JPH07502725A - Amino acid, ester and/or catechol contrast agents for MRI - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

Amino acids, esters and/or proteins for MRI are foolproof! This application is a part of U.S. Patent Application No. 743゜143 filed on August 9, 1991. This invention is a continuation-in-part application of No. 7 44.470. Beauty? Concerning the production and use of amino acids and cabkol containing shredded viscera. do. This contrast agent has a conventional carboxyl group and chelates various metals (I+) or (IIN). Contrast Agents Contrast agents are exogenous substances that enhance or suppress normal A/Vivo MRI/contrast information. theory (12), although the use of various types of contrast agents has been described in the literature (1°2). It was. Arabic numerals in parentheses in this section refer to papers cited in this section. The use of a given MR1+3 contrast agent is precluded by the availability of that contrast agent in Innovide. The mechanisms that control the biodistribution of rivers are classified14. In other words, it is a physicochemical type that depends only on properties such as the molecular number, 44-carboxylic acid, lipophilicity, and surface properties, or it is a receptor-mediated type. Different organs may process the same contrast agent by different mechanisms. For example, depending on the molecular size of the drug, it may be filtered by the kidneys (or otherwise sequestered into the vascular lumen). On the other hand, it is removed in the liver by receptor-mediated transport. Contrast agents that exhibit a physicochemical distribution mechanism include gadolinium(III) diethylenetriaminepentaacetic acid (Gd-DTPA), which is distributed in plasma and extracellular fluid, and albumin-(Gd-DTPA), which mostly remains in the blood vessels. DTPA), including (1.2). The former reveals damage to the blood-brain barrier or reveals renal anatomy and function (3). On the other hand, the latter has been used experimentally to depict vasculature (4) and to measure cerebral blood volume (5,6+). (12 h) and is used as an intravascular T2 contrast agent (7), as well as some supermagnetic iron oxide particle preparations (8,9).It removes foreign substances from the systemic circulation. Because of this role, the liver can actively take up and concentrate soluble contrast agents consisting of fine particles. The routes that solutes follow from plasma to bile have been summarized (10-1), and are shown in Figure 4. Illustration t2. Crossing the cell membrane Passage into the hepatic rostrum can occur by: pinocytosis, passive diffusion, and/or bile acids, hirirubin, organic anions, organic cations, neutral A carrier-mediated system for transporting organic compounds or inorganic ions. The substrate specificities of the various carrier systems may be partially overlapping (eg, organic anions and bile acids). The substrate may be metabolized intracellularly and/or May be combined with lutadeone. Finally, excretion into the bile canaliculi also involves passage through the cell membrane. The mechanism of biliary excretion of any given compound; Yo The clearance of various metabolites is determined, and their persistence in any one organ system is determined. However, currently the factors that cause certain compounds to be excreted into bile and urine are not completely understood. Regarding binding to plasma and transporter proteins, molecular weight, polarity, and The structure is important. If there is a general molecular weight threshold, depending on the species, below which urinary excretion takes precedence (approximately 300 for rats and approximately 600 for humans) (10-II), I! Hydrolipid balance plays an important role in bile excretion. (26-28). However, ex ante prediction is currently not possible. It is impossible. The MR contrast agent Fe-EHPG(E)IPG provided the first example of receptor-mediated localization of ethylene-bis(hydroxyphenylglyph)) in the liver (12). Afterwards, other irons (13-15), manogans (16-17), and galaxies It has been shown that chelate of dolinium (18) can be taken up into hepatocytes via receptors, or this has been demonstrated. Anionic chelate Fe-EHPG, Fe-41BED (HBED) A system in which Fe-IGDF (PGDF = N-3-(phenylglutaryl)desferrioxamine B) is inhibited with BSP (promosulfophthaliso) or It has been reported that it is transported into the liver by multiple systems (13. is). The lipophilic chelate Gd-BOPTA (a derivative of DTPA) Robioninoctetraacetate J) has significant biliary excretion (injected into bile within 6 hours). (18). Import of this compound No knowledge of the mechanism of transport (e.g. passive diffusion or anion transport) has been reported. Gd-BOPTA is a T1-weighted spinoe at 05 Tesla. Coimaging produced a greater signal enhancement (48%) than Gd-DTPA (16%). Additionally, other organs and structures may be used, such as amino acids, peptides or catechols. They may have receptors with affinity for certain classes of substrates such as amines (19-24). Molecules similar to the substrate may also bind to these receptors, such as, for example, derivatives of amino acids present in peptide substrates (22) or amide derivatives of natural catecholamines such as dopamine. The contrast agent of the present invention is partially due to this mechanism. can be localized by rhythm. Furthermore, localization of catechol containing contrast agents of the invention may depend in part on their respective redox properties. To date, Magnetic Resonance Imaging (MHI) has limited use in imaging the human liver and abdomen due to degradation of image quality due to motion artifacts and lack of adequate contrast agents. play a role came. Mechanical engineering (e.g. self-nord granoenotocoil) and pulse nord (e.g. echo planar technology and turbo flannel saw technology) Recent advances in technology are expected to alleviate problems with Paulownia and W segment motion, making the development of contrast agents even more important for the continued advancement of abdominal MHI. MRI! General background on the use of contrast agents and their preparation and purification is described, for example, in: H. Gries et al., U.S. Patent No. 4.647.447; , U.S. Pat. No. 4,899,755 and 4. No. 8a0.008; B, L. EngelsLad et al., U.S. Pat. No. 4.909.257: D. L. White et al., U.S. Pat. No. 4.999.445. 1, R, B, Lauf Ier, r Paramagnetic Metal Complexes as Water Protonorelaxants for NMlt Imaging Theory and Design J Chem-Flood Law (+987), 87:901-927° 2, S, M , Raeklage et al., "Contrast Agents in Magnetic Resonance Imaging" Chapter 14, In '43 netic Re5ona, -n? =I'', 2nd edition, co-edited by 5tark DD, Bradley WG, SL, Louis: C, V, Mo5 by Co, (1992). 3. G. Rydder, “Clinical Application of Gadolinium DTPA” 1.1.5 tark DD% Bradley W.G. ed., St., 1. ouls: C, L Mo5by Co, (1988): 1 82-200 (Chapter 10). 4, M.E., Mo5eley et al., [Albumin-(Gd-DTPA), Vascular Vascular Mapping Using Both Internal MR Contrast and Projection MR Imaging JJ, 1StToIIu for Coq Control A, (1988): H: 219-2 21°5, T, A, Kent et al. [Ml+ image at 47, cerebral blood volume j in rat model of cerebral ischemia lt- AJNR (1189): lO: 335-358°6, D 1. , White et al., “Using intravascular MR contrast agent Measurement of the perfused cerebral blood volume used in J Book of Abslrac+z: 5ociety of Magnetic Re5ance in Medicine (1989); 2:806n? , D.L., White et al., "Iron-Dextra as a Magnetoreceptive Contrast Agent: Flow-Related Contrast Effects in 12-weighted Spin-Echo MRI of the Normal Rat and Cat Brain" J. Mign, Re5on, Med. (1992), Vol. 24, pp. +4-18. 8. D. L. White et al. Plasma clearance of ferrosomes JL Abstracts: 5ociety or Magnetic Re5onance Medicine (1990), 9. R, Weissleder et al. [Mi Small superparamagnetic iron oxides: a new class for MR imaging contrast agent Characteristics of J Rad Dane JLy (19901+175:489-493゜10, L, S, 5chanker, ``The fraction of organic compounds into bile i/=J In Thel (andbook of Ph LheStruha■lzIshiol BL''l) iment LCa ↓ V, Washington, D, C,: American Physiol, 5ociety, ChR9,114 12433-2449° Il, C, D, Klaassen et al. discharge Mechanism of J Phart Rev, (1984) + 36:1-67゜12, R, B, 1. Auffer et al. [Iron-F as a hepatobiliary MR contrast agent,] IPG: initial imaging and biodistribution studies J L "Crying Uter As 5ist Tow+. Eng J, - (19115): 9:431-438° + 3.8. Roener et al., "Iron-HBED and Iron as a Magnetic Resonance Contrast Agent for the Evaluation of Hepatobiliary Function. -Evaluation of IPG JL'■n, Re5on I*ainl, (1991); 1:3ST-362゜14, K, A, MuetterLies et al. Cow Corner 78m Conductor J■■Re5on Med (1991), Vol. 22, pp. 88-100. 15. B. Hoener et al., "Magnetic Resonance Imaging Contrast Agent, Iron(II+)-N-(3-Phenyl -Glucryl〉Hepatic transport of desferrioxamine B'' 11L Hyy Yu up (+990): +7.509-51°+6. D, L, Whie et al., ``New MR + contrast agent, manganese dipyly Doxal diphosphoric acid (Mn-DPDP) Abstract Book: 5oci ety or Magnetic Re5onance in Medicine (198!l) I:S31° +7. S, W, Young, [MR,I measurement of liver 1fBI12+ toxicity using a new MRI contrast agent, manganese dipyridoxal diphosphate, manganese/pyridoxal (pyrdoxa 1) S-phosphate chelate JM Re5on Md, (1 989);lQ:1-13゜ 18. P., Pavone et al., [Comparison of Gd-B OPTA and Gd-DTPA in MHI imaging of rat liver Jh Tanduan (1990); 176:61-64 °+9. P. Ascher, “Glutamate Receptors and Glutamatergic 5 Synapses in Brain Trans art and Sina l Transduct'on,” E. Evans. elopoulis et al., Berlin: Springer Verlag, (1989 ): 127-1 46゜20, F, P, Leh an, [Stereoselective molecular recognition in biology IJRecetors and Reo n1Lion, No. 5 @, /Lee A, Cutreeasas P and Greaves MF, London: Chapman-Hall (1978). 21, R, D, 0°Br1enlC4 Collection, The Reee Toers 2 People', Treatise, Volume 1, New York: Pla enum Press (1979). 22, S. Schiffman et al., “The Search for Receptors Mediating Taste,” in The Rece Lots, Volume 4, edited by Conn PM, 0 ando: Academic Press (1986). 23, A, S, Horn et al., eds., Neu ob'o ae, Acade +nic Press, New York, +979°24, B, J, C1 ark, rRole of dopamine in the periphery. In "Yu B±", edited by B. Halasz et al., Springer-1/erlag, Berlin, 1 985. pp. 27-29 All reference articles, patents, etc. cited in this application are incorporated by reference in their entirety. and is incorporated herein by reference. It would be very useful to have specific organobate metal ion complexes for MRI imaging of liver, biliary tree, upper small intestine, or myocardial tissue. Ru. The present invention provides complexes and methods that have these useful advantages. Ordinarily

[Effective effect] The present invention provides a contrast agent for magnetic resonance imaging, wherein the contrast agent contains the following complexes or pharmaceutically acceptable salts thereof. , metals with atomic numbers 21-31, metals with atomic numbers 39-50, ranknide metals with atomic numbers 57-1, and metals with atomic numbers 72-82 (11 ) is (II+1Ilin), and is a polydentate organic chelate moiety of structural formula 1a: Q, J, Xl, X', Y and Z are each independently -CH2(C1 ) -CH1 or -CI+2 (CaO)NIICH-(R)-(A); where each R of Q, J, XSX', Y and 2 is hydrogen, or an alkyl group, an aromatic group , substituted aromatic, alkylene aromatic, alkylene substituted aromatic, heteroaromatic, substituted heteroaromatic c), alkyleno6teroaromatic group, or an organic structure containing an alkylene-substituted heteroaromatic group (alkylene 5substituted heteroaromatic group), wherein at least one of Q, J, Y and 2 is -CHt(C.0)-NHCH(R) -8; and ^ is independently selected from -(C·0)OR', -(C·0)-N-(R2)R', or R', where R' is -CH aryl, -CI+2-substituted aryl independently selected from nor, -CH2C1 (2-aryl, or -CH2CH2-substituted arylcarbohydrate), but when A is -(C.0)OR' and R1 is hydrogen, R is not hydrogen; R1 , R2 and R3 are independently selected from hydrogen, alkylphenyl having 1 to 7 carbon atoms or benoyl when present in QSJ, X, X, Y and z+7) A; and - is selected from 0, [, 2 or 3, and n is selected from 0 or 1. In another aspect, the present invention provides polydentate organic chelate compounds of Structural Formula 1 below; One of them that is scientifically acceptable<#A! 1m):Q. J. X, X'. Y-o and Z are each independently selected from -CH2(CaO)-0H, or -CH2(CaO)NHCH-(R)-(Al); Each of the RL, hydrogen, and carbon atoms is Q.J.Y and Z (7) at least one alkyl group is C, -CH2(C-0)-NHC)1(R)-8, Aromatic group, substituted aromatic group, alkyleno-magnetic group, alkyleno-substituted aromatic group Aromatic groups, heteroaromatic groups, substituted heteroaromatic groups, alkylene/heteroaromatic groups, or or an alkylated/substituted heteroaromatic group, and ^ is -(C.0)OR', -(C.Q)-N-(R2)R ', or independently selected from R4:! t'L, cocote, R'+1, -C)+2-7') -l, -Cl12-rIL-substituted aryl, CH2C)1-aryl, or -CJ+2C112-+I-substituted aryl, , A is -(C・0IOR' and R1 is hydrogen, then R is hydrogen: R1, R2, R311, Q, ', xSx', l and Z(7) respectively 17 ) When present in A, hydrogen, alkyl containing 1 to 7 carbon atoms, phenyl or is selected from benzyl; and - is selected from 0.1.2 or 3; and n is selected from O or 1. Accordingly, the present invention provides a method for preparing a chelate compound of structural formula (1a), which method comprises: (a structure of formula ai1, where A and D are each -CI+2 (CJ) -Off, and The structure defined herein is t2,1hN-C11(R)-COGR'. amino acid or ester or N112CI12CI+2 aryl or substituted substituted aryl, where R is an alkyl, aromatic or heteroaromatic group, and R+, hydrogen, alkyl having 1 to 7 carbon atoms, phenyl or benzyl and is selected from 0.1.2 or 3, and n is selected from 0 or 1, and between about 50 and 150"C in an anhydrous polar aprotic solvent. Approximately 2 to IO hours (b) removing the solvent and recycling the compound of structure 1; It also relates to a method comprising the steps of: These metal ion chelates produce T I contrast effects in the heart, liver, biliary tree, and upper small intestine. These effects improve function and anatomical structure. The structure becomes clear. These contrast agents have low toxicity. And, due to superparamagnetic particles, Unlike conventional iron, metals derived from these compounds are rapidly and relatively completely absorbed by the body. excluded from within. Therefore, these contrast agents are of great significance for useful abdominal MHI. Figures IA, IB, IC and ID are the compound BOPTA, respectively. This is a representation of the structure of BSP, DPDP, and DTPA. Figures 2A, 2B, 2C and 2D show chelate E[lTA, respectively. A representation of the structure of EDTPSE1 (PG, HBED). Figure 3 is a representation of the chemical species of a general reaction that forms a chelate to bis-amino acid 11111. Figure 4 shows a representation of cells found in the hepatobiliary duct region. Figure 5A is a photograph of T-1 weighted magnetic resonance images of a rat at various times (expressed in minutes) after Gd-DTPA-(bisphenylalanino) injection. Dosage: 0.1 wo+ol/kg. Figure 6A shows T- at various times (expressed in minutes) obtained similarly to Figures 5A and 5B for Gd-DTPA-bis(phenylalanine ethyl ester). 1-weighted magnetic resonance images. Figures 5B and 6B are magnifications of the images of Figures 5A and 6A, respectively, before and 0 minutes after injection. Figure 7 is described in Example 8 below. T-1 weighted images of two mice shown side by side at various times (expressed in minutes) after co-injection of Gd-DTPA-bisphenyl-alanine (bis acid) at a dose of approximately 0.1 mmol/kg. Photographs of magnetic resonance images. These images are 2-mi thick slices in the coronal plane at the location of the heart. The heart, liver and intestines are clearly visible. Figures 9 to 13 are photographs of T-1 weighted magnetic resonance images similar to those obtained in Figure 6, except that different g forms of bis-(phenylalanine ethyl ester) were used. Graphical representation of MHI imaging of lung, kidney, liver and skeletal muscle tissue. Figure 14A shows rat T-1 strong XII MR+ similar to that obtained in Figure 5 using Gd(III)-DTPA-(3HTA)2. Figure 14B is a photograph of the second coronal plane at the location of the kidney, similar to that displayed in Figure 14A. Figure 15A is a photograph of the image (expressed in minutes). Figure 15B is a photograph of a T-1 strong RM old image of a rat similar to that obtained in Figure 5 using DMPE) 2 (expressed in minutes). Figures 16-20 are graphical representations of MHI imaging of the heart, lungs, kidneys, liver and skeletal muscle tissue, respectively.Gd(I11>-DTPA- Percent enhancement is shown versus time (min) for (L-PheOEL)2 and Gd(lII)-DTPA-(D-PheOEt)2. 21A and 21B are the results obtained in FIGS. 14 and 15 using Gd(If I)-DTPA-(L-PheOE[)2 and Gd(IIII)-DTPA-(D-PheOEL)2, respectively. T-1 strong RMR + copy of l) similar to the above It is a true image. However, the dose level is 0.05+u+ol/kg. In Figures 9-13 and 16-20, the solid vertical lines in the graphs indicate the ends of the range of horizontal lines. The box in the center of this vertical line is the average value of the observations at each point. The horizontal lines at either end of the vertical line are placed one standard deviation from the central value. θ-na! 6 and na As used herein, "alkylene" refers to methylene, ethylene, propyle/etc., and the like up to 6 carbon units. Amino acid J refers to the class of α-amino acids commonly found in living subjects or mammals. However, synthetic alpha-amino acids not found in nature are also useful. Additionally, these D- and L-amino acids as separate chiral isomers are each useful. Mixtures of D- and L-isomers were also investigated in the present invention. "Metals with atomic numbers 21 to 29" include scandium, titanium, vanadium, and nickel, copper, zinc and gallium respectively. point to. Paramagnetic ions are particularly preferred. Iron, manganese, nickel, chromium, and metals are preferred. [Metals with atomic numbers S7 to 71 (lanotanide)'' refer to lanthanide, cerium, praseodymium, etc., and up to lutetium. um (l l +) is preferred. The talus 1 of the present invention is localized in several organ systems, such as the kidneys, urinary tract, and and in the bladder; liver, bile ducts, intestinal lumen, and myocardium. This localization results in increased MR17 normal and image contrast. image obtained Image 1 both shows improved anatomical detail and makes it possible to confirm the functional status of specific organ systems, such as the urinary system and the biliary system. This localization is probably due to a combination of physicochemical and receptor-based mechanisms. related to For example, binding to the m-fluid component causes an increase in the resolution of the surface fluid pool. This can contribute to increasing the resolution of the heart. Localization to the liver is determined by recognition and recognition by hepatocytes. and transportation. Other mechanisms may also be involved. Metal sharpness 1・Structure By selective modification of the structure of the contrast agent, it may also be possible to target other organs and tissues. Chelates of amino acids with esters The following is an overview of the synthesis of chelate liganodes. A detailed description can be found in 1 Experimental Example. In the synthesis of compounds of the formula 111I, the precursor is a DTPA-bis anhydride (or similar structures, such as EDTA-bisanhydride). Generally, only one amino acid residue is added at one or more positions designated Q, J, XSX', Y or 2. i.e. polype Peptide bonds are not normally formed. If a small amount (e.g. 05 equivalents) of an amino acid is used with the bis-anhydride, the mole Preference is given to the production of non-amino acid derivatives. Bis-amino acid derivatives are then produced when two equivalents of amino acids are used. For higher analogs of DTPA or polycarboxylic acids (hiII herher wholesale alags), more aggressive conditions may be required, such as the use of hexavalent agents and an excess of amino acids or protected diamino acids. . Any anhydrous dipolar aprotic solvent can be used in the synthesis; dimethylformamide (DMF), dimethylacetamide nitrile, etc. are useful. Ru. DMF is preferable. The reaction mixture is heated at 70-100°C for 2 to 12 hours, preferably at 90-100°C for 4-5 hours, especially for 6 hours. The reaction mixture is cooled and the solvent removed using a conventional rotor IJ-enovolator or equivalent. In one aspect, the invention provides structural formula l Novel preparation of compounds: Concerning this. Ionochelate LM's -1 chelate metal ionocomplex, LM's: General (1') g self-contained from A (this is prior art. Please refer to the above references. Metal chelate is In a suitable aqueous solution (or organic solvent), gold III The method involves reacting metal oxides and chelate compounds in appropriate stoichiometric ratios. Accordingly, typical f)! Prepare 11 pieces. It is then necessary to raise the pH by 1 degree. Next, the pH of the reaction mixture is adjusted to What about the corresponding chelate salt? Ill. Alternatively, protonated +4 chelate Me1ko, Shiif L If. Acids may be used. The R groups are selected independently from aromatic groups, anolekylene aromatic groups, substituted aromatic groups, or heteroaromatic groups (preferably).Particularly preferred are the following: Is an aryl aromatic group:? The R1 group of the chelating ligand L in each of Q, J, X% di-, tri-, etc.), cyclophenyl, phenyl, benzyl, or cyclic groups such as 1- or 2-naphthyl. Paramagnetic metal ions are preferred, including iron (11) and (II+) and gadolinium. (II+) is particularly preferred. In aminoamide embodiments, the present invention relates to certain structures in which A is independently selected from -(Co)N(R2)R3, where R2 and R3 are each independently selected from the group specified for R1. Amides and related structures (free amides, monosubstituted amides, or disubstituted amides) are produced by starting with the appropriate amino acid amide (usually )-hydrochloride. Some purification of the amino acids may be necessary. The amino acid amide is then combined with the corresponding amino acid amide as described above for the amino acid ester. The horizontal axis is the dianhydride. When less than 1 equivalent of amino acid amide is used after being highly diluted in a solvent, monoamino acid amide is preferentially produced. Acid amide constructs are obtained. The amide constructs are also described in Examples 12-22. These amide constructs are useful in MHI because they In another aspect, the invention provides a method for treating EDTA and DTPA because they have good contrast properties for tissues and have longer useful half-lives in mammalian systems. Substitution of structure of type The present invention relates to alkylene aryl derivatives (e.g. 11 methylene catechols). Aryl groups and substituted aryl groups are defined as part of the R'' group.N1(2cH2cH2-substituted aryl groups are defined as part of the R'' group. When 7 is brought into contact with a substance, the expected compound is obtained. When the substituent of the aryl group is a hydroxyl group, an aqueous base should be avoided. Ru. More particularly, the present invention provides crystals having one or more catecholamide groups. The present invention also relates to preparing stable chelates of Gant with useful metal ions, and using the chelates in diagnostic imaging or spectroscopy. If the metal ion is paramagnetic, such as Gd(III) or Dy(III), the chelating agent may result in increased contrast in MRI, or a soft, broadened, or magnetic resonance spectrum. may cause other changes in . Collet et al.'s IF [substances have been identified as specific types based on their similarity to naturally occurring catecholamines and/or their redox and other physicochemical properties. This improves on the prior art, which tends to localize in the tissue of the tissue. In particular, dopamine (3-hydrochloride) Two derivatives of roxytyramine (r3-HTAJ), DTPA-bis(3-hydroxytyramide), and DTPA-bis(3,4-softquinphene tylamides) are useful. These ligands were reacted with GD(11) to produce the present rates, DTPA-(3-HTA)2 and GD-DTPA-(3,4-DMPE>2, respectively. As described in the examples, it was used as a contrast agent in the MHI of rats. Both chelates showed useful enhancement of the heart, lungs, kidneys and liver. Ino-pivo magnetic resonance imaging of human organs and tissues is a conventional and well-established technique. It is erected. Figure 5 shows Gd-DTPA-bis(phenyl) at a dose of 0.1+smol/kg body weight. Figure 3 is a photograph of T-1 weighted magnetic resonance imaging of a rat obtained before and 10.15.25.45 and 60 minutes after injection of alanine). This image is a GhmX 60+u+X 3+u+ thick slice in the coronal plane. The area covered is from just above the heart to slightly below the liver. Enlarged images before and 0 minutes after injection are shown in Figure 5B. The imaging normal meters are shown on the left side of the figure and include repetition time (3,000,000 microseconds), eco-hour (6,000 microseconds), number of null averages (4), and image matrix size (128X 25G). Increased signal intensity is readily apparent, especially in the heart and liver. An increase in the intensity of the intestinal lumen was particularly evident in the 25 minute and subsequent images, suggesting expulsion of the contrast agent into the organ. Figures 6A and 6B show Gd-DTPA-bis(phenylalanine ethyl ester) 5A and 5B are photographs of T-1 weighted magnetic resonance images obtained in the same manner as described in FIGS. Is this compound distinctly different in the liver and heart when compared to the enhancement shown in Figures 5A and 5B? : It must be noted that this may lead to reinforcement. These results indicate that the two compounds This suggests that they have different biodistribution and pharmacokinetics. Specific experiments are described in detail in the Examples below. Any physician can determine the best method of administering this contrast agent. Generally, intravenous injection is used. The contrast agents described herein are useful for magnetic resonance imaging of the heart, liver, biliary tree, bladder, and intestines of subjects, such as animals, mammals, and particularly humans. The following examples are provided to further illustrate and describe the invention. squid They should not be construed as limiting in any respect. (Left below) DTPA-bis(anhydride>mdrieh Chemical Co.) 1 in a 50-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser and heated in an oil bath. .10 g (3,08 m+*ol), 0.93 g (6,15 m5 ol) of d,1-a-phenylglycine (Fluka Chemical Co.), and 25+*L of dry dimethylformamide (Aldrleh Chemical Co.) were added. The reaction mixture was heated to 90-100°C and the temperature range It was kept in the enclosure for 6 hours. Then, it is naturally cooled to room temperature and rotary evaporated. The solvent was removed using a rotor. The residue was washed by trituration with ether, yielding 2 g of a white solid of structure 1b (Figure 3). Support 1 DTPA-bis phenylglycine Gd]1-water 151. A solution in which 2 mg (30 μ5 ol) of DTPA-bis(phenylglycine) of Example 1 was dissolved was treated with 14 μmol of GdCIt.6H2016H2O. The pH of the product was adjusted to 70 by addition of dilute sodium hydroxide solution. 022μ filter Insoluble Gd(O)l)x was removed from the reaction mixture by filtration. During T1 relaxation of the resulting solution (volume 1.3 mL) at 0.25 Tesla and 37 °C The time interval was 7 milliseconds (IIs). A 300 g male Sprague-Davley rat was anesthetized by intraperitoneal injection of a mixture of ketamine hydrochloride and diazepam. , insert a catheter into the lateral tail vein. Ta. The rat was then placed inside the bore of a 2-Tesla imager spectrometer system (GECSI; General Electric Co., Fre+eont, Calif.) with internal diameters (i, d,) S-e. − was placed in the imaging filter. T1-weighted spin-echo images of the animal's abdomen in the U ill plane were obtained (TR 315 ms; Te Is ms: 128 NEX = 4 + 3-m slice thickness). The Gd-DTPA-bis(phenylglycine) solution described in Example 2 was then injected through the catheter. A series of post-injection images were obtained. These images showed slight enhancement in the liver initially. As this hepatic enhancement decreased over time, an increase in intensity was observed in the rat small intestine, indicating hepatobiliary transport of the contrast agent. The strength data is required below. promise Topsoil 100 women, O □□□ muscle (minutes after injection) Is -ill 7 42 2 Dog JilL± DTPA-bis-L-phenylalanine ethyl ester -1-phenylalanine 4.6 g (20 mmol; Sigma Chemical Co., SL, Louis, Mo.) of ethyl ester hydrochloride was dissolved in 15 mL of water and treated with 33 mL of saturated sodium bicarbonate solution. Pour the generated solution Extracted 4 times with 1 OiL of ethylene chloride, and extracted the organic extract with anhydrous magnesium sulfate. dried with sium. Next, filter the dried methylene chloride solution and remove the remaining dry solution. Desiccant was removed. The filtrate was then concentrated to an oil using a rotary flash evaporator. The residue was further dried under high vacuum for several hours to yield 3.75 g of free base. death Ta. DTPA-bis (anhydride 12.85 g (8,0+++ mol), dimethylporm 10 mL of amide (DMF) and 4.2 mL (24 mmol) of DIPEA (Sigffia Chemical Co., Louis, MO) were added to Magnetinox. The combination was carried out in a St)+L round bottom flask equipped with a taller. The above phenylara Nin was dissolved in DMFI□sL and the resulting solution was added to the flask with a syringe. The reaction mixture was heated to 40"C and then stirred for 13 hours at ambient temperature without external heating. After 12 hours, the reaction mixture was concentrated under reduced pressure to produce a viscous residue. This material was 710011L and the volatile components of the resulting mixture were removed under reduced pressure. The solid residue was recrystallized from 125 ml of a 60/40 water/ethanol mixture. White crystalline product The material was washed twice with 251 L volumes of chilled ethanol, and the washed solid was dried under reduced pressure at 40° C. for 1 hour, yielding 3.0 g (50% of theory). Analytically pure The product is obtained by dissolving 1 g of the above crystals in 75°C of ethanol at 80-85°C, treating the resulting solution with decolorizing charcoal, removing the latter by filtration, and draining the filtrate. obtained by cooling in a water bath It was. Seed crystals were then added and after 45 minutes 0.6 g of recrystallized solid was isolated by filtration. Bhikkhu: C36+ (Calculated value of 49N5012: C, 5g, 13; H1664; and N, 9.42° Detected value: C, 57,75; )l, 657: and N, 9.36° Support 51 DTPA -DTPA-bis(phenylalanine benzyl ester) Phenylalanine benzyl ester) was similarly prepared (according to Example 4) from 4.28 g of L-phenylalanine benzyl ester p-toluene sulfonate (10 auol: Sigma Chemical Co., St. Louis, Mo.). Use ethyl acetate instead of ethanol for recrystallization. Ta. Yield was 2.6 g (75% of theory). 41 DTPA-bisL-phenylalanine in 15iL of methanol Dissolution of (phenylalanine benzyl ester H, 23g (1,42iIIol)) The solution was combined with palladium/carbon catalyst (Aldrich Chemical Co, Milwaukee, IFI) Q,Ig in a 25 mL round bottom flask. Ta. This mixture was treated with hydrogen gas at 1 atmosphere for 6 hours. Then, the reaction mixture The mixture was filtered through diatomaceous earth filter aid. Volatile components were removed from liquid 1a under reduced pressure. The yield of product was 0.94 g (97% of theory) and the product was a white solid with some hygroscopic properties. Bhikkhu: Calculated for Cz2H3+N5(h22) 1011: C, 53,10; I+, 6.27; and N, 9.6B. Detected values 2 C, 53, 13,) I, 6.24; and N, 9.32 ° Bisacid, 45% bisester and 45% monoacid monoester. This is the contrast agent actually used for the MHI image in Figure 6. Blood support and Yu 1? gadolinium (11) m of phenylalanine and its esters (a) A solution of 0.176 g (0,2 5+*m01) of DTPA-bis(phenylalanine) in 4 mL of water was prepared as GdC13 (Aldrich Chemieil Co., Milwaukee). Wl) 0093g. The pH of the resulting solution was adjusted to rA 70 with an aqueous sodium hydroxide solution. Reduce the volume to 5. with water. Toned to OwL This solution was passed through a 0.22 micron sterile filter into a sterile serum vial. and filtered. The resulting 005M solution is suitable for small animal imaging. The T1 relaxation time of a 5-fold dilution of the above solution at a magnetic field strength of 0.025 Tesla and 37°C was 21 ms. (b) DTPA-bis(phenylalanine) mono and bis esters were made rA in a similar manner. A 300 g male Spray-Dawley rat was anesthetized by intraperitoneal injection of a mixture of ketamine hydrochloride and diazepam, and a catheter was inserted into the lateral tail vein. Next The rat was then placed in a 5 cm inner diameter (i, d,) imaging coil in the bore of a 2 Tesla Imager Spectrometer System (GE CSI: General Electric Co., Fremont, Calif.). A τ1 strongly emphasized pin-eff image of the animal's abdomen at the frontal region was obtained (τR300 mm). 128 x 256 image matrix: NEX I I4; 3 mm slice thickness). Then, 0.6 g of the Gd-DTP A-bis(phenylalanine) solution described in X1j19117 was injected through the catheter. A series of post-injection images were obtained. These images showed initial slight enhancement in the liver and heart. As this enhancement decreased somewhat over time, an increase in intensity was observed in the small intestine of the rats, indicating hepatobiliary transport of the contrast agent. The strength data is summarized below. Intensity values show some fluctuations due to respiratory motion and other small artifacts. (Leaving space below) Expression of 100 crosses of O kui - fixation - Li tun - 1 muscle (minute after injection) ``1 row'' - Gd-DTPA-bisphenylalanine ethyl ester in rats 9. 100゛ This imaging method was carried out in the same manner as in Example 8. The strength data is summarized below. (Left below) Table 1 Hundred uLJ! Tun-11L! ILM (post-injection) S -81094630 Is -181136631 PHE-OO% 7 Two male BALB mice were treated as in Example 8, except that the slice thickness was 21 mm. Images were taken side by side using the same equipment and under the same conditions. 0 minutes to 2.5 o'clock With an illustrated time course up to It can be seen to be present in the gallbladder (e.g. 90 minutes) and in the intestinal lumen (2-2.5 hours). It can also be found in the bladder. Plan 11 MHI data of mice Figure 8 shows T1-weighted magnetic resonance data obtained in the same manner as in Figure 6, except that a different R type of Gd-DTPA-(Phe-Et)2 was used. This is a photo of the image. HPLC (4,6x 15Os* PRP-1) column; mobile phase - 25 mmol ammonium forsate aqueous solution (solvent A) and and 50150 ([1/V) Nor Setonitrile/Water (Solvent B) for 15 minutes programmed from 10% B to 95% B and then held at 95% B; flow rate 1 ml/min: υ/V and/or as measured by a radioisotope detector. The substances used as contrast agents in FIG. Phe)2 (approximately 10χ) was found to be partially hydrolyzed.The pH was carefully adjusted to neutrality and the freshly prepared material was stored under cooling. As a result, about 90% was Gd-DTPA-(Phe-Et)2, and the rest was mostly Gd-DTPA-(Phe) (Phe-El). , produced enhancement in the heart and liver (74 and 163%, respectively), similar to that shown in Figure 6 (84 and 53%, respectively). The extent of liver enhancement was about 3 times greater. These results indicate that the esterified DTPA amino acid chelate has a low contrast suggests that it may be particularly useful for enhancing Support work 1 DTPA-bis(D-phenylalanine ethyl ester) D-phenylalanine ethyl ester) and the corresponding monoisomer of D-phenylalanine ethyl ester and DTPA-bis(anhydride) were prepared from R (Example 4). The yield was 65%. Analysis: Calculated value for CtaH49N50+2: C,511,13; H,6,6 4: and N, 9.42° Detected value: C,57,8f; H,6,55; N, 9.4g. A suspension of 2.07 g (10,43-ol) of L-phenylarine methyl amide hydrochloride of 1LI DTPA-bisphenylarine methylamide in ethyl acetate (75 L) was added to sodium carbonate (20 L). was treated with a saturated aqueous solution of The resulting solution was extracted with ethyl acetate (2X 75L) and the combined organic extracts were dried over anhydrous sodium sulfate. Remove desiccant by filtration and rotary - Concentrated to an oil using an evaporator. The residue was further dried with P2O5 under high vacuum overnight to produce amino 1.72[ as a white solid. A solution of the dried amine in anhydrous pyridine (15 L) was combined with DT PA-bis(anhydride) (1.80 g, 5.04 mmol) under argon. The reaction mixture was heated at reflux in an oil bath (95°C) for 60 minutes. The mixture was cooled to room temperature (0.5 h) and concentrated under reduced pressure to produce a viscous residue. This material was dissolved in 100 L of water and the water was then evaporated under reduced pressure to produce a yellow oil. Dissolve this oil in a solution of water in a minimum amount of methanol (20 V/V) and and treated with acetonitrile until a small amount of precipitate was observed. The precipitate was removed by filtration (0.45 μm membrane filter) and the inn was concentrated under reduced pressure. Ta. This process was repeated two more times, discarding the precipitate each time. Finally, the residue obtained by evaporation of the solvent was dissolved in a methanol solution of water (10 L, 20 mm V/V) and the desired product was precipitated out by addition of a minimum amount of acetonitrile. The resulting white suspension was cooled in the freezer (-20°C) overnight and then Then, the solvent was removed by decantation. The product was dried under high vacuum (0.05 Torr, 48 hours) with P2O5 and NaOH to yield 1.38 g (39%) of an analytically pure white solid. Analysis: Calculated value of Ci+HAyN70+@・O,S)+20: C,56,50; )I,6.69;N, 1L57°Detected value: C,56,34; 11.6. 61; N, H, 66° dog 1 sub[LI DTPA-bis) enylalanine amide and 0-bis phenylalaninamide The title compound of dimethylamide was combined with DTPA-bis(anhydride) and L-phenylalanine amide 7% hydrochloride and L-phenylalanine dimethane. Prepared from tyramide in a similar manner to the dimethylamide compound (Example 13) in yields of 20% and 59%, respectively. Completion Mido C32R43NtOIl+・21 (calculated value of 20: C, 53.25; H, 6.5) Electric N, 1358. Detection value: C, 53.43; H, 6.30; N, H. 59. Dimethylamide C: Calculated for I et al. ToultO+i1: C, 56.90; I+, 703: and N, 1290. Detected value: C, 56.82. L 6.74. N. 12.760L plate clay DTPA-bis(anhydride+(3.57 g: 1.OOII mol, Aldrich Che+ical Co., Milwaukee, Wl) of DTPA-3-HTA2 was dissolved in anhydrous dimethyl DMF (DMF; Aldrlch) was suspended in 2s-s of dichloroformamide (DMF; Ommol: Aldrich Chewieal Co.). Next The mixture was then briefly heated to 100°C and sonicated for several minutes to dissolve most of the solids. After stirring for 4-6 hours at 50-60°C, a dark yellow solution was formed. The reaction mixture was then cooled to room temperature. After stirring overnight at ambient temperature, the reaction mixture was concentrated to a volume of approximately 10@L using a rotary evaporator at 50.degree. There was no diisopropylethylamine odor at this point. Water (25-L) was added and the resulting solution was washed twice with 201 L volumes of ethyl ester to remove residual DMF. The water is then removed under reduced pressure. was removed to produce a beige paste. Add this substance to 10-20% of absolute ethanol! Suspended in IL and dried by cofA distillation of aqueous ethanol under reduced pressure. The crude product (7 g - 97% of theory) was a sandy, off-white, hygroscopic solid. Analytically pure samples (1.76 g + 26% of theory) were analyzed using a 4.6×15011 Microsorb C-111 reverse phase column (Rallin Instrument Co., Emeryv. CA). , isolated by preparative high pressure liquid chromatography (RPLC). The mobile phase (flow rate 1 sL/min) was a linear gradient of 5-50% acetonitrile J and aqueous solution for 12 min. It was arranged. p)I was kept acidic by 01% v/v fluoroacetic acid present in both components of the mobile phase. Using a UV detector to determine the absorption of 276na used. Under these conditions, the product retention time was 135 minutes. 'HNMRs Spectrum: δ 6.75, -, 68.63.81 to 262.26 H1 aliphatic H2 No further assignments. Liquid secondary ion mass spectra (LS IMs) CM-Itdo-662 (Physical Theoretical value 662). Support n plate 34-Dimethacinphene 34-Dimethacinphene L"-E"G L-main"Using mouth 1 34-DMPE Mu-stop λ skin beads equivalent molar amount of DTPA-Bis(anhydride) and 3.4-Dimethacinphene Netylamine (Aldrich Chemical Co.) was contacted as in Example 15 above to obtain the crude product in 100% yield. This material was purified by preparative HPLC to yield 23 g (17%) of the title compound L. 'RNMR spectrum: 6680, false, 68. δ 382, s, 6H, CH 30-1 δ 380, S, 68: C1hO-; δ 345-276.26H, aliphatic H1 No further assignments were made. 1. sIMsii quantity spectrum: [MH]-=vu (theoretical value 718). A solution of Gd-DTPA-(3-HTA)2 for image quality experiments was mixed with DTP A-(3-+(TA)2) in an aqueous solution and water. A was prepared by reacting with a stoichiometric amount of GdCl3 dissolved in . did. Next, Ki/Lenol Oren Aqueous dichloromethane (Img/mL) was added, and GdC1z solution M was added dropwise until the indicator turned from yellow to purple (pH (6)). The pH was adjusted to between 7 and 8 with aqueous solution and HCI if necessary. reaction mixture The compounds were passed through a 0.2211 sterile filter into sterile serum vials. The final concentration, which ranges from 0.02 to 0.5M, depends on the initial concentration of the reactants and the volume of base and acid added for the pH:A section. A mass spectroscopic sample of the product was obtained by HPLC (4,6X 150PRP-1 column; flow rate 1 mL/min: 5-45% acetonitrile in water gradient in 15 minutes). LSIMS [M+old degree parent ion peak was observed between 815 and 824, with the highest intensity at 819. The percentage of peak intensities were as expected by theory Cr5tlf fQGdN50+2. This chelate of Gd-DTPA-34-DME was prepared from DTPA-(3,4-DMPE) in the same manner as Gd-DTPA-<3-11T^)2 in Example 17 above. 2 and GdCl3. L blood history soil Gd-DTPA-3-HTA 2 and Gd-DP^-3-DMPE Magnetic resonance imaging was performed using a C5I2 Tesla Image+ (GE, Inc., Fresont, CA) equipped with a 5 cm diameter distributed capacitance imaging coil (formerly 5 cm diameter distributed capacitance imaging coil). D1 emphasis (TR300/TE 6:NEX 4) spin echo system I used columns. The image matrix is 128 × 256, the slice thickness is 3 mm, and the projection area is The field-of-view was 90 mm. Anterior (heart location) and posterior (kidney location) coronal plane images were used. Spray Goudry rats (250-3 sog; n; 4 for each contrast agent) were anesthetized with ketamine hydrochloride (90 mg/kg) and diazepam (10@g/kg) and an intravenous catheter was inserted into the lateral tail vein. Installed. Anesthesia was maintained during imaging with bendoparbital delivered through the peritoneal catheter. The anesthetized animal was placed in an imaging coil and secured with tape. Next, the motion Place the filled coil in the magnet bore and I made rough adjustments to the venue. Pre-injection contrast images were obtained. Contrast medium (100μ pot. l/kg) was then injected through the lateral tail vein catheter and further images were obtained at various intervals up to 90 minutes after injection. Contrast agent enhancement was determined by measuring the average knobal intensity (S+) within the region of interest (Ro+) specified by the operator. These were normalized to the pre-injection value for each Rot according to the following formula: % enhancement = 100 x (S+..s+ -5lo1*)/5Io = heart, lung, kidney, Liver and skeletal muscle control Last enhancement (mean ± standard deviation, n·4) as a function of time is shown in Figures 9-13, respectively. Gd-DTPA-(3-HTA)2 also tends to produce higher lung enhancement (186%±51% vs. 141%±4%). However, the difference in effects produced by the two drugs was smaller than in the heart (compare Figures 9 and 10). There was no significant difference in renal enhancement (Figure 11). Both drugs produced approximately 175% potentiation 5 minutes after injection. The level of enhancement gradually decreased to approximately 100% over a period of 70 minutes. Both drugs produced approximately 50% enhancement in the liver immediately after injection (Figure 12). Furthermore, the time course of potentiation was very similar, with the level of potentiation dropping to about 30% in the first 20 minutes after injection for both drugs. Skeletal muscle showed a peak enhancement of approximately 40% immediately after injection. Enhancement of both drugs for one hour The lines were almost identical; they each dropped to pre-injection levels at 80 minutes (Figure 13). Typical images using each drug are shown as MHI photographic images in Figures 14A and 14B and 15A and 15B. [1] In vivo study of Gd-DTPA-L-PheOEt 2 and Gd-DTPA-D-PheOE L 2 Two contrast agents Gd-DTPA-(L-PheOEt) 2 and Gd-DTPA-(D The magnetic resonance imaging properties of -PheOE[)2 were compared as in the previous example using groups of 4 and 5 animals, respectively. Figures 16-20 illustrate contrast enhancement versus time variation for each drug in heart, lung, kidney, liver and skeletal muscle, respectively. Typical images using each drug are shown as MRI photographic images in Figures 21A and 21B and 22A and 22B. 87, 4 - Andu・uJ艷東二ΩGd-DTPA-1,-PheOEL and Gd-TPA--PheOEt"L迦-丞"L-diluted plasma or pH 7,4 HEPES buffer The rate of hydrolysis of the esters in the solution was determined by adding 10% by volume of G d-153 radiolabeled 0.025M chelate solution and or by incubation at 25°C. (Take aliquots at IJ'l intervals for each time, tlPLc [PRI'-1 column, water-acetonitrile column, Le gradient; measured with ZSwμ ammonium formate, l for transfer of p17. L- or is 00-bis(ester) #Jl ffin 11 corresponding mono(ester) Hydrolysis to mono(acid) and then to bis(acid) is very slow, with a half-life of each step on the order of days. However, in the plasma of dogs, LL-bis(ester) is very rapidly hydrolyzed to mono(ester) (see below). It has much greater resistance to water decomposition than the Essentially no reaction was observed during this period. In contrast, DD-bis(ester) is less likely to undergo ester hydrolysis under these conditions. Even the first stage of the solution has low resistance (see below). iヱ) (7) The phase-wise stability of the bis(ester) to hydrolysis with aqueous 1α suggests that the plasma reaction is enzyme-catalyzed. In addition, Since the rate of water splitting is very slow, it is clear that the mono(acid)-mono(ester) Always a poor basis. This is due to the change in the effective N’A of the chelate (from 0 to -1) and/or the change in the effective N’A of the chelate (from 0 to -1) and/or This is due to the con7, I-no/ran change in the molecule based on the coordination of Gd by the phenylalania carboquinrad group i). Changing the stereochemistry of the amino acid moiety of the chelate to the non-natural D-enantiomer causes a faster or greater reduction in the IXI water splitting of the ester in plasma. A mixture of ketamine hydrochloride (90 mg/kg) and noazepam (2 mg/kg) was administered to Sadao's 4-year-old Spray Goo Dolly rats. Inject the compound into the abdominal cavity! After 14 hours of anesthesia, a 23-gauge cannula was attached to the lateral tail vein. A midline incision was then made and a small cut was made above the bile duct to expose the bile duct. The bile duct was loosely ligated at the proximal 2+i1 point. A small incision is made distally and the bile duct is incised with a 15 cm long PE-1o polyethylene tube tied in two places. Cannylate was inserted. A second tube was placed in the bladder and secured with a purse string Ia fitting. The n-wall tissue flap was closed and the incision was covered with gauze. Heparinized (1 unit/1.) saline was infused through the intravenous catheter at a rate of 0.075 sL/min. After a 15 minute stabilization period, the infusion was stopped long enough to administer a bolus dose of Gd-153 (0.1 m5 ol/kg) and then resumed. Bile and urine Sanoblu, radioactive 1jl! ! built Samples were taken into tared test tubes at regular intervals before and after injection of the contrast medium. The net fl amount of these Sanoburu was measured. The concentration of Gd-1 53 present in each sample was measured using a TI-type gamma ray counter 1'4 (chamber gamma counter). The uncorrected steps were corrected for t('y kg/d) and normalized to the total amount of Gd-153 injected. The results obtained regarding the number of contrast agents used Summarize the results (cumulative excretion for 1 hour; average of 3 animals): Yujubukun' L Claim Gd-T) TI'^-(1,-Phe)2 9.3 Sat1.3 t6. s:V:B 7Gd-t)TP^-(1,-PheOF, t)230. S soil 7.4 t6.9±80Gd-DTPA-(D-PheOEt)251.3±5.1 39.2 ±5.5Gd-DTPA-(L-PheNHCH3h 3.5 soil0.4 TO, 9± 65 Only a few embodiments of the present invention, shown and described herein as 1, include amino acid-containing hepatobiliary contrast agents or have undergone various modifications and improvements in their use in abdominal magnetic resonance imaging. It will be apparent to those skilled in the art that modifications may be made without departing from the spirit and spirit of the invention. The R or R1 group of Sugand L is an aromatic or heteroaromatic moiety. The number of officers included in the appointment. All such modifications and variations within the scope of the appended claims are meant to be practiced by the present invention. Special table Hei 7-502725 (16) (-11- FIG, 5A Continuation of front page (51) Int, C1,' Identification code Internal serial number C07F 11100 A 9155-4H13100A 9155-4H GOIR33/28 (81) Designated countries EP (AT, BE, CH, DE. DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE), CA, JP I (72) Inventor Eason, Robert Gee. United States of America California 94617゜San Francisco, Pages treat

Claims (1)

[Claims] 1. A contrast agent for magnetic resonance imaging, the contrast agent containing the following complexes or pharmaceutically acceptable salts thereof: LM where M is an atomic number of 21 to 31 metals, runs with atomic numbers from 57 to ε2 a metal (II) or (III) independently selected from the group consisting of tanide metals; and L is a polydentate organic chelate moiety of structural formula Ia: ▲Mathical formula, chemical formula, table, etc.▼(Ia) where O, J, Y and Z and λ and X are , when present, are each independently selected from -CH2(C=O)-〇H, or -CH2(C=O)NHCH-(R)-(A): where O, J , X, group, heteroaromatic group, substituted heteroaromatic group, alkylene heteroaromatic group, or at least one of O, J, Y and Z is -CH2(C=O)-NHCH(R)-A; and A is independently selected from -(C=O)OR1, -(C=O)-N-(R2)R3, or R4, where R4 is -CH2-ary independently selected from -CH2-substituted aryl, -CH2CH2-aryl, or -CH2C H2-substituted aryl, when A is -(C=O)OR1 and R1 is hydrogen; is not hydrogen; R1, R2 and R3, when present in each A of O, J, X, X, Y and Z, independently from hydrogen, alkyl having 1 to 7 carbon atoms, phenyl or benzyl selected: and M is selected from 0, 1, 2 or 3, and n is selected from O or 1. A contrast agent. 2. The α-amino acid (α-amino acids), if present, is in the D or Rhino configuration. 2. A contrast agent according to claim 1, wherein the contrast agent is selected from: 3. At least one of J or Z is -CH2(C=O)NHCH=(R)-(A), A is -(C=O)-N(R2)-R3, and R2 and R3 3. A contrast agent according to claim 2, wherein is independently selected from H or alkyl having 1 to 6 carbon atoms. 4. When O and Y are -CH2(C=O)-〇H, and X and XI are present, , -CH2(C=O)-〇H, and is O or I, and n is ○. The contrast agent according to claim 3. 5. The contrast agent according to claim 4, wherein one of R2 or R3 is hydrogen. 6. 6. The contrast agent of claim 5, wherein both J and Z are each -CH2(C=O)NH(CH)-(A). 7. 5. The contrast agent according to claim 4, wherein R2 and R3 are each alkyl. 8. The contrast agent according to claim 7, wherein J and Z are each -CH2(C=O)NHCH-(R)-(A). 9. At least one of R or A comprises an aryl group, substituted aryl group, alkylene aryl group, alkylene substituted aryl group, heteroaromatic group, substituted heteroaromatic group, alkylene heteroaromatic group, or alkylene substituted heteroaromatic group , request The contrast agent according to claim 1. 10, O, X, XI and Y are each -CH2(C=O)-〇H, and and at least one of J and Z is -CH2(C=O)NHCH(R)-A, where A is -CH2-aryl, -CH2-substituted aryl, -CH2CH2-aryl, or -CH2CH2-substituted aryl, where aryl is selected from phenyl or naphthyl, and the substituted aryl is independent from halogen, alkyl having 1 to 7 carbon atoms, hydroxy, alkoxy having 1 to 7 carbon atoms, nitro, nitroso, amino or trifluoromethyl. selected for 2. The contrast agent according to claim 1, wherein the contrast agent is substituted with 1 to 3 groups selected from the group consisting of 1 to 3 groups. 11. A is -CH2-substituted aryl, where aryl is phenyl The contrast agent according to claim 10, wherein the contrast agent is substituted with 1 to 3 alkoxy groups or hydroxy groups. 12. m is O or I, n is O or I: O, X, XI and Y, if present, are each -CH2(C=O)-OH, and at least I of J and Z is -CH2-(C=O)NH-CH(R)-A, and this The shaping agent according to claim 11, wherein R is hydrogen and A is -CH2 substituted aryl substituted with two alkoxy groups. 13. The contrast agent according to claim 12, wherein J and Z are -CH2(C=O)NH(R)-A. 14. 12. A contrast agent according to claim 11, wherein A is -CH2-substituted aryl, where aryl is phenyl and is substituted with two methoxy groups. 15. m is O or I, n is O or I; O, X, XI and Y, if present, are each -CH2(C=O)-○H; At least one is -CH2(C=O)NH-CH(R)-A, where R is water. and A is -CH2-aryl substituted with two hydroxyl groups. 16. 16. The contrast agent according to claim 15, wherein J and Z are each -CH2(C=O)NH(R)-A. 11. m is O or I, n is O or l; O, X, xI and Y, if present, are each -CH2(C=O)-○H; and at least l of J and is -CH2(C=O)NHCH(R)-A, where R is hydrogen and A is -CH2-aryl, the aryl is phenyl, and the 3 and 4 positions of the ring are hydroxyl group or two methoxy groups at the 3 and 4 positions of the ring. The contrast agent according to claim 11, which is substituted with a cy group. 18. A contrast agent for magnetic resonance imaging, the contrast agent comprising the following complexes or drugs. including chemically acceptable salts thereof: LM where M is a metal with an atomic number of 21 to 31, a metal with an atomic number of 39 to 50, a lanthanide with an atomic number of 57 to 71; a metal (ll) or (III) ion independently selected from the group consisting of metals, and metals with atomic numbers 72 to 82; , L is a multidentate organic chelate moiety of structural formula Ia: ▲ has a mathematical formula, chemical formula, table, etc. ▼ (Ia) where O, J, X, XI, Y and Z are each independently , -CH2(O=O)-C1 1, or -CH2(C=O)NHCH-(R)-A where A is COOR1, and each R of O, J, X, X, Y and Z is hydrogen or alkyl O, J, Y and less of Z and one of each of O, J, X, is hydrogen, having 1 to 7 carbon atoms and m is selected from 0, 1, 2 or 3, and n is selected from 0 or 1. 19. α-amino acids (α-amino acids) are in the D- or L-configuration, or 19. A contrast agent according to claim 18, selected from a mixture thereof. 20. According to claim 19, M is a paramagnetic metal ion (II) or (III). Contrast agent. 21. O and Y are each -CH2(C=O)NHCH(R)COOR1, J, X, X1, and Z are each -CH2(C=O)OH, and The contrast agent according to claim 20, wherein m and n are each 0. 22. The contrast agent of claim 2I, wherein R is -CH2-phenyl and R1 is hydrogen. 23. M is an (llI) metal ion, and ○ and Y are each -CH2-(C=O)NHCH(R)-COOH, where R is benzyl, p-hydroxyphenylmethyl, 2 -Methylnaphthyl or 3-methylisodori J and Z are each -CH2(C=O)-OH, 0 or 1, and X is -CH2(C=O)OH, and 19. A contrast agent according to claim 18. 24. 24. A contrast agent according to claim 23, wherein the metal ion is selected from chromium (III), iron (III), cobalt (III), gadolinium (III) or manganese (II) or (III). 25. 19. The shaping agent LM according to claim 18, selected from the group of compounds of structural formula 1 consisting of the group: M is iron(III), chloro(III), manganese(II), dysprosium(III). ) or gadolinium(III); Q is -CH-(C=O)NHCH(R)-COOH, R is -CH2-phenyl, J, Y and Z are each -CH2-(C= O)OH, and m and n are each 0; Q is -CH2(C=O)NHCH(R)-COOH, R is -CH2-phenyl, J, X, Y and Z are each -CH2-( C=O)OH, and m is I and n is O; Q is -CH2(C=O)HHCH(R)-COOH, R is -CH2-phenyl, and J, X, XY and Z are -CH2(C=O)OH, and m and n are each I; ○ and Y are each CH2(C=O)NH-CH-(R)-COOH, R is -CH2-phenyl, J and Z are each -CH2COOH, and m and n are each 0; and Q and Y are each -CH2(C=O)-NH-CH-(R)-COOH, R is CH2phenyl, J , X and Z are each -CH2COOH, and m is 1 and n is 0. 26. At least one R or one A is an aryl group, substituted aryl group, a 19. The contrast agent of claim 18, comprising an alkylene aryl group, an alkylene substituted aryl group, a heteroaromatic group, a substituted heteroaromatic group, an alkylene heteroaromatic group, or an alkylene substituted heteroaromatic group. 27. A composition useful as a contrast agent for magnetic resonance imaging of tissue of a living subject, the composition comprising the following LM or pharmaceutically acceptable fields thereof: :LM where M is independent from the group consisting of metals with atomic numbers 21-31, metals with atomic numbers 39-50, lanthanide metals with atomic numbers 57-82, and metals with atomic numbers 72-82. It is a metal (lI) or (III) ion that can be selected as and L is a polydentate organic chelate moiety of structural formula la: ▲ mathematical formula, chemical formula, table, etc. ▼ (Ia) where Q, J, Y and Z and X and XI are present where O, J, X, ．． , Y and Z each R is hydrogen or alkyl group, aryl group, substituted aryl group, alkylene aryl group, alkylene substituted aryl group, Q, J, Y and Z are independently selected from organic structures comprising a lyl group, a heteroaromatic group, a substituted heteroaromatic group, an alkylene heteroaromatic group, or an alkylene substituted heteroaromatic group; At least one is -CH2(C=0)-NHCH(R)-A; A is independent from -(C=0)OR1, -(C=O)-N-(R2)R3, or R4 where R4 is -CH2-aryl, -CH2-substituted aryl aryl, -CH2CH2-aryl, or -CH2CH2-substituted aryl however, if A is -(C=O)OR1 and R1 is hydrogen, then R is not hydrogen; R1, R2 and R3 are O, J, X, X, Y and Z. and m is selected from 0, 1, 2 or 3, and n is O. or a composition selected from 1. 28. A claim in which O and Y are each -CH2(C=O)HHCH(R)COOR1, J and Z are each -CH2(C=O)OH, and m and n are each 0. The composition according to item 27. 29. 29. The composition of claim 28, wherein R is -CH2-phenyl and R1 is hydrogen. 30. M is a (III) metal ion, ○ and Y are each -CH2-(C=O)NHCH(R)-COOH, where R is benzyl, p-hydrocarbon selected from roxyphenylmethyl, 2-methylnaphthyl, or 3-methylindolyl, J and Z are each -CH2(C=O)-〇H, and m is up to 0. or I, and X is -CH2(C=O)OH and n is O. 31. 28. A contrast agent according to claim 27, wherein the metal ion is selected from iron(III), cobalt(III), chromium(III), gadolinium(III) or manganese(II) or (III). 32. 28. The composition of claim 27, which is useful as an injectable contrast agent at a concentration of from about 0.5 to 5000 micromoles/kilogram of human body weight. 33. Polydentate organic chelate compounds of structural formula Ia or pharmaceutically acceptable thereof Their salts (salts): ▲Mathematical formulas, chemical formulas, tables, etc.▼(Ia) where Q, J, Y and Z and X and XI, if present, each independently represent -CH2(C =O)-〇H, or -CH2(C=O)NHCH-(R)-(A), where each R of Q, J, X, X, Y and Z is hydrogen, or alkyl group, aryl group, substituted aryl group, alkylene aryl group, alkylene substituted aryl group, group, heteroaromatic group, substituted heteroaromatic group, alkylene heteroaromatic group, or or an alkylene-substituted heteroaromatic group, at least one of Q, J, Y and Z is -CH2(C=O)-NHCH(R)-A; : and A is independently selected from -(C=O)OR1, -(C=O)-N-(R2)R3, or R4, where R4 is -CH2-aryl, -CH2 -substituted aryl, -CE2CH2-aryl, or -CH2CH2- substituted aryl, where A is -(C=O)OR1 and R1 is water. R1, R2 and R3, when present in each A of Q, J, X, X, Y and Z, are hydrogen, alkyl having 1 to 7 carbon atoms, independently selected from phenyl or pendyl; and m is selected from 0, 1, 2 or 3, and n is selected from 0 or 1. 34. 34. A contrast agent according to claim 33, wherein the alpha-amino acid (alpha-amino acids), when present, is selected from the D- or Rhinomorphic configuration, or a mixture thereof. 35. At least one of R or A includes an aryl group, a substituted aryl group, an alkylene aryl group, an alkylene substituted aryl group, a heteroaromatic group, a substituted heteroaromatic group, an alkylene heteroaromatic group, or an alkylene substituted heteroaromatic group, 34. A contrast agent according to claim 33. 36. A method of examining human tissue in a diagnostic manner, the method comprising: (a) administering a contrast agent of structural formula Ia of claim 1 to about 0.5 to 5000 micromoles/kg of human body weight; (b) placing the human in a magnetic field and applying a radiofrequency beam to the torso and abdomen of the subject of step (a) such that nuclear magnetic resonance is detected; A method comprising the steps of: applying energy; and (c) dividing the resulting imaged nuclear magnetic resonance signal. 37. 34. A method of preparing a chelate compound according to claim 33 of structural formula (Ia). So, how to cough: (a) Structure of formula 11: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) Here, A and D are CH2(C=O)-〇H. , the amino acid or ester of the structure H2N-CH(R)-COOR1, or the amide or CH2CH2-CH2-A position of the structure 112N-C11(R)COHR2R3, as defined herein above. Derivatives of structures that are substituted aryl, where R is an alkyl group, aryl group, alkylenearyl group, heteroaromatic group, or an organic structure containing an alkyleneheteroaromatic group, and R1 or R3 is hydrogen , alkyl having 1 to 7 carbon atoms, phenyl or are independently selected from benzyl and are selected from 0, 1, 2 or 3. and n is selected from 0 or 1, and in an anhydrous dipolar aprotic solvent at between about 50 and 150°C for about 2 to 10 hours. and (b) removing the solvent and recycling the compound of structural formula I. A method of incorporating; 38. The dipolar aprotic solvent is dimethylformamide, diethylform amide, hexamethylphosphoramide, dimethyl sulfoxide or mixtures thereof, and the heating temperature is between about 90 and 100°C and the time is between about 4 and 7 hours. 38. The method of claim 37. 39. M is selected from iron(ll), iron(III) or gadolinium(III) and O and Y are each -CH2(C=O)NHCH(R)-(COOR1), where R is benzyl and R1 of Q and Y are each hydrogen, or R1 of Q is H and R1 of γ is ethyl, or Q and 2. The contrast agent of claim 1, wherein R1 in and Y is each ethyl, and J, X, X and Z are each -CH2(C=O)OH. 40. M is selected from iron(II), iron(ll), or gadolinium(lII), and Q and Y are each -CH2(C=O)NHCH(R)-(COORI), where R is phenyl , and R1 of Q and Y are each water or R1 of Q is H and R1 of Y is ethyl, or Claim 1, wherein R1 of O and Y are each ethyl, and J, X, X and Z are each -CH2(C=O)OH, and M is 1 and n is O. Contrast agent described in 41. M is 1 and n is O The contrast agent according to claim 1. 42. The contrast agent according to claim 1, wherein R is independently selected from the following: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Detailed description of the invention