WO2003093284A1 - Polymetallic molecular complexes used as contrast agents in magnetic image resonance - Google Patents
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- WO2003093284A1 WO2003093284A1 PCT/ES2003/000190 ES0300190W WO03093284A1 WO 2003093284 A1 WO2003093284 A1 WO 2003093284A1 ES 0300190 W ES0300190 W ES 0300190W WO 03093284 A1 WO03093284 A1 WO 03093284A1
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- 239000002872 contrast media Substances 0.000 title claims abstract description 38
- 230000005291 magnetic effect Effects 0.000 title claims abstract description 27
- 229910052751 metal Inorganic materials 0.000 claims description 19
- ITWBWJFEJCHKSN-UHFFFAOYSA-N 1,4,7-triazonane Chemical compound C1CNCCNCCN1 ITWBWJFEJCHKSN-UHFFFAOYSA-N 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 14
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 13
- 150000002739 metals Chemical class 0.000 claims description 5
- 230000005290 antiferromagnetic effect Effects 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 230000008863 intramolecular interaction Effects 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 239000013110 organic ligand Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 230000005298 paramagnetic effect Effects 0.000 abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 239000002245 particle Substances 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 9
- 230000007423 decrease Effects 0.000 description 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000005294 ferromagnetic effect Effects 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000005415 magnetization Effects 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 150000004696 coordination complex Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- -1 1,4,7-triazacyclononan amine Chemical class 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 150000000921 Gadolinium Chemical class 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003302 ferromagnetic material Substances 0.000 description 1
- IZOOGPBRAOKZFK-UHFFFAOYSA-K gadopentetate Chemical compound [Gd+3].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O IZOOGPBRAOKZFK-UHFFFAOYSA-K 0.000 description 1
- LGMLJQFQKXPRGA-VPVMAENOSA-K gadopentetate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O LGMLJQFQKXPRGA-VPVMAENOSA-K 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000696 magnetic material Substances 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- 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
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
- C07F15/025—Iron compounds without a metal-carbon linkage
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
Definitions
- the present invention consists of a new type of contrast agent for use in Magnetic Resonance Imaging (RMI). Said contrast agent can result in substantial improvements for imaging the interior of the human body by increasing tissue contrast.
- the area of the technique would be, therefore, the broad sector of nuclear medicine: diagnosis of cancers and tumors, study of the Nervous System and Musculoskeletal System.
- NMR is a physical phenomenon whereby atomic nuclei with an odd number of protons and / or neutrons can selectively absorb electromagnetic energy in the radio frequency range when placed under a magnetic field.
- the proton is the nucleus to study due to its biological abundance, (63% hydrogen atoms), and its high gyro-magnetic constant (42.58 MHz / T).
- the relaxation signal of magnetization we can obtain three different types of information: one related to the density D of the hydrogen nuclei existing in the voxel and the other two related to the histochemical medium, relaxation times TI and T2.
- the TI and T2 parameters are obtained in the analysis of the nuclear relaxation on the longitudinal axis and on the transverse plane, respectively.
- the contrast (black, gray and white) of the images obtained by RMI will depend on these three parameters.
- Contrast agents are currently used in MRI to obtain better contrast images.
- the function of the contrast agent is to decrease the relaxation times of the hydrogen nuclei close to the contrast agent.
- These contrast agents are not directly visualized in the image obtained, unlike other ionizing contrast agents used for X-rays. Contrast agents are classified into three types according to their behavior under an applied magnetic field:
- Paramagnetic compounds are the most studied and used contrast agents due to the optimal results obtained when using Gd as a metallic center. This type of compound is characterized by presenting unpaired electrons, establishing dipole-dipole interactions between the unpaired electrons of the metal and the hydrogen nuclei of the water molecules. Those water molecules that are directly coordinated to the metal, decrease their longitudinal relaxation time (TI) very effectively. This effectiveness decreases as the distance between the water molecules and the metal complex increases.
- the metal centers of this type of contrast agent are metals of the first series of transition, lanthanides and free radicals.
- the most common ferromagnetic contrast agents are iron (III) oxide particles. Unlike paramagnetic compounds that mainly affect TI relaxation times, iron oxide particles mainly affect the transverse relaxation time, T2, as they cause significant heterogeneity in the external magnetic field, decreasing the signal intensity unlike of the IT agents that increase it.
- patents are: patent US4675173 "Method of magnetic resonance imaging of the liver and spleen” Widder Kenneth J. (June 23, 1987); US4863715 patent "Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material” Jacobsen Trond (September 5, 1989).
- One of the problems of these particles is their tendency to aggregate in the presence of an external magnetic field, so it is necessary to combine them with a surfactant: dextran or some polymer, without altering relaxation times.
- Superparamagnetic contrast agents represent a new type of agent. They generally affect relaxation times T2 and T2 *. The fact that these compounds have large magnetic moments, makes the proton nuclei relax faster than in the presence of paramagnetic agents [Coroiu L, Journal of Magnetism and Magnetic Materials, 201, 449-452 (1999)]. Unlike ferromagnetic particles, once the magnetic field is no longer applied, magnetization drops to zero. Due to its particle size, on the order of the nanometer, it has an intermediate magnetic behavior between paramagnetic and ferromagnetic compounds. Examples of patents of this type of superparamagnetic contrast agents are: patent US6207134 "Ultrafine lightly coated superparamagnetic particles for MRI" Naelig Vestad A. (March 27, 2001) and patent US5314679 "Vascular magnetic resonance imaging agent comprising nanoparticles” Lee J. (24 May 1994).
- Nanostructured magnetic systems are being of considerable interest, both from the point of view of basic and applied research.
- Polymetallic molecular complexes are an example of nanostructured systems. These complexes are being widely studied due to their magnetic properties and as they serve as a bridge to understand the passage of the properties of a simple paramagnet and the properties of a solid.
- chemistry provides us with new synthetic strategies to design polymetallic molecular complexes in a controlled way; Physics helps us understand magnetic properties at the nanometer scale; and biochemistry can make use of these as models of biomineralization of magnetic particles.
- the object of our invention has been to synthesize a new type of superparamagnetic behavioral contrast agent at room temperature to be used as a contrast agent in RMI.
- This patent describes the use of a polymetallic molecular complex as a contrast agent that exhibits superparamagnetic behavior at room temperature and decreases the longitudinal relaxation time (TI).
- the compounds described later in this patent are formed by organometallic molecules with a magnetic core inside surrounded by a non-magnetic layer.
- the magnetic nucleus is made up of several metal atoms joined together by bridges of electronegative elements. To complete the coordination sphere of the different metals, they can also have coordinated water molecules.
- this type of compound behaves similarly to a paramagnet, that is, the resulting magnetization fluctuates with time with a characteristic frequency that depends on temperature.
- the resulting magnetic moment is greater than for paramagnetic compounds, so that superparamagnetic compounds will more effectively decrease the relaxation times of the hydrogen nuclei of water molecules.
- Fe in such small concentrations, is not toxic to the body like Gd.
- the Gd must be strongly coordinated by ligands, protecting the organism from its free circulation.
- the size of the molecule is greater than that of the gadolinium complexes, this implies that the intertisular diffusion will be slower and less than that of the iron oxide particles, which could access areas less permeable. This intermediate size can enhance its effect on some specific tissues, such as blood vessels.
- FIGURES Figure la Crystalline structure of the metal center coordinated with the 1,4,7-triazacyclononan amine.
- Polymorph (II) has been characterized by elemental analysis, powder X-ray diffraction and single crystal (unpublished results). The molecule that constitutes the 'building block' of both compounds is represented in figure la. Figure Ib presents the packaging of said molecules in polymorph II, as well as the parameters of the unit cell.
- the stability constant of the metal complex defined by equation (1) has a value of 10 14 62
- Figures 2 and 3 represent the relaxation times, TI and T2 respectively vs. concentration.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- High Energy & Nuclear Physics (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Radiology & Medical Imaging (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Immunology (AREA)
- General Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
Abstract
According to the invention, a novel type of contrast agent having a superparamagnetic behaviour at ambient temperature is synthesised for use as a contrast agent in magnetic image resonance. The invention relates to the use of a polymetallic molecular complex as a contrast agent which has a superparamagnetic behaviour at ambient temperature and which reduces the longitudinal relaxation time (T1). At ambient temperature, said type of compounds behaves in a similar manner to a paramagnet, i.e. the resulting magnetisation fluctuates with time at a characteristic frequency that depends on temperature. In the case of superparamagnetic compounds, the resulting magnetic moment is greater than for paramagnetic compounds and, as a result, superparamagnetic compounds reduce the relaxation time of the hydrogen nuclei of water molecules more effectively.
Description
TÍTULOTITLE
Complejos moleculares polimetálicos como agentes de contraste para su uso en Resonancia Magnética de ImagenPolymetallic molecular complexes as contrast agents for use in Magnetic Resonance Imaging
SECTOR DE LA TÉCNICATECHNICAL SECTOR
La presente invención consiste en un nuevo tipo de agente de contraste para su uso en Resonancia Magnética de Imagen (RMI). Dicho agente de contraste puede resultar en mejoras sustanciales para la obtención de imágenes del interior del cuerpo humano aumentando el contraste tisular. El área de la técnica sería, por lo tanto, el amplio sector de la medicina nuclear: diagnosis de cánceres y tumores, estudio del Sistema Nervioso y Sistema Músculo- Esquelético.The present invention consists of a new type of contrast agent for use in Magnetic Resonance Imaging (RMI). Said contrast agent can result in substantial improvements for imaging the interior of the human body by increasing tissue contrast. The area of the technique would be, therefore, the broad sector of nuclear medicine: diagnosis of cancers and tumors, study of the Nervous System and Musculoskeletal System.
ESTADO DE LA TÉCNICA La técnica de RMI ha experimentado un ascenso vertiginoso en los últimos años y en la actualidad se ha convertido en herramienta imprescindible para detectar muchas patologías. Su éxito se debe principalmente a la posibilidad de obtener imágenes tomográíϊcas en cualquier dirección del espacio, fácilmente interpretables y a no utilizar radiaciones ionizantes. La RMI se basa en los principios físicos de la Resonancia Magnética Nuclear (RMN). La RMN nace en 1946 gracias a Félix Bloch y Edward Purcell. En el año 1977 Raymond Damadian consiguió imágenes de todo el cuerpo [Damadian, R.: Physiol. Chem. Phys. 9, 97 (1977)]. La RMN es un fenómeno físico por el cual núcleos atómicos con un número impar de protones y/o neutrones pueden absorber selectivamente energía electromagnética en el rango de radiofrecuencia al ser colocados bajo un campo magnético. En la rutina clínica, el protón es el núcleo a estudiar debido a su abundancia biológica, (63% átomos de hidrógeno), y a su constante giromagnética elevada (42.58 MHz/T). Estudiando la señal de relajación de la magnetización podemos obtener tres tipos de información diferente: una relacionada con la densidad D de los núcleos de hidrógeno existentes en el vóxel y las otras dos relacionadas con el medio histoquímico, tiempos de relajación TI y T2. Los parámetros TI y T2, se obtienen en el análisis de la
relajación nuclear sobre el eje longitudinal y sobre el plano transversal, respectivamente. El contraste (negros, grises y blancos) de las imágenes obtenidas por RMI dependerá de estos tres parámetros.STATE OF THE ART The RMI technique has experienced a dizzying rise in recent years and today it has become an essential tool to detect many pathologies. Its success is mainly due to the possibility of obtaining tomographic images in any direction of space, easily interpretable and not using ionizing radiation. MRI is based on the physical principles of Nuclear Magnetic Resonance (NMR). NMR was born in 1946 thanks to Félix Bloch and Edward Purcell. In 1977 Raymond Damadian obtained images of the entire body [Damadian, R .: Physiol. Chem. Phys. 9, 97 (1977)]. NMR is a physical phenomenon whereby atomic nuclei with an odd number of protons and / or neutrons can selectively absorb electromagnetic energy in the radio frequency range when placed under a magnetic field. In the clinical routine, the proton is the nucleus to study due to its biological abundance, (63% hydrogen atoms), and its high gyro-magnetic constant (42.58 MHz / T). By studying the relaxation signal of magnetization we can obtain three different types of information: one related to the density D of the hydrogen nuclei existing in the voxel and the other two related to the histochemical medium, relaxation times TI and T2. The TI and T2 parameters are obtained in the analysis of the nuclear relaxation on the longitudinal axis and on the transverse plane, respectively. The contrast (black, gray and white) of the images obtained by RMI will depend on these three parameters.
Actualmente se utilizan agentes de contraste de diagnosis en RMI para obtener imágenes mejor contrastadas. La función del agente de contraste es la de disminuir los tiempos de relajación de los núcleos de hidrógeno próximos al agente de contraste. Estos agentes de contraste no se visualizan directamente en la imagen obtenida, a diferencia de otros agentes de contraste ionizantes utilizados para rayos X. Los agentes de contraste se clasifican en tres tipos según sea su comportamiento bajo un campo magnético aplicado:Diagnostic contrast agents are currently used in MRI to obtain better contrast images. The function of the contrast agent is to decrease the relaxation times of the hydrogen nuclei close to the contrast agent. These contrast agents are not directly visualized in the image obtained, unlike other ionizing contrast agents used for X-rays. Contrast agents are classified into three types according to their behavior under an applied magnetic field:
• agentes de contraste paramagnéticos• paramagnetic contrast agents
• agentes de contraste superparamagnéticos• superparamagnetic contrast agents
• agentes de contraste ferromagnéticos• ferromagnetic contrast agents
Bloch descubrió que el uso de una sal paramagnética de nitrato de hierro modificaba los tiempos de relajación de los protones del agua [Bloch, F.:Phys. Rev. 70, 474 (1948)]. Los compuestos paramagnéticos son los agentes de contraste más estudiados y utilizados debido a los óptimos resultados obtenidos al utilizar Gd como centro metálico. Este tipo de compuesto se caracteriza por presentar electrones desapareados, estableciendo interacciones dipolo-dipolo entre los electrones desapareados del metal y los núcleos de hidrógeno de las moléculas de agua. Aquellas moléculas de agua que se encuentran directamente coordinadas al metal, disminuyen su tiempo de relajación longitudinal (TI) de forma muy efectiva. Esta efectividad disminuye a medida que aumenta la distancia entre las moléculas de agua y el complejo metálico. Los centros metálicos de este tipo de agentes de contraste son metales de la primera serie de transición, lantánidos y radicales libres. El estudio teórico de la relajación en presencia de partículas paramagnéticas fue desarrollado por Bloembergen, Solomon y otros [Bloembergen, N.: Phys. Rev. 73, 678 (1948)]. Desde que en 1988 se sintetizó [Gd(DTPA)(H2O)]2~, se han administrado cerca de 30 toneladas de Gd a millones de pacientes. Diversas patentes de agentes de contraste de Gd han sido registradas para su empleo en RMI. Un ejemplo es la Patente Europea 3,302,410 de A. G. Shering, que protege al complejo gadopentato de dimeglumina
(gadolinio-DTPA). Otros ejemplos de agentes de contraste con Gd como centro metálico son EP 1034796 "MRI contrast media recognizing minor environmental changes", Masahito M. (13 septiembre 2000), patente WO0016811 "MRI contrast agent", Masahito M. (30 marzo 2000), patente US57077605 "Magnetic Resonance Imaging agents for the detection of physiological agents", Meade T., Fraser S., Russell J. (13 enero 1998), patente US4933441 "Constrast enhancing agents for magnetic resonance images", Gibby A. (12 junio 1990).Bloch found that the use of a paramagnetic iron nitrate salt altered the relaxation times of protons in water [Bloch, F.:Phys. Rev. 70, 474 (1948)]. Paramagnetic compounds are the most studied and used contrast agents due to the optimal results obtained when using Gd as a metallic center. This type of compound is characterized by presenting unpaired electrons, establishing dipole-dipole interactions between the unpaired electrons of the metal and the hydrogen nuclei of the water molecules. Those water molecules that are directly coordinated to the metal, decrease their longitudinal relaxation time (TI) very effectively. This effectiveness decreases as the distance between the water molecules and the metal complex increases. The metal centers of this type of contrast agent are metals of the first series of transition, lanthanides and free radicals. The theoretical study of relaxation in the presence of paramagnetic particles was developed by Bloembergen, Solomon, and others [Bloembergen, N .: Phys. Rev. 73, 678 (1948)]. Since [Gd (DTPA) (H 2 O)] 2 ~ was synthesized in 1988, nearly 30 tons of Gd have been administered to millions of patients. Various Gd contrast agent patents have been filed for use at RMI. An example is AG Shering's European Patent 3,302,410, which protects the dimeglumine gadopentate complex. (gadolinium-DTPA). Other examples of contrast agents with Gd as metal center are EP 1034796 "MRI contrast media recognizing minor environmental changes", Masahito M. (September 13, 2000), patent WO0016811 "MRI contrast agent", Masahito M. (March 30, 2000), US57077605 patent "Magnetic Resonance Imaging agents for the detection of physiological agents", Meade T., Fraser S., Russell J. (January 13, 1998), US4933441 patent "Constrast enhancing agents for magnetic resonance images", Gibby A. (June 12 1990).
Uno de los problemas de estos agentes de contraste es la toxicidad del centro metálico, por lo que la constante de estabilidad del complejo metálico ha de ser alta. El hecho de que el centro metálico deba estar protegido tiene el inconveniente de que su efectividad dependa de la accesibilidad de las moléculas de agua al metal por lo que ha de disponer como mínimo de una posición libre para que en dicha posición se puedan coordinar moléculas de agua tisular y se puedan relajar más rápidamente, disminuyendo el TI. La patente WO9410182 "High relaxivity, paramagnetic, metal complexes for magnetic resonance imaging", Beaty J. A. (11 mayo 1994), describe el uso de clústeres metálicos con comportamiento paramagnético, donde los metales que integran el clúster son Mn.One of the problems of these contrast agents is the toxicity of the metal center, so the stability constant of the metal complex must be high. The fact that the metal center must be protected has the drawback that its effectiveness depends on the accessibility of the water molecules to the metal, so it must have at least one free position so that in this position molecules of tissue water and can relax more quickly, lowering the TI. WO9410182 "High relaxivity, paramagnetic, metal complexes for magnetic resonance imaging", Beaty J. A. (May 11, 1994), describes the use of metal clusters with paramagnetic behavior, where the metals that make up the cluster are Mn.
Los agentes de contraste ferromagnéticos más comunes son partículas de óxido de hierro (III). A diferencia de los compuestos paramagnéticos que afectan principalmente a los tiempos de relajación TI, las partículas de óxido de hierro afectan principalmente el tiempo de relajación transversal, T2 ya que provocan una importante heterogeneidad del campo magnético externo, disminuyendo la intensidad de la señal a diferencia de los agentes TI que la aumentan. Ejemplos de patentes son: patente US4675173 "Method of magnetic resonance imaging of the liver and spleen" Widder Kenneth J. (23 junio 1987); patente US4863715 "Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material" Jacobsen Trond (5 setiembre 1989). Uno de los problemas de estas partículas es su tendencia a agregarse en presencia de un campo magnético externo, por lo que es necesario combinarlas con un tensoactivo: dextrano o algún polímero, sin que eso altere los tiempos de relajación.The most common ferromagnetic contrast agents are iron (III) oxide particles. Unlike paramagnetic compounds that mainly affect TI relaxation times, iron oxide particles mainly affect the transverse relaxation time, T2, as they cause significant heterogeneity in the external magnetic field, decreasing the signal intensity unlike of the IT agents that increase it. Examples of patents are: patent US4675173 "Method of magnetic resonance imaging of the liver and spleen" Widder Kenneth J. (June 23, 1987); US4863715 patent "Method of NMK imaging using a contrast agent comprising particles of a ferromagnetic material" Jacobsen Trond (September 5, 1989). One of the problems of these particles is their tendency to aggregate in the presence of an external magnetic field, so it is necessary to combine them with a surfactant: dextran or some polymer, without altering relaxation times.
Los agentes de contraste superparamagnéticos representan un nuevo tipo de agentes. Generalmente afectan a los tiempos de relajación T2 y al T2*. El hecho de que estos
compuestos presenten momentos magnéticos grandes, hace que los núcleos de protón se relajen más rápido que en presencia de agentes paramagnéticos [Coroiu L, Journal of Magnetism and Magnetic Materials, 201, 449-452 (1999)]. A diferencia de las partículas ferromagnéticas, una vez que se deja de aplicar el campo magnético, la magnetización disminuye a cero. Debido a su tamaño de partícula, del orden del nanómetro, tiene un comportamiento magnético intermedio entre los compuestos paramagnéticos y los ferromagnéticos. Ejemplos de patentes de este tipo de agentes de contraste superparamagnéticos son: patente US6207134 "Ultrafine lightly coated superparamagnetic particles for MRI" Naelig Vestad A. (27 marzo 2001) y patente US5314679 "Vascular magnetic resonance imaging agent comprising nanoparticles" Lee J. (24 mayo 1994).Superparamagnetic contrast agents represent a new type of agent. They generally affect relaxation times T2 and T2 *. The fact that these compounds have large magnetic moments, makes the proton nuclei relax faster than in the presence of paramagnetic agents [Coroiu L, Journal of Magnetism and Magnetic Materials, 201, 449-452 (1999)]. Unlike ferromagnetic particles, once the magnetic field is no longer applied, magnetization drops to zero. Due to its particle size, on the order of the nanometer, it has an intermediate magnetic behavior between paramagnetic and ferromagnetic compounds. Examples of patents of this type of superparamagnetic contrast agents are: patent US6207134 "Ultrafine lightly coated superparamagnetic particles for MRI" Naelig Vestad A. (March 27, 2001) and patent US5314679 "Vascular magnetic resonance imaging agent comprising nanoparticles" Lee J. (24 May 1994).
Cabe destacar que en la patente WO9003190 "Methods and compositions for magnetic resonance imaging" Ranney D. (5 abril 1990) se describe el uso de complejos poliatómicos superparamagnéticos que reducen el tiempo de relajación TI respecto al TI en ausencia de agente de contraste. Se trata de clústeres de Cr donde el acoplamiento intramolecular entre los Cr que integran el clúster es ferromagnético. Este tipo de complejos tiene la ventaja en que disminuye el TI de forma más efectiva que el Gd- DTPA y no es tan tóxico como el Gd.It should be noted that patent WO9003190 "Methods and compositions for magnetic resonance imaging" Ranney D. (April 5, 1990) describes the use of superparamagnetic polyatomic complexes that reduce the relaxation time TI with respect to TI in the absence of contrast agent. These are Cr clusters where the intramolecular coupling between the Cr that make up the cluster is ferromagnetic. This type of complex has the advantage that it decreases TI more effectively than Gd-DTPA and is not as toxic as Gd.
DESCRIPCIÓN DE LA INVENCIÓNDESCRIPTION OF THE INVENTION
Los sistemas magnéticos nanoestructurados están siendo objeto de un notable interés, tanto desde el punto de vista de la investigación básica como de la aplicada. Los complejos moleculares de polimetálicos son un ejemplo de sistemas nanoestructurados. Estos complejos están siendo ampliamente estudiados debido a sus propiedades magnéticas ya que sirven de puente de unión para entender el paso de las propiedades de un simple paramagneto y a las propiedades de un sólido.Nanostructured magnetic systems are being of considerable interest, both from the point of view of basic and applied research. Polymetallic molecular complexes are an example of nanostructured systems. These complexes are being widely studied due to their magnetic properties and as they serve as a bridge to understand the passage of the properties of a simple paramagnet and the properties of a solid.
El interés por este tipo de complejos es interdisciplinar: la química nos proporciona nuevas estrategias sintéticas para diseñar complejos moleculares polimetálicos de forma controlada; la física nos ayuda a entender las propiedades magnéticas a escala nanométrica; y la bioquímica puede hacer uso de éstos como modelos de biomineralización de partículas magnéticas.
El objeto de nuestra invención ha sido el de sintetizar un nuevo tipo de agente de contraste de comportarmiento superparamagnético a temperatura ambiente para ser usado como agente de contraste en RMI.The interest in this type of complex is interdisciplinary: chemistry provides us with new synthetic strategies to design polymetallic molecular complexes in a controlled way; Physics helps us understand magnetic properties at the nanometer scale; and biochemistry can make use of these as models of biomineralization of magnetic particles. The object of our invention has been to synthesize a new type of superparamagnetic behavioral contrast agent at room temperature to be used as a contrast agent in RMI.
En esta patente se describe el uso de un complejo molecular polimetálico como agente de contraste que presenta comportamiento superparamagnético a temperatura ambiente y disminuye el tiempo de relajación longitudinal (TI).This patent describes the use of a polymetallic molecular complex as a contrast agent that exhibits superparamagnetic behavior at room temperature and decreases the longitudinal relaxation time (TI).
Los compuestos descritos más adelante en esta patente están formados por moléculas órgano-metálicas con un núcleo magnético en su interior rodeado por una capa no magnética. El núcleo magnético, está formado por varios átomos metálicos unidos entre ellos por puentes de elementos electronegativos. Para completar la esfera de coordinación de los diferentes metales también pueden tener coordinadas moléculas de agua.The compounds described later in this patent are formed by organometallic molecules with a magnetic core inside surrounded by a non-magnetic layer. The magnetic nucleus is made up of several metal atoms joined together by bridges of electronegative elements. To complete the coordination sphere of the different metals, they can also have coordinated water molecules.
Un grupo muy reducido de este tipo de compuestos presenta un comportamiento superparamagnético debido a la presencia de una barrera de anisotropía magnética. Además estos complejos moleculares polimetálicos presentan estados fundamentales de espín muy elevados, como resultado del acoplamiento antiferromagnético entre los iones metálicos.A very small group of this type of compound exhibits superparamagnetic behavior due to the presence of a magnetic anisotropy barrier. Furthermore, these polymetallic molecular complexes have very high spin fundamental states, as a result of antiferromagnetic coupling between metal ions.
A temperatura ambiente, este tipo de compuestos se comporta de forma similar a un paramagneto, es decir la magnetización resultante fluctúa con el tiempo con una frecuencia característica que depende de la temperatura. En el caso de los compuestos superparamagnéticos el momento magnético resultante es más grande que para los compuestos paramagnéticos por lo que los compuestos superparamagnéticos disminuirán de forma más efectiva los tiempos de relajación de los núcleos de hidrógeno de las moléculas de aguas. Las ventajas de la utilización de estos complejos como agentes de contraste con respecto al Gd-DTPA que cabría esperar son:At room temperature, this type of compound behaves similarly to a paramagnet, that is, the resulting magnetization fluctuates with time with a characteristic frequency that depends on temperature. In the case of superparamagnetic compounds, the resulting magnetic moment is greater than for paramagnetic compounds, so that superparamagnetic compounds will more effectively decrease the relaxation times of the hydrogen nuclei of water molecules. The advantages of using these complexes as contrast agents with respect to the Gd-DTPA that would be expected are:
1. El Fe, en tan pequeñas concentraciones, no es tóxico para el organismo como lo es el Gd. El Gd ha de estar fuertemente coordinado por ligandos protegiendo al organismo de su libre circulación.1. Fe, in such small concentrations, is not toxic to the body like Gd. The Gd must be strongly coordinated by ligands, protecting the organism from its free circulation.
2. Se trata de un compuesto molecular por lo que hay homogeneidad en el tamaño de las partículas y por ser superparamagnético no tendrá problemas de agregación entre las partículas, como pasa en el caso de utilizar partículas de óxido de hierro.
3. Presenta un momento magnético resultante más alto que los compuestos de Gd por lo que cabe esperar que disminuya con mayor eficacia el TI .2. It is a molecular compound so there is homogeneity in the size of the particles and being superparamagnetic it will not have problems of aggregation between the particles, as happens in the case of using iron oxide particles. 3. It has a higher resulting magnetic moment than Gd compounds, so it can be expected to decrease the TI more effectively.
4. Otro aspecto importante es que el tamaño de la molécula es mayor que la de los complejos de gadolinio, esto implica que la difusión intertisular será más lenta y menor que la de las partículas de óxidos de hierro con lo que se podría acceder a zonas menos permeables. Este tamaño intermedio puede potenciar su efecto en algunos tejidos específicos, como por ejemplo los vasos sanguíneos.4. Another important aspect is that the size of the molecule is greater than that of the gadolinium complexes, this implies that the intertisular diffusion will be slower and less than that of the iron oxide particles, which could access areas less permeable. This intermediate size can enhance its effect on some specific tissues, such as blood vessels.
DESCRIPCIÓN DE LAS FIGURAS Figura la. Estructura cristalina del centro metálico coordinado con la amina 1,4,7- triazaciclononan.DESCRIPTION OF THE FIGURES Figure la. Crystalline structure of the metal center coordinated with the 1,4,7-triazacyclononan amine.
Figura Ib. Empaquetamiento de [(tacn)6Fe8(μ -O)2(μ2-OH)12]Br8 9H2O en el polimorfo IIFigure Ib. Packaging of [(tacn) 6 Fe 8 (μ -O) 2 (μ 2 -OH) 12 ] Br 8 9H 2 O in polymorph II
Medidas de los tiempos de relajación para el compuesto [(tacn)6Fe8(μ3-O)2(μ2-
Relaxation time measurements for compound [(tacn) 6Fe8 (μ3-O) 2 (μ2-
Figura 2. Representación de los tiempos TI vs la concentración. Figura 3. Representación de los tiempos T2 vs la concentraciónFigure 2. Representation of TI times vs. concentration. Figure 3. Representation of T2 times vs. concentration
Medidas de los tiempos de relajación para el compuesto Gd-DTPA Figura 4. Representación de los tiempos TI vs la concentración Figura 5. Representación de los tiempos T2 vs la concentración
Measurements of relaxation times for compound Gd-DTPA Figure 4. Representation of TI times vs. concentration Figure 5. Representation of T2 times vs. concentration
EJEMPLO DE REALIZACIÓN DE LA INVENCIÓNEXAMPLE OF IMPLEMENTATION OF THE INVENTION
Ejemplo 1Example 1
Síntesis y caracterización del compuesto [(tacn)6Fe8(μ3-O)2(μ2-OH)i2]Br8 9H2O (1)Synthesis and characterization of compound [(tacn) 6 Fe 8 (μ 3 -O) 2 (μ 2 -OH) i 2 ] Br 8 9H 2 O (1)
El compuesto [(tacn)6Fe8(μ -O)2(μ2-OH)ι2]Brg 9H2O fue sintetizado y caracterizado por Wieghardt K., [Wieghardt K.: Angew. Chem. Ed. Engl. (1984), 23, 1, 77], donde tacn = 1 ,4,7-triazaciclononan. A partir de la sal (tacn)FeCl3 disuelta en agua y medio básico, se trata con NaBr y al cabo de 24 horas precipita el compuesto (1) en forma de cristales marrones. En nuestro laboratorio se ha obtenido además el polimorfo II del compuesto presentado en la referencia anterior. El polimorfo (II) se ha caracterizado por análisis elemental, difracción de Rayos X de polvo y monocristal (resultados no publicados). La molécula que constituye el 'building block' de ambos compuestos está representada en la figura la. La figura Ib presenta el empaquetamiento de dichas moléculas en el polimorfo II, así como los parámetros de la celda unidad.Compound [(tacn) 6 Fe 8 (μ -O) 2 (μ 2 -OH) ι 2 ] Brg 9H 2 O was synthesized and characterized by Wieghardt K., [Wieghardt K .: Angew. Chem. Ed. Engl. (1984), 23, 1, 77], where tacn = 1, 4,7-triazacyclononan. From the FeCl 3 salt (tacn) dissolved in water and basic medium, it is treated with NaBr and after 24 hours compound (1) precipitates in the form of brown crystals. In our laboratory, polymorph II of the compound presented in the previous reference has also been obtained. Polymorph (II) has been characterized by elemental analysis, powder X-ray diffraction and single crystal (unpublished results). The molecule that constitutes the 'building block' of both compounds is represented in figure la. Figure Ib presents the packaging of said molecules in polymorph II, as well as the parameters of the unit cell.
Tabla 1. Parámetros de la celda unidadTable 1. Unit cell parameters
[(tacn)6Fe8(μ3-O)2(μ2-OH)ι2]Br¡3 9H2O sintetizado por Wieghardt K. Pl, Z = 1, a = 10.522(7) A, b = 14.05(1) A, c = 15.00(1) A, α = 89.90(6), β = 109.65(5), γ = 109.27(6) °, V = 1956 A3 (T = -30 °C) [(tacn)6Feg(μ3-O)2(μ2-OH)ι2]Br8 9H2O sintetizado en nuestro grupo. P-l, Z = 1, a = 13.28(1), b = 13.56(1), c = 15.08(1) A, α = 114.77(1), β = 108.14(2), γ = 101.43(1) °, V = 2162.85 A3 (T = 25 °C)[(tacn) 6 Fe 8 (μ 3 -O) 2 (μ 2 -OH) ι 2 ] Br¡ 3 9H 2 O synthesized by Wieghardt K. Pl, Z = 1, a = 10.522 (7) A, b = 14.05 (1) A, c = 15.00 (1) A, α = 89.90 (6), β = 109.65 (5), γ = 109.27 (6) °, V = 1956 A 3 (T = -30 ° C) [ (tacn) 6 Feg (μ 3 -O) 2 (μ 2 -OH) ι 2 ] Br 8 9H 2 O synthesized in our group. Pl, Z = 1, a = 13.28 (1), b = 13.56 (1), c = 15.08 (1) A, α = 114.77 (1), β = 108.14 (2), γ = 101.43 (1) °, V = 2162.85 A 3 (T = 25 ° C)
La constante de estabilidad del complejo metálico definida por la ecuación (1), tiene un valor de 10 14 62The stability constant of the metal complex defined by equation (1), has a value of 10 14 62
[ML][ML]
M + L = ML KML ~ M + L = ML K ML ~
[M] [L] (1)
Medidas de relajatividad[M] [L] (1) Relaxation measures
Las medidas de los tiempos de relajación TI y T2 del compuesto [(tacn)6Fe8(μ3-O)2(μ2-Measurements of the relaxation times TI and T2 of compound [(tacn) 6 Fe 8 (μ 3 -O) 2 (μ 2 -
OH)ι2]Brg 9H2O han sido realizadas en un espectrómetro ARX400 (Bruker) bajo un campo magnético de 9.4 Teslas (400 MHz) y a 298 K.OH) ι 2 ] Brg 9H 2 O have been performed on an ARX400 (Bruker) spectrometer under a magnetic field of 9.4 Teslas (400 MHz) and at 298 K.
Se han llevado a cabo las siguientes secuencias para conocer los valores de TI y de T2,The following sequences have been carried out to know the TI and T2 values,
'inversion-recovery' (180°x-τ-90°x-τ-180°x) y 'spin-echo' (90°x-τ-180°y-τ-acquire) respectivamente.'inversion-recovery' (180 ° x-τ-90 ° x-τ-180 ° x) and 'spin-echo' (90 ° x-τ-180 ° and-τ-acquire) respectively.
Los valores experimentales de TI se han ajustado a la siguiente ecuación, y = a l-2*exp(-x-x0/Tl)) (2)The experimental values of TI have been adjusted to the following equation, y = a l-2 * exp (-xx 0 / Tl)) (2)
Los valores experimentales de T2 se han ajustado a la siguiente ecuación, y = a exp[-x*(l/T2)] (3)The experimental values of T2 have been adjusted to the following equation, y = a exp [-x * (l / T2)] (3)
El fenómeno de la 'radiation dumping' se manifiesta en muestras con un alto contenido en agua, es decir muestras saturadas de núcleos de H y al trabajar a campos magnéticos altos [Mao Xi-An, Chemical Physics Letters 222, 417-421, 1994]. Para obtener una señal sinosuidal de la recuperación de la magnetización longitudinal respecto al tiempo se optimizó el método trabajando con menos cantidad de agua y desintonizando la muestra. Para medir los tiempos de relajación, el compuesto (1) fue disuelto en tampón PBS,The phenomenon of 'radiation dumping' manifests itself in samples with a high water content, that is, samples saturated with H nuclei and when working in high magnetic fields [Mao Xi-An, Chemical Physics Letters 222, 417-421, 1994 ]. To obtain a sinosuidal signal of the recovery of the longitudinal magnetization with respect to time, the method was optimized by working with less water and detuning the sample. To measure relaxation times, compound (1) was dissolved in PBS buffer,
(PBS - 8 g NaCl, 0.2 g KC1, 1.44 g Na2HPO4, 0.24 g KH2PO4, ldm3 H2O).(PBS - 8 g NaCl, 0.2 g KC1, 1.44 g Na 2 HPO 4 , 0.24 g KH 2 PO 4 , ldm 3 H2O).
El rango de concentraciones estudiado ha sido entre 4.46 10"3 mM i 8.91 10"1 mM deThe range of concentrations studied has been between 4.46 10 "3 mM and 8.91 10 " 1 mM of
[(tacn)6Fe8(μ3-O)2(μ2-OH),2]Brg 9H2O en PBS.[(tacn) 6 Fe 8 (μ 3 -O) 2 (μ 2 -OH), 2 ] Brg 9H 2 O in PBS.
En las figuras 2 y 3 se han representado los tiempos de relajación, TI y T2 respectivamente vs la concentración.Figures 2 and 3 represent the relaxation times, TI and T2 respectively vs. concentration.
A partir de las siguientes ecuaciones se han obtenido las relajatividades ri y r2 ,From the following equations the relaxations ri and r 2 have been obtained,
(τr')p - (τr1)0 = rI p](τr ') p - (τr 1 ) 0 = r I p]
(T2-1)p - (T2-,)0 = r2- [P] donde [P] es la concentración del agente de contraste en mM (mmolL" ); (Ti )p y (T2 -"h ) p son los tiempos de relajación en presencia del agente de contraste y
y (T2 "')0 son los tiempos de relajación en ausencia del agente de contraste.
Los resultados obtenidos han sido los siguientes: rι = 5.10 ± 0.30 mMV r2 = 16.62 ± 0.75 mMV Se han efectuado medidas de relajatividad a 310 K pero no se han observado diferencias significativas.(T 2 - 1 ) p - (T 2 - , ) 0 = r 2 - [P] where [P] is the concentration of the contrast agent in mM (mmolL " ); (Ti) p and (T 2 - " h) p are the relaxation times in the presence of the contrast agent and and (T 2 " ') 0 are the relaxation times in the absence of the contrast agent. The results obtained were as follows: rι = 5.10 ± 0.30 mMV r 2 = 16.62 ± 0.75 mMV Relaxation measurements were carried out at 310 K but no significant differences were observed.
Como los tiempos de relajación, sobretodo el TI depende mucho del campo magnético al cual se está trabajando, para poder comparar la efectividad de este compuesto como agente de contraste, también se han efectuado las medidas de TI y T2 para Gd-DTPA a campo magnético alto. Se ha trabajado con Magnevist® y con Gd-DTPA de Aldrich. Las representaciones de los valores de TI y T2 en función de la concentración se pueden observar en las figuras 4 y 5.
As the relaxation times, especially the TI depends a lot on the magnetic field to which we are working, in order to compare the effectiveness of this compound as a contrast agent, the TI and T2 measurements have also been made for Gd-DTPA to the magnetic field high. We have worked with Magnevist® and with Gd-DTPA from Aldrich. The representations of the TI and T2 values as a function of the concentration can be seen in Figures 4 and 5.
Los resultados obtenidos están representados en la siguiente tabla:The results obtained are represented in the following table:
Tal como se puede observar, en nuestro compuesto se han obtenido valores de ri y r2 más altos que las relajatividades obtenidas para el Gd-DTPA, trabajando a campo magnético alto. En un principio, a partir de los resultados se puede pensar en que el compuesto [(tacn)6Fes(μ3-O)2(μ2-OH)]2]Brg 9H2O sea más efectivo disminuyendo el TI que el Gd-DTPA.As can be seen, our compound has obtained ri and r 2 values higher than the relaxations obtained for the Gd-DTPA, working in a high magnetic field. Initially, from the results it can be thought that the compound [(tacn) 6 Fes (μ 3 -O) 2 (μ 2 -OH)] 2 ] Brg 9H 2 O is more effective in decreasing the TI than the Gd-DTPA.
Tabla 1. Parámetros de la celda unidadTable 1. Unit cell parameters
[(tacn)6Fe8(μ3-O)2(μ2-OH)ι2]Br8 9H2O sintetizado por Wieghardt K. Pl, Z = 1, a = 10.522(7) A, b = 14.05(1) A, c - 15.00(1) A, α = 89.90(6), β - 109.65(5), γ = 109.27(6) °, V = 1956 A3 (T = -30 °C) [(tacn)6Fe8(μ -O)2(μ2-OH)ι2]Br8 9H2O sintetizado en nuestro grupo. P-l, Z = 1, a = 13.28(1), b = 13.56(1), c = 15.08(1) A, α = 114.77(1), β = 108.14(2), γ - 101.43(1) °, V = 2162.85 A3 (T = 25 °C)
[(tacn) 6 Fe 8 (μ 3 -O) 2 (μ 2 -OH) ι 2 ] Br 8 9H 2 O synthesized by Wieghardt K. Pl, Z = 1, a = 10.522 (7) A, b = 14.05 (1) A, c - 15.00 (1) A, α = 89.90 (6), β - 109.65 (5), γ = 109.27 (6) °, V = 1956 A 3 (T = -30 ° C) [( tacn) 6 Fe 8 (μ -O) 2 (μ 2 -OH) ι 2 ] Br 8 9H 2 O synthesized in our group. Pl, Z = 1, a = 13.28 (1), b = 13.56 (1), c = 15.08 (1) A, α = 114.77 (1), β = 108.14 (2), γ - 101.43 (1) °, V = 2162.85 A 3 (T = 25 ° C)
Claims
1. Complejos moleculares polimetálicos con comportamiento superparamagnético a temperatura ambiente para su uso en Resonancia Magnética de Imagen.1. Polymetallic molecular complexes with superparamagnetic behavior at room temperature for use in Magnetic Resonance Imaging.
2. Complejos según reivindicación 2 con alta multiplicidad de espín en el estado fundamental.2. Complexes according to claim 2 with high spin multiplicity in the fundamental state.
3. Complejos según reivindicación 2 donde las interacciones intramoleculares entre los distintos centros metálicos son antiferromagnéticas.3. Complexes according to claim 2 wherein the intramolecular interactions between the different metal centers are antiferromagnetic.
4. Complejos según reivindicación 2 donde la unión entre los metales del núcleo magnético sea por puentes de elementos electronegativos. 4. Complexes according to claim 2 wherein the union between the metals of the magnetic core is by bridges of electronegative elements.
5. Complejos según reivindicación 2 donde el núcleo metálico está rodeado de una capa no magnética formada por ligandos orgánicos.5. Complexes according to claim 2 wherein the metal core is surrounded by a non-magnetic layer formed by organic ligands.
6. Complejos según reivindicación 2 donde Fe o Mn son los metales que integran el centro metálico.6. Complexes according to claim 2 wherein Fe or Mn are the metals that make up the metal center.
7. El uso de complejos moleculares polimetálicos como agentes de contraste para Resonancia Magnética de Imagen.7. The use of polymetallic molecular complexes as contrast agents for Magnetic Resonance Imaging.
8. El uso de [(tacn)6Fe8(μ -O)2(μ2-OH)ι2]Br8 9H2O como agente de contraste para RMI.8. The use of [(tacn) 6 Fe 8 (μ -O) 2 (μ 2 -OH) ι 2 ] Br 8 9H 2 O as a contrast agent for RMI.
9. El uso de [Mnι2(μ-O)ι2(μ-OOCCH3),6(H2O)4]2CH3COOH 4H2O como agente de contraste para RMI. 9. The use of [Mnι 2 (μ-O) ι 2 (μ-OOCCH 3 ), 6 (H 2 O) 4 ] 2CH 3 COOH 4H 2 O as a contrast agent for RMI.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003224179A AU2003224179A1 (en) | 2002-05-03 | 2003-04-30 | Polymetallic molecular complexes used as contrast agents in magnetic image resonance |
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| ESP200201023 | 2002-05-03 | ||
| ES200201023A ES2204281B1 (en) | 2002-05-03 | 2002-05-03 | MOLECULAR POLYMETAL COMPLEXES AS CONTRAST AGENTS FOR USE IN MAGNETIC IMAGE RESONANCE. |
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| WO2003093284A1 true WO2003093284A1 (en) | 2003-11-13 |
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| PCT/ES2003/000190 WO2003093284A1 (en) | 2002-05-03 | 2003-04-30 | Polymetallic molecular complexes used as contrast agents in magnetic image resonance |
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| Country | Link |
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| AU (1) | AU2003224179A1 (en) |
| ES (1) | ES2204281B1 (en) |
| WO (1) | WO2003093284A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8592617B2 (en) | 2005-12-21 | 2013-11-26 | Roche Diagnostics Operations, Inc. | Redox mediators |
| CN108191921A (en) * | 2017-12-29 | 2018-06-22 | 李辉 | A kind of multi-nuclear metal cluster compound and preparation method based on iminodiacetic acid ligand |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990003190A1 (en) * | 1988-09-29 | 1990-04-05 | Ranney David F | Methods and compositions for magnetic resonance imaging |
-
2002
- 2002-05-03 ES ES200201023A patent/ES2204281B1/en not_active Expired - Fee Related
-
2003
- 2003-04-30 WO PCT/ES2003/000190 patent/WO2003093284A1/en not_active Application Discontinuation
- 2003-04-30 AU AU2003224179A patent/AU2003224179A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990003190A1 (en) * | 1988-09-29 | 1990-04-05 | Ranney David F | Methods and compositions for magnetic resonance imaging |
Non-Patent Citations (3)
| Title |
|---|
| CHRISTOU G. ET AL.: "Single-molecule magnets", MRS BULLETIN, vol. 25, no. 11, November 2000 (2000-11-01), pages 66 - 71 * |
| GATTESCHI D. ET AL.: "Single-molecule magnets based on iron(III) oxo clusters", CHEMICAL COMMUNICATIONS, vol. 9, 2000, pages 725 - 732 * |
| SESSOLI D. ET AL.: "The molecular approach to nanoscale magnetism", JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS, vol. 200, no. 1-3, 1999, pages 182 - 201, XP004364014, DOI: doi:10.1016/S0304-8853(99)00408-4 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8592617B2 (en) | 2005-12-21 | 2013-11-26 | Roche Diagnostics Operations, Inc. | Redox mediators |
| CN108191921A (en) * | 2017-12-29 | 2018-06-22 | 李辉 | A kind of multi-nuclear metal cluster compound and preparation method based on iminodiacetic acid ligand |
| CN108191921B (en) * | 2017-12-29 | 2020-07-24 | 李辉 | Multi-core metal cluster compound based on iminodiacetic acid ligand and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2204281A1 (en) | 2004-04-16 |
| AU2003224179A1 (en) | 2003-11-17 |
| ES2204281B1 (en) | 2005-08-01 |
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