrotic lesion (arrow).
  • FIG. 3 (A - D). MRI and macroscopic photographs of a rat with partial renal infarction in the right kidney.
  • FIG. 4 A-D Axial Tl W SE MR images and macroscopic photographs of rat liver with alcohol induced coagulation necrosis.
  • Gd-MP gadolinium mesoporphyrin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Utilisation de composés à base d'un complexe de porphyrine ou d'un complexe de porphyrine étendue dans la fabrication d'une préparation diagnostique pour la localisation d'un infarctus et d'une nécrose, l'infarctus ou la nécrose pouvant être un infarctus cardiaque, rénal, intestinal, pulmonaire et/ou cérébral, et le composé à base d'un complexe de porphyrine pouvant être le Gd-MP et/ou le Mn-TPP. Gd-MP: sel sodique bis, Bis-Gd-DTPA-{Mésoporphyrin-IX-13,17-bis[2-oxo-4,7,10,10-tétra-(carboxylatométhyl)-1,4,7,10-tétraazadécyl]-13, 17-diamide} de formule (A); Mn-TPP: sel sodique tétra, Manganèse-(III)-{Tétrakis-[3]-(carboxylatométhoxy-phényl)-porphyrin}-acétate de formule (B).
EP95920012A 1994-05-11 1995-05-10 Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus Withdrawn EP0758907A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP95920012A EP0758907A1 (fr) 1994-05-11 1995-05-10 Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP94201333 1994-05-11
EP94201333 1994-05-11
EP95920012A EP0758907A1 (fr) 1994-05-11 1995-05-10 Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus
PCT/EP1995/001762 WO1995031219A1 (fr) 1994-05-11 1995-05-10 Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus

Publications (1)

Publication Number Publication Date
EP0758907A1 true EP0758907A1 (fr) 1997-02-26

Family

ID=8216871

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95920012A Withdrawn EP0758907A1 (fr) 1994-05-11 1995-05-10 Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus

Country Status (5)

Country Link
EP (1) EP0758907A1 (fr)
JP (1) JPH10500122A (fr)
CA (1) CA2189967A1 (fr)
NO (1) NO964780D0 (fr)
WO (1) WO1995031219A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19835082A1 (de) * 1998-07-24 2000-02-03 Schering Ag Paramagnetische 3-,8-substituierte Deuteroporphyrinderivate, diese enthaltende pharmazeutische Mittel, Verfahren zu ihrer Herstellung und ihre Verwendung für das Nekrose- und Infarkt-MR-Imaging

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6495118B1 (en) 1997-09-26 2002-12-17 Schering Aktiengesellschaft Lipophilic metal complexes for necrosis and infarction imaging
DE19744004C1 (de) * 1997-09-26 1999-07-22 Schering Ag Lipophile Metall-Komplexe für Nekrose und Infarkt-Imaging
DE19824653A1 (de) * 1998-02-25 1999-08-26 Schering Ag Nekrose-affine Verbindungen und ihre Verwendung zur Herstellung von Präparaten zur Pharmakotherapie
US6056939A (en) * 1998-08-28 2000-05-02 Desreux; Jean F. Self-assembling heteropolymetallic chelates as imaging agents and radiopharmaceuticals
US7097826B2 (en) * 1999-12-23 2006-08-29 Health Research, Inc. Chlorin and bacteriochlorin-based difunctional aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals
DE10240343A1 (de) * 2002-08-27 2004-03-11 Schering Ag Peroxynitrit-Umlagerungskatalysatoren
FR2867473B1 (fr) 2004-03-12 2006-06-23 Guerbet Sa Compose de porphyrines et utilisation a haut champ en irm
US20100120738A1 (en) * 2006-09-11 2010-05-13 Bernard Malfroy-Camine Anti-apoptotic benzodiazepine receptor ligand inhibitors
CN101235036A (zh) * 2007-02-02 2008-08-06 济南赛文医药技术有限公司 一类卟啉衍生物及其作为小分子抗氧化剂的应用
GB0723124D0 (en) 2007-11-26 2008-01-02 Univ Leuven Kath Targeted radiotherapy

Family Cites Families (4)

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DE3809671A1 (de) * 1988-03-18 1989-09-28 Schering Ag Porphyrin-komplexverbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
CA2093361C (fr) * 1990-10-05 2002-04-23 Michel Ringuet Derive porphyrine
DE4232925A1 (de) * 1992-09-28 1994-03-31 Diagnostikforschung Inst 3-,8-substituierte Deuteroporphyrinderivate, diese enthaltende pharmazeutische Mittel und Verfahren zu ihrer Herstellung
DE4305523A1 (de) * 1993-02-17 1994-08-18 Diagnostikforschung Inst Meso-Tetraphenylporphyrin-Komplexverbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9531219A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19835082A1 (de) * 1998-07-24 2000-02-03 Schering Ag Paramagnetische 3-,8-substituierte Deuteroporphyrinderivate, diese enthaltende pharmazeutische Mittel, Verfahren zu ihrer Herstellung und ihre Verwendung für das Nekrose- und Infarkt-MR-Imaging

Also Published As

Publication number Publication date
CA2189967A1 (fr) 1995-11-23
NO964780L (no) 1996-11-11
WO1995031219A1 (fr) 1995-11-23
JPH10500122A (ja) 1998-01-06
NO964780D0 (no) 1996-11-11

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