MXPA97005823A - Agents of contrast for formation of images for diagnosis that exhibit a greater retention in the san - Google Patents

Abstract

The present invention relates to contrast agents for diagnostic imaging with prolonged retention in the blood. In particular, the present invention relates to novel compounds that are characterized by an image enhancing portion (IEM), a plasma protein binding portion (PPBM), and a prolonged portion of the half-life in the blood (BHEM). . The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using the compounds and compositions for prolonging the half-life in the blood and to enhance the contrast in diagnostic imaging.

Description

AGENTS OF CONTRAST FOR FORMATION OF I MÁGENS FOR DIAGNOSIS THAT EXHIBIT A GREATER RETENTION IN THE BLOOD BACKGROUND OF THE INVENTION Technical Field The present invention relates to contrast agents for diagnostic imaging. In particular, the present invention relates to new compounds that exhibit better retention in the blood. Compounds comprise: a) an image enhancing portion (or signal generator) (I EM); b) a plasma protein binding portion (PPBM); and c) a prolonged portion of the half-life in the blood (BHEM). The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for prolonging the half-life in the blood and for improving contrast in diagnostic imaging. BACKGROUND OF THE INVENTION Diagnostic imaging techniques such as magnetic resonance imaging (MRI), X-ray, nuclear radiopharmaceutical imaging, ultraviolet / visible / infrared light, and ultrasound, have been employed for diagnosis in medicine several years. In some cases the use of contrast media to improve the quality of the image or to provide specific information has continued to be used for my entire years. In other cases, such as light imaging or ultrasound imaging, the introduction of contrast media is imminent. The contrast agent must interfere with the wavelength of the electromagnetic radiation used in the imaging technique, alter the physical properties of the tissue to provide an altered signal or, as in the case of radiopharmaceuticals, provide the source of radiation same Commonly used materials include organic molecules, metal ions, salts or chelates, particles (especially iron particles) or labeled peptides, proteins, polymers or liposomes. After administration, the agent can diffuse in a non-specific manner through all compartments of the body before being metabolized and / or excreted, these agents are generally known as non-specific agents. Alternatively, the agent may have a specific affinity. for a compartment, cell, organ, or tissue of the body in particular; these agents can be mentioned as target agents. It is convenient that the agents that are injected or absorbed in the body and distributed by the blood, have an appropriate half-life in the blood. Although, the long half-lives (ie days or weeks) are unnecessary in clinical situations of imaging and are possibly dangerous (due to the increased likelihood of toxicity and metabolic decomposition to more toxic molecules) , short half-lives are also not convenient. If the enhancement or improvement of the image lasts for a too short period of time, it is difficult to acquire a high-quality image of the patient. In addition, the rapid disappearance of an agent directed to the target will reduce the amount of agent available to bind to the target site and will therefore reduce the "brightness" of the desired image site. The increase in the half-life in the blood of an imaging agent comprises interfering with one or more of the following evacuation mechanisms: 1) Renal excretion. Molecules of molecular weight below sixty thousand Daltons, particularly small molecules, can be removed from the blood by non-specific glomerular filtration in the kidneys. If the molecules exhibit a certain degree of binding with the plasma proteins or with other constituents of the blood, only that free fraction will be produced for filtration, and the rate of renal excretion will be reduced accordingly. 2) Hepatocellular absorption. If a molecule has a hydrophobic character, some fraction of the complex is collected by the cells of the liver and is excreted to the bile. In general, the greater the degree of hydrophobicity that a molecule possesses, the greater the absorption rate of hepatocytes. Although hydrophobicity also leads to the binding of plasma protein and a reduction in the apparent free concentration of the molecule, the hepatocellular uptake rate may still be very high (D. Sorrentino et al., Prog. Liver Disease, pp. 203 -24 (1990)), which reduces the half-life in the blood. The reduction of the half-life in the blood may be accompanied or not by an increase in total hepatobiliary excretion, that is, by the fraction of the administered dose that eventually appears in the faeces. This latter amount is determined by many factors other than the hepatocellular absorption regime, including the degree of cytosolic protein binding within the hepatocyte, affinity for canalicular transport systems (hepatocytes to bile), effects on the bile flow and enterohepatic recirculation. The prolongation of the half-life in the blood must be demonstrated by sampling the blood or plasma, and not simply by measuring the decrease in total hepatobiliary excretion. Similarly, simply obtaining and measuring a significant binding of the plasma protein with a contemplated contrast agent is not sufficient to show that its half-life in the blood is longer due to a lower renal excretion. 3) Endothelial reticulum (ER) or other systems. High molecular weight substances such as liposomes, polymers, proteins, and particles, can be rapidly evacuated from the blood by recognition (eg, ozonation or protein coating prior to cell uptake) and absorption into cells, particularly cells. RE cells of the liver (Kupfer cells), the spleen and the spinal cord. Two general strategies have been described, in order to increase the half-life in the blood for the imaging agents. One of them is to covalently bind the image forming agent through strong bonds or metabolizable chemical bonds to a polymer, protein, liposome, or large molecular weight particle. For example, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) has been ligated with human serum albumin (HSA), poly-L-lysine, or dextran (AN Oksendal et al., J. Magn. Reson. Imaging, 3 , pages 157-165 (1993); S. M. Rocklage, "Contrast Agents", Magnetic Resonance Imaging, Mosby Year Book, pages 372 to 437 (1992). This is done to reduce the rate of glomerular filtration in the kidneys and to retain the agent in the blood. However, this can lead in the long term to agent retention. In addition, tightly linked imaging agents can release potentially toxic by-products, such as free metal ions at the metabolism sites for the macromolecule. In addition, large conjugates can be difficult to direct to specific sites in the body. The second strategy has been applied to liposomes, polymers, proteins and particles that are usually removed quickly from the circulation by the ER system or by other means. The placement of large hydrophilic polymers such as polyethylene glycol (PEG) on the surface of the substance reduces absorption in the ER or in other systems (C. Tilcock et al., Biochimica et Biophysica Acta. 1148, pages 77-84 ( 1993), A. Bogdanoy et al., Radiology, 187, pages 701-706 (1993) The hypothesis has been raised that large strongly hydrated groups interfere with the molecular procedure required for the recognition and absorption of substances. The disadvantages of this strategy include: a) High cost and cumbersome manufacturing procedures; b) Lack of objectivity of the great conjugates; c) The applicability seems to be limited to substances of great molecular weight. A particular challenge is that of the small molecules that constitute the target, which has a certain lipophilic character. These can undergo rapid hepatocellular absorption and evacuation of the blood, possibly reducing the "brightness" at the site that is the target. This is a particular problem in which lipophilicity is required, to achieve production in the target constituted by proteins or other biological objectives. A special case of this problem is the development of small molecule blood collection agents. Non-specific current agents of small molecules, such as Gd-DTPA for MR I, have a relatively rapid evacuation of blood and therefore are not optimal for imaging blood vessels (ie MR angiography) or for control the flow of blood to the heart, brain, tumors or other organs or injuries. Lipophilic agents directed to plasma proteins are known in the art. See U.S. Patents Nos. 4,880,008 and 5,250,285. Although these agents bind with plasma proteins, in particular with human serum albumin, they may also be subject to rapid hepatocellular absorption and a reduction in half-life in the blood. There is still a need to find contrast agents that are retained in the blood for a prolonged period of time.

SUMMARY OF THE INVENTION The present invention provides contrast agents for the formation of diagnostic images, which exhibit a better retention in the blood. The new compounds comprise: a) An image enhancing portion (or signal generator) (I EM); b) A plasma protein binding portion (PPBM); and c) A prolonged portion of the half-life in the blood (BHEM).

The present invention also relates to pharmaceutical compositions comprising compounds and methods of using the compounds and compositions for prolonging the half-life in the blood, and to improve the contrast in diagnostic imaging. These contrast agents exhibit reduced regimens of both renal absorption and hepatocellular absorption and no apparent absorption in the ER system. The agents can be directed to the collection of blood or to any other biological component. Since the agent disappears less quickly in the bloodstream, lower doses can be used with a greater margin of safety. The realization is general, both for large and small molecules.

DETAILED DESCRIPTION OF THE INVENTION In order that the present invention can be fully understood, the following detailed description will be established. The term "specific affinity" or "molecular affinity" as used in the present invention, refers to the ability of the contrast agent to be absorbed, retained, or bound to a particular biological component to a degree substantially greater than other components. . It is said of the contrast agents that have this property, that they are "directed" to the component "that constitutes the objective". The present invention relates to new compounds that enhance the contrast in diagnostic imaging. These compounds comprise: a) an image enhancing (or signal generating) portion (IEM); b) a plasma protein binding portion (PPBM); and c) a prolonged portion of the half-life in the blood (GHEM). Imaging for diagnosis includes, but is not limited to, MRI, X-rays, nuclear radiopharmaceutical imaging, ultraviolet / visible / infrared light, and ultrasound.

Image Enhancing Portion ("IEM") In accordance with the present invention, the first IEM domain may be any chemical compound or substance that is used to provide the signal or contrast in the images. The signal enhancing domain may be an organic molecule, a metal ion, a salt or a chelate, a particle (especially iron particles), or a labeled peptide, protein or polymer or liposome. A particularly useful IEM is a physiologically compatible metal chelate compound consisting of one or more cyclic or non-cyclic organic chelating agents, complexed with one or more metal ions with atomic numbers 21 -29, 42, 44, or 57- 83 For X-ray imaging, IEM can consist of iodinated organic molecules or heavy metal ion chelates of atomic numbers from 57 to 83. Examples of appropriate compounds are described in the publication of M. Sovak Editors "Radiocontrast Agents ", Sprinoer-Verlao. pages 23 to 125 (1984), and in U.S. Patent No. 4,467,447.

For ultrasound imaging, the IEM consists of gas-filled bubbles, such as Albunex, Exhovist, or Levovist, or metal particles or chelates in which the metal ions, have atomic numbers 21 -29, 42, 44, or 57-83. Examples of suitable compounds have been described by Tyler and Associates, in Ultrasonic Imaging, 3, pages 323 through 329 (1982) and by D. P Swanson, in "Enhacement Agents for Ultrasound: Fundamental", Pharmaceuticals in Medical I imagine, pages from 682 to 687 (1990). For radiotherapy or nuclear radiopharmaceutical imaging, the IEM consists of a radioactive molecule. The preferred ones are Tc chelates, Re, Co, Cu, Au, Ag, Pb, Bi, In, and Ga. Tc-99m chelates are even more preferred. Examples of the appropriate compounds have been described by Rayudu GVS, in Radiotracers for Medical Applications. I, page 201 and by D. P. Swanson and Associates, in the edition Pharmaceuticals in Medical Imagino, pages 276 to 644 (1990). For imaging with ultraviolet / visible / infrared light, the IEM consists of a metal-ligand complexko of a paramagnetic form of a metal ion with atomic numbers 21 -19, 42, 44, or 57-83. In order to effectively improve nuclear magnetic resonance (NMR) imaging, the complex must be able to improve the 1 / T-? Relaxation regimes. (longitudinal, or rotating lattices) and / or 1 T2 (transverse, or rotation-rotation) of water protons or other spectroscopic or image-forming nuclei, including protons, P-31, C-13, Na -23 or F-19 in other biomolecules or injected biomarkers. The relaxations R-j and R- | , are defined as the capacity to increase 1 / T-j or I T2 respectively, for each nM of metal ion; the units are mM.1 S.-5. For the most common form of clinical MRI, which is MRI of water protons, relaxation is optimal when the paramagnetic ion attached to the chelating ligand, still has one or more coordination sites open for water exchange (RB Lauffer, Chemical Reviews, 87, pages from 901 to 927 (1987)). However, this must be balanced with the stability of the metal chelate (see below), which generally decreases with increasing number of open coordination sites. Therefore, it is more preferred that the complex contain only one or two open coordination sites. In addition to increasing the 1 / Tj or I / T2 of tissue nuclei through dipole-dipole interactions, MRI agents can affect two other magnetic properties, and therefore can be used clinically: 1) One particle of iron or a metallic chelate of high magnetic susceptibility, particularly the chelates of Dy, Gd, or Ho, can alter the intensity of the MRI signal of the tissue, by creating microscopic magnetic susceptibility (A. Villringer and Associates, Magn. Reson Med 6, p 164-174 (1988)). No open coordination site is required in a chelate for this application. 2) An iron particle or a metal chelate can also be used to change the resonance frequency of water protons or other spectroscopic or imaging cores, including protons, P-31, C-13, Na-23 or F-19, of other biomolecules or injected biomarkers. In this case, depending on the cores and the strategy used, 0 to 3 open coordination sites can be used. The preferred paramagnetic metal is selected from the group consisting of Gd (11), Fe (11), Mn (II and III), Cr (11), Cu (II), Dy (III), Tb (III). , Ho (lll), Er (lll) and Eu (ll l), the most preferred one is Gd (l ll). Although the paramagnetic metal is used in the form of a complex, toxic effects may still arise due to the dissociation of the metal ion from the complex. The organic chelating ligand should be physiologically compatible. The molecular size of the chelating ligand should be compatible with the size of the paramagnetic metal. Therefore, gadolinium (III), which has a crystalline ionic radius of 0.938 x 10"1 0 m (0.938A), requires a chelating ligand greater than iron (III), which has a crystalline ionic radius of 0.64. x 10-1 0 m (0.64A) In general, the degree of toxicity of a metal chelate is related to its degree of dissociation in vivo before excretion.The toxicity generally increases with the amount of free metal ion. complexes in which kinetic stability is low, a high thermodynamic stability (a constant formation of at least 10 ^ M "1 and more preferably at least 1? 20 M" 1) is desirable, in order to minimize dissociation and its consequent toxicity.For complexes in which the kinetic stability is comparatively higher, dissociation can be minimized with a constant lower deformation, that is, 10"^ M" 1 0. The toxicity is also a function of the amount of coordination sites open in the complex. The fewer the coordination sites, there will be less general tendency for the chelating agent to release the paramagnetic substance. Therefore, preferably the complex contains two, one or zero open coordination sites. The presence of more than two open sites will, in general, unacceptably increase the toxicity by releasing the metal ion in vivo. Many chelating ligands suitable for MRI agents are known in the art. These can also be used for metal chelates for other forms of biological imaging. For imaging with MRI, the preferred IEMs include: Plasma Protein Linker Portion ("PPBM") In accordance with the present invention, the second component of the contrast agents thereof is a PPBM. This portion of the compound binds the contrast agent with the plasma porteins and reduces the renal excretion regimen. The proteins of the plasma of interest include albumin, particularly human serum albumin (HSA), which binds the molecules that possess certain lipophilic portions and any negative charge to the physiological pH and negatively charged partial or fluorines or sulfur, or partial fluorine; alpha acid glycoprotein, which binds mainly positively charged molecules, globulins, which bind oidal ester molecules; and lipoproteins, which bind lipophilic or fatty acid molecules. Therefore, the PPBM must be appropriately selected in order to achieve binding with the appropriate protein. Since HSA is present in the highest serum concentration and has a high affinity and ability to bind a wide range of molecules, this is the preferred protein plasma to be used to increase half-lives in the blood. HSA also constitutes the preferred plasma protein as a target, because it binds to the charged molecules hegatively, which tend to be less toxic than the positively charged molecules. To link to HSA, a wide variety of hydrophobic or amphiphilic substances, such as PPBM (U. Kragh-Hansen, Pharm. Rev., 33, page 17 through 53 (1981; XM He and Associates, Nature, may be useful. , 358, page from 209 to 215 (1 192), DC Carter, Adv. Protein Chem., 45, page from 153 to 203 (1994).) These include, but are not limited to aliphatic or aryl groups with 1 to 60 carbons, as well as any amount of nitrogens, oxygens, sulfurs, halogens, alkyl groups, amides, esters and sulfonamides as substituents, Alternatively, the PPBM may be a peptide containing hydrophobic amino acid residues and / or substituents with or without hydrophobic or hydrophilic termination groups. In order to obtain 10% of the binding in the plasma, the preferred PPBM has at least 7 carbon atoms, more preferably 13, and even more preferably 18 carbon atoms. As stated previously , to link to HSA, a wide range of hydrophobic substances such as PPBM may be useful. In general, the binding affinity to HSA and possibly other proteins will increase with the hydrophobicity of PPBM. Theoretical estimates of the hydrophobicity of a substituent such as a PPBM can be obtained by calculating the contribution to the logarithmic division coefficient of octanol-water (or octanol-regulator) (logarithm P) for the same PPBM using the Hansch constant TI for substituents . See A. Leo and C. Hansch, "Partition Coefficients and their Uses," Chemical Reviews, 71, pages 525 through 616 (1971); K. C. Che, "The Quantitative Analysis of Structure-Activity Relationships," Burger's Medicinal Chemnistrv, Part 1, pages 393-418, (4th ed., 1980). The binding affinity will be increased by increasing the contributions of the logarithm P. For example for the substituents in the aliphatic groups, the following TI constants can be used: Fl-aliphatic group CH3 0.50 Phenyl 2, 15 For the substituents on the aryl groups, the following TI constants can be used: Ri-aliphatic group CH3 0.56 CH2CH3 1. 02 Phenyl 1, 96 Therefore, the contribution of logarithm P, for the p-methylbenzyl group bound to an IEM, could be calculated in the following way (using the value of flr-aliphatic for CH3 as an estimate for the -CH2- group): contribution of the logarithm P = 0.50 + 2, 15 + 0.56 = 3.21 In binding to HSA, a minimum contribution of the P logarithm of 2 (equivalent to 4 CH3 groups or a phenyl ring), is necessary to achieve a significant union. A contribution of the P logarithm of 3 is preferred. Even more preferred, a contribution of logarithm P of 4. The binding of HSA, can be verified by equilibrium dialysis or ultrfiltration using HSA of 4.5% weight / volume, in a pH 7.4 regulator. Preferably at least 10%, and even more preferably at least 50%, and more preferably 80%, and still more preferably at least 95% of the contrast agent, is bound to HSA at relevant physiological concentrations (0.01 -mM in plasma for MRI, X-rays, light, ultrasound; < 1 uM for radiopharmaceuticals). In this application, the measurement of the percentage union of the HSA contrast agent has an error of approximately +/- 5%. The binding of the protein to other proteins can be verified in a similar way. The addition of the lipophilic groups to the contrast agent will probably decrease the solubility of the agent. In order to retain an efficient solubility of the contrast agent at clinically effective or higher dosage levels, it is preferable to incorporate one or more hydrogen fixing groups (oxygen, nitrogen, etc.) into the PPBM. Although purely aliphatic groups such as PPBM can be used, these may not be preferred as mixed aliphatic-aryl groups, or purely aryl groups. Especially when a negative charge is bound to purely aliphatic groups, particularly to long and flexible ones, the contrast agent may interfere with the metabolism of endogenous molecules, such as fatty acids or the interactions between lipids and membrane proteins. . This can increase the toxicity of the agent, therefore it is preferred that the PPBM contain at least one aryl ring. In the case of MRI agents linked to HSA, in order to improve the collection of blood, tumors or tissues, it is especially preferred that the contrast agent contains two or more different lipophilic groups, in order to completely immobilize the agent when it is bound. to the protein. These groups can be in a PPBM, or as two or more separate chemical groups attached to the contrast agent. Because of its stiffness and voluminous nature, it is preferable that the two or more groups each consist of an aromatic ring, the two or more rings in the entire molecule being placed in a rigid, non-planar orientation.

The magnetic efficiency or ralajación of an agent MR, is generally higher when the agent has a time of rotational correlation, which is approximately equal to that of HSA (RB Lauffer, Chemical Reviews, 87, pages from 901 to 927 (1987 Although a small molecule such as Gd-DTPA has a rotational correlation time of approximately 0.1 nanosecond (nsec), the HSA has a correlation time greater than 5-10 nsec, if a chelate has this correlation time longer, there will be magnetic fluctuations between the paramagnetic ion and water protons on the same time scale as the Larmor frequency, which generates the most efficient longitudinal relaxation (Ti) possible, and therefore the greatest possible relaxation Any flexibility of the chelate bound to the protein is supposed to decrease the effective rotational correlation time, and therefore decreases the relaxation. protein can provide flexibility in several directions, additional binding sites may be preferred. The degree to which an agent has been adjusted for maximum relaxation can be verified by measuring the relaxation-union (R-Limit) in the presence of HSA. This will require measuring the relaxation of the free chelate (Ri-Free), as well as the relaxation (R-observed), and the percentage of binding of the agent in 4.5% of HSA. The R - observed, is a weighted average of the molar fraction of R - Free and R? -United: R -observed = (fraction-free * R-) -free) + (fraction-union * Ri -union) Thus: Rl -Union = fRj-observed-free-fracction * R ^ -free) 1 fraction-union The benefit of having two or more aryl rings, maintained in a rigid and not flat, can be seen in the following table which shows the relaxation-limit values for Ms-322 (56 mM "1 s" 1) and Ms-325 42 mM "s-1) against MS-317 (34 mM-V) The biphenyl and diphenyl groups of MS-322 and MS-325 appear to be limiting the mobility of the contrast agent bound to HSA. the error associated with the measurement of the relaxation-limit values is approximately +/- 5% As can be seen in the table above, the compounds that have two rings maintained in a rigid form in non-planar orientation, had higher relaxation-limit values. As can be seen in the above equations, the actual R-observed can increase, when the binding-fraction is increased, that is when the binding end of the agent to the HSA is increased. This can also lead to lower renal excretion, and to longer half-lives in the blood and therefore it is synergistic. However, in order to use the lowest dose, and to have the widest safety margin, it is still important to maximize the power of the agent maximizing the union R i.

Prolongation Portion of the Average Life in the Blood ("BHEM") The third domain of the contrast agents of the present invention, BHEM, reduces the absorption rate of hepatocytes of the contrast agent. The balance of hydrophobicity and lipophilicity and the exact molecular structure of a molecule determines its rate of absorption of hepatocytes. In the contrast agents of the present invention, the BHEMs reduce or eliminate the absorption of hepatocytes, without unduly interfering with the efficiency of the PPBM. The BHEMs, are extremely hydrophilic groups that can be linked by hydrogen with water. The presence of a hydrophilic BHEM contrast agent reduces the absorption of hepatocytes of the agent. Examples of chemical groups that would serve as BHEM include carbon, phosphorus, tungsten, molybdenum or sulfur atoms that have adhered to them, charged heteroatoms or neutral such as oxygen, nitrogen, sulfur or halogen (especially fluorine), which have two or more pairs of electrons alone (ie total or partial negative charge) or electropositive hydrogen atoms (ie protonated amine), for the union of hydrogen with water. These include groups such as sulfone, ether, urea, thio-urea, aminesulfonamide, carbamate, peptides, esters, carbonates and acetals. Preferred groups include those which possess one or more positive or total partial charges, in aqueous solution at physiological pH in which, the negatively charged atoms can not be partially or totally neutralized by covalent or covalently coordinated junctions to the IEM. Examples of these preferred BHEMs include negatively charged groups such as phosphate monoester, phosphate diester, carboxylate and sulfonate. More preferred are those having phosphate groups, or any ester form thereof. The phosphate diesters are even more preferred, since: a) they are highly hydrophilic with oxygens of four hydrogen bonds; b) can be synthesized relatively quickly using the techniques shown below; c) they serve as excellent linkers between IEM and PPBM; d) because phosphate compounds exist and are metabolized naturally in the body, and contrast agents containing phosphate diester are expected to be non-toxic. All the previous groups may be linked in turn to a binding portion which binds them to any IEM, PPBM, or both. A "binding portion" is any physiologically compatible chemical group that does not interfere with the functions of IEM, PPB, or BHEM. Preferred linkers are synthetically easy to incorporate into the contrast agent. Neither are they unduly large enough to manifest their own undesirable biological function, or their influence of the target on the contrast agent. Preferably the length of the linker is between 1 and 50 Angstroms, more preferably between 1 and 10 Angstroms. The incorporation of the contrast agent of the present invention into a BHEM results in prolonged retention of the agent in the blood. Blood retention is preferably measured by calculating, in a rat plasma pharmacokinetic experiment, the area under the plasma concentration vs. time curve ("area under the curve" or "AUC-conc.") For a period of time. specific time (eg, -10 minutes, 0-30 minutes, 0-120 minutes, or 0-infinity). Retention (measured by conc.-AUC) can be evaluated experientially by administering a contrast agent to rats, rabbits, or higher mammals. It has been observed that the extension of the half-life in the blood is higher in rabbits and in higher mammals than in rats. In the present application, the data of the half-life in the blood measured by the conc-AUC, represents the experimentation in rats. The error associated with these data is approximately +/- 10%. The reason d'e that the measurement of the average life by itself is not used, is that the mathematical definition of this quantity, is often unclear and the resulting estimates are variable depending on the pharmacokinetic model used, and the period of time It takes a while to get the blood samples. For example, the average plasma concentrations observed after injecting two rats with 0.1 mmol / Kg of Gd-DPTA labeled with GD1 53 in the tail vein are shown below. Using the KaleidaGraph program from Macintonsh, this conc-AUC from 0 to 10 minutes was calculated as 3.5mM minutes.

Time (mm) The contrast agents of the present invention exhibit an increase in conc-AUC of at least 20%, when BHEM is added to IEM and PPBM. Preferably they exhibit an increase in conc-AUC of at least 40%, more preferably at least 70% and even more preferably at least 100%. In general, the increase in conc-AUC caused by BHEM is greater when the adhesion in the plasma is significant, for example 20% -50% or more. The calculated percentage increase of the conc-AUC may be different for the conc-AUC determined in different time periods. In general, the percentage increase in conc-AUC caused by BHEM is greater for conc-AUC taken for longer periods of time, for example from 0 to 30 minutes, instead of 0 to 10 minutes.

Since the structure and physical characteristics of the entire molecule of the contrast agent will govern its binding in the plasma, it is important to select the EMs and BHEMs that are compatible with the desired binding. For example, to achieve a binding with the positively charged binding sites in HSA, it is preferred to have net neutral or negative net charge EMEMs and BHEMs, to reduce the possibility of repulsion and perhaps even to increase the affinity of the binding. For binding with the alpha acid glycoprotein, at least some of the contrast agent should be positively charged. For binding with globulins, at least some of the contrast agent should be of a steroidal nature. For binding with the glycoproteins, at least some of the contrast agent should be lipophilic or of the fatty acid type. The contrast agents of the present invention are generally found in three categories: 1) Blood collection agents. When the affinity for binding to the plasma proteins is high (ie greater than 50% binding, or preferably greater than 80% binding, more preferably more than 95% binding), agents tend to act primarily as agents blood collectors. Although agents can access the interstitial space (the extracellular space between the cells) outside the blood capillaries, generally the concentration of relevant plasma proteins such as HSA are lower in that space compared to the plasma. Therefore, the plasma concentration of the agents is higher than the interstitial concentration, and therefore structures such as blood vessels are more enhanced than structures with low blood content. Applications for this type of agent include angiography (imaging of blood vessels) perfusion (determination of the blood flow rate in a tissue or tumor, using rapid imaging), and blood volume determinations (eg, to distinguish malignant tumors with good blood supply from beningnous tumors with lower blood volume). 2) Tissue or Tumor Enhancing Agents, In some cases, it is convenient to let the contrast agent have a quick access to the interstitial space, and join there with the plasma proteins. For example in MRI, it may be convenient to obtain the greatest possible enhancement of a tissue or tumor as soon as possible after the injection. Since MRI agents that bind to proteins provide greater enhancement than free agents, the best agent would be one that can enter the interstitial space and bind to proteins. However, if the agent is extremely bound to the plasma, say, bound by more than 95%, its rate of transfer through the capillaries (determined by the free concentration) will be too slow, and very few of the agents will enter the interstitial space and will produce the signal of tissue enhancement. Also, if the union is only 10%, then the agent will be free to enter the interstitial space, but will have little power to boost the signal. Therefore, an adequate balance of the transfer rate and binding affinity is required. For these applications, the union of the agents with the plam should be higher than 10% and lower than 95%, or preferably higher than 50% and lower than 95%.

This method is particularly useful in tumor imaging of MRI tumors. Malignant tumors often have better blood flow than benign tumors and therefore rapid tumor imaging (and interstitial) imaging can often distinguish this type of tumor, however for clinical applications, it is It is necessary that there is a difference in signals between the two tissues to allow clearer discrimination. The enhancement of signals through the binding with proteins will be useful in this regard. In addition, new rapidly developing capillaries of malignant tumors are permeable, which allows for a higher concentration of plasma proteins in the interstitial space of these tumors. This can lead to superior signal enhancement in malignant tumors, compared to benign tumors with less permeable capillaries. 3) Targeted Agents. When the agent is directed to a specific tissue or lesion in the body, a logic similar to that described in the two preceding paragraphs is applied. The relative affinities of the agent for the plasma proteins and target site need to be balanced so that the agent has some access to bind to the target, and at the same time must have some binding to the plasma proteins to increase the half life in the blood. For targeted applications, the binding of the agents to the plasma must be greater than 10% and lower than 95%, or preferably greater than 50% ß lower than 95%. The targeting portion may be a lipophilic substance, a receptor ligand, an antibody or other biomolecule that is known to be concentrated in the specific biological component from which an image is desired.

Structural Positioning It has been contemplated that the three portions of the contacting agents of the present invention may be arranged in a variety of positions with respect to each other. However, the position of the portions can not be one in which a portion interferes with the proposed function. For example, in an HSA-binding contrast agent, the location of BHEM should not block the ability of PPBM to bind the agent to HSA. Since the main sites of union with HSA, are of the type of a short average (XM He and Associates, Nature, 358, pages from 209 to 215 (1992), DC Cárter, Adv. Protein Chem .. 45. pages from 153 to 203 (1994), with hydrophobic interiors (especially near the "tip" region), and the positively charged regions of the ankle, binding affinity to a PPBM would decrease if the distal portion of the PPBM, was extremely hydrophilic As an illustrative example, if the PPBM is a phenyl ring, the most preferred position for BHEM in the ring is ortho, followed by meta .. A hydrophilic group in the para position, would reduce the binding affinity of the PPBJ to HSA For lEMs consisting of a metal chelate, it is preferred that the BHEMs and PPBMs are not bound to IEM in order to significantly reduce the strength of the bond between the metal ion and the chelating ligand, for example when the chelating arm is acetate, BHEM or PPBM will not be preferably bound to the oxygen of the acetate.

Another positional requirement is that the negatively charged BHEM atoms can not be partially or totally neutralized by covalent or covalent binding coordinated with IEM; this ensures that in aqueous systems, the highly hydrophilic BHEM atoms will be highly solvated. For example, when IEM is a metal chelate, it is important to place the negatively charged atoms of BHEM so that they can not be produced neutralized by the positively charged metal ion (Mn +) of the IEM, through covalent binding coordinated by the formation of rings. of chelate of five or six members, which are the most stable ring sizes. Since five-membered chelate rings are the most stable for metal ions of interest for IEM (such as gadolinium), it is very important to avoid their training. Therefore, as shown in the drawing below, a BHEM of phosphinate (-PO2-) or of phosphonate (-PO3-), can not be attached to the nitrogen atom of an aminocarboxylate chelating agent. through a linker -CO2-, since this could form a six-membered chelate ring. However, both BHEMs can be attached to other positions, such as to the ethylene skeleton of the ligand. In some cases, as shown, it may be preferred to increase the length of the linker group to be certain that five or six member rings can not be formed.

BHBM "ft * fQMUn t.Q.

It has been contemplated, that the portions of the present invention may be in a position in the contrast agent, so that they can re- sulcate the following structures: (1) IEM - [(L) m -. { (BHEM) S - (PPBM) 0} p] q (2) IEM - [(PPBM) 0 (BHEM) s] r (3) IEM - (PPBM) 0 (L) m - (BHEM) S where IEM is an image enhancing portion, L is a binding portion, BHEM is a prolongation portion of the half-life in the blood, PPBM is a fixative portion of the plasma protein, m can be equal to 0-4, s, or, and p can be the same or different, and equal to 1-4 yryq are at least 1.

If the portions of the present invention are in a position in the contrast agent as in structure (1) above, the BHEM is preferably sulfone, urea, thio-urea, amine, sulfonamide, carbamate, peptide, ester, carbonate, acétales and more preferably Y - II Y3-Z-Y4 I Y2-R2 where Z = P, W, Mo, or S? 1,? 2 = O or S Y3,? 4 = o, S or are not present. R2 = H, C alkyl? _g or not present.

More preferably if BHEM is a phosphate group. If the portions of the present invention are in a position in the contrast agent such as in structure (2) above, BHEM is preferably sulfone, urea, thio-urea, amine, sulfonamide, carbamate, peptide, ester, carbonate , acétales and more preferably BHEM has the following formula where 2 = P, W, Mo? 1, Y2 = O or S? 3 (? 4-o, S or are not present, R2 = H, C? _6 alkyl or are not present. More preferably BHEM is a group phosphate If the portions of the present invention are in a position in the contrast agent as in structure (3) above, BHEM is preferably SO 3, or the ester, sulfone, urea, thio-urea, amine, sulfonamide, carbamate, peptide, ester, carbonate, acetic acid and more preferably Y1 II Y3- Z-Y < I Y > -R2 where Z = P, W, Mo, or S Y-! , Y2 = O or S? 3 (? 4 = o, S or are not present, R2 = H, Cf.goalkyl are not present.Most preferably BHEM is a phosphate group.It has been contemplated that if the portions of the present invention, are in a position in the contrast agent such as in the structure (3) indicated above, the preferred contrast agents have the formulas: M where M is a metal ion with an atomic number of 21 -29, 42, 44 or 57-83, where R-j, R2, R3, R4. R5- R6- R7- R8- R9- R10. R11 and R16 may be the same or different, and are selected from the group consisting of H, PPBM, BHEM and alkyl of C f .5, with the proviso that at least one of these Rs, is PPBM and at least one other be BHEM, R 2- R13- and 14 can be the same or different, and be selected from the group consisting of O and N (H) Ri 7, R 15 = H, CH 2 CH (OH) CH 3, hydroxy alkyl or CH (R? 6) COR? 2 and R17 = H or C alquilo alkyl. For the contrast agents comprising the formulas shown above, the metal ion M is preferably Gd (III), Fe (III), Mn (II), Mn (III). ), Cr (lll), Cu (II), Dy (lll), Tb (lll), Ho (lll), Er (lll) or Eu (lll), and more preferably Gd (lll). The BHEM is more preferably sulfone, ether, urea, thio-urea, amine, amide, sulfonamide, carbamate, peptides, ester, carbonate, acetal and most preferably COO *, or the ester forms, SO3"or the ester forms and Y1 Y - Z-Y4 Y2-R2 where Z = P, W, Mo, or S Y1, Y2 = O or S? 3? 4 = o, S or are not present. R2 = H, C_6 alkyl or are not present. In the case of an HSA binding contrast agent, the BHEM can be located between the IEM and the PPBM, as shown in structure (1) above, or in the IEM away from PPBM, as shown previously in the structure (3). In this way, the total binding potential of the hydrophobic PPBM group can be expressed without interference from the hydrophilic BHEM group. The following two pairs of examples, serve to show the benefits of a phosphate BHEM, inserted between the Gd-DTPA and two PPBMs, an octyl aliphatic Cß group, and a naphthylmethyl group. The rats were injected intravenously (vein of the tail), with 0.1 mmol / Kg of the complexes radiorotulados with Gd 1 53. The plasma concentrations, were determined in a period of 30 minutes and adjusted to the conventional bi-exponential model of two compartments. The results for the elimination half-life, as well as the area under the plasma concentration versus time curve (conc-AUC), for the first 10 minutes are illustrated. Also, were 1 / T recorded? s, after plasma samples (at 20 MHZ, 37 degrees C), to determine efficacy as MRI agents.

These values were expressed as the area under the curve of 1 / T? against time (1 / T-AUC), during the first 10 minutes. 1 attached to AUC-conc AUC-l / Tj Cmp R HSA ci 2- "an M • min ß-j. a DTPA H 0 16.0 3.5 2"» MS-301, 44 6.2 2.7 59 0-o-O-CH? - MS-315 CH, ÍCF? I ¿56 14.0 3.4 81 MS-310 sr 30 6.8 1.8 29 MS-321 < r 14. C 3.2 5 As shown in the table above, the addition of BHEM phosphate to MS-301 and MS-310 (which results in an MS-315 and MS 321, respectively), increased the half-life of the contrast agent in the blood (measured by conc-AUC) in 26% and 78%, respectively. The Gd-DTPA of IEM is relatively hydrophilic and exhibits little or no binding to HSA. Therefore, its relaxation in the plasma is not optimized and its capacity to alter the 1 / Tf (and the blood signal in the MRI) over time is limited (see the relatively low value of 1 / T? -AUC). This is despite its relatively long half-life in the blood of 15 minutes. In order to improve the binding with HSA and relaxation, an octyl group of Cg can be placed in position 1 of the DTPA skeleton. Although this actually imparts the binding of HSA to the chelate, and some improvement in the blood signal, the lipophilic group only leads to a very reduced plasma half-life. The insertion of BHEM based on phosphate, actually enhances the binding of HSA and restores the plasma half-life to a value close to GD-DTPA. As a result, it greatly improves the blood signal. The proper location of the BHEM portion in these examples shows the importance of this aspect of the present invention. The addition of highly hydrophilic groups to MS-301 or MS-310 enhanced the binding to a certain degree. The location of the phosphate groups in MS-315 and MS-321 between IEM and PPBM, may allow the total hydrophobic surface of PPBMs to interact with the interior of the HSA sites, and at the same time create new beneficial interactions (eg electrostatic or hydrogen bonding), between the compound and the "ankle" region of the HSA sites. In particular it is possible that the negatively charged phosphate groups are well placed to interact with the positively charged residues, which cover the "ankle" region. As indicated above, the percentage increase in conc-AUC may depend on the time at which the measurements are made. For example, the addition of BHEM phosphate on MS-310 to prepare MS-321 increased the conc-AUC in 0-10 minutes, from 1.8 to 3.2 mM minutes, which constitutes an increase of 78%. However the conc-AUC for 0-30 minutes, increase from 2.46 to 5.57 mM minutes, which is an increase of 126%. The following contrast agents were prepared: 15 20 In the previous agents, n can be equal to 1 -4. wherein R, comprises an aliphatic group and / or at least one aryl group, or comprises a peptide containing hydrophobic amino acid residues and / or substituents with or without hydrophobic or hydrophilic terminating groups. Preferred contrast agents of the present invention are: KJ-15 MS-322 lß-323 MS-325 M-32Í K3-327 The most preferred contrast agents of the present invention are: MS-317, MS-322, MS-325 and MS-328. The most preferred is MS-325.

Additional Properties of the Contrast Agents Since the different chiral forms of the drugs or biomolecules can influence their performance in vivo, the same will possibly happen with the contrast agents of the present invention. For each given chiral center, one form may have relaxation, a longer half-life in the blood, lower toxicity, fewer metabolites or some other advantage or a combination of these advantages. These chiral forms will be preferred. To facilitate administration and absorption, the contrast agents of the present invention should have good solubility in water. Preferably, the contrast agents are soluble in a concentration of at least 1.0 rnM, and preferably 10 mM, and more preferably 100 mM in water at room temperature.

For injection, the formulated agents should only have a moderate viscosity to allow rapid and convenient injections. The viscosity should be less than 10.20 x 10"4 kg-s / m2 (10 centipoise), or preferably be less than 5, 10 x 10-4 kg-s / m2 (5 centipoise), or more preferably less than 2.04 x 10"4 kg-s / m2 (2 centipoises). For injection, the formulated agents should not have excessive osmolarity either, since this could increase the toxicity. The osmolarity should be less than 3000 milliosmoles / kg, or preferably less than 2500 millimoles / kg, or even more preferably less than 900 millomoles / kg.

Use of the Contrast Agents It has also been contemplated that the IEM may comprise a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the present invention include those derived from inorganic or organic bases and acids. Included among said salts or acids are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate. hexanoate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. The base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium, magnesium and zinc salts, salts with organic bases such as dicyclohexylamine salts, N- methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc. Likewise the basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others. The dispersible or water or oil soluble products are obtained in this way. The preferred salts of the present invention are N-methyl-D-glucoamine, salts of, calcium and sodium. The pharmaceutical compositions of the present invention, comprise any of the complexes of the present invention, or their pharmaceutically acceptable salts in conjunction with any pharmaceutically acceptable adjuvant carrier or vehicle. The adjuvant carriers or pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, alumina stearate, lecithin, whey proteins such as human serum albumin, regulatory substances. such as phosphates, glycine, sorbic acid, potassium sorbate, TRIS (tris (hydroxymethyl) aminomethane), partial mixtures of glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica colloidal, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and wool grease. In accordance with the present invention, the pharmaceutical compositions can take the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art, using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable solvent or diluent, for example as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed, there may be mentioned: water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed sterile oils, in the form of solvents or suspension medium, are conventionally employed. For this purpose, any soft fixed oil can be used, including mono or synthetic diglycerides. Fatty acids such as oleic acid, and their glyceride derivatives are useful in the preparation of injections, such as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as Ph. Helv or a similar alcohol. Since the contrast agents of the present invention bind to the plasma proteins, depending in some cases on the dose and rate of injection, the binding sites in the plasma proteins can be saturated. This will lead to a decrease in the binding of the agent, and could compromise the half-life or tolerability. Therefore, it may be convenient to inject the pre-ligated agent into sterile albumin or plasma replacement solution. Alternatively, an apparatus / syringe which contains the contrast agent and mix it with blood drawn into the syringe can be used.; then this is injected back into the patient. The compounds of the pharmaceutical compositions of the present invention can be administered orally, parenterally, by spray for inhalation, topically, rectally, nasally, buccally, vaginally, or through a reservoir implanted in dosage formulations containing adjuvant carriers and conventional carriers not toxic pharmaceutically acceptable. The term "parenteral" as used herein, includes intravenous, intramuscular, intra-articular, intra-synovial, intralesional, intrathecal, intrahepatic, intralesional and intracranial infusion or subcutaneous injection techniques. When the compositions of the present invention are administered orally, they can be administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, the carriers that are commonly employed include lactose and corn starch. Lubricating agents such as magnesium stearate are also commonly added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added. Alternatively, when administered in the form of suppositories for rectal administration, the pharmaceutical compositions of the present invention can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and that therefore it melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. As indicated above, the pharmaceutical compositions of the present invention can also be administered topically, especially when the purpose of the treatment includes easily accessible areas or organs for topical application including the eyes, the skin and the lower intestinal tract. Appropriate topical formulations can be prepared quickly for each of these areas or organs. Topical application for the lower intestinal tract can be made in a rectal suppository formulation (see the above description), or an appropriate enema formulation. Topically transdermal patches can also be used. For topical applications, the pharmaceutical compositions may be formulated in the form of an appropriate ointment, which contains the active component in suspension or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention, include but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in the form of an appropriate lotion or cream with a content of the active components in suspension or dissolved in one or more pharmaceutically acceptable carriers. Acceptable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. For ophthalmic use the pharmaceutical compositions can be formulated in the form of micronized suspensions in isotonic sterile saline solutions of regulated pH, or preferably in the form of sterile, isotonic, pH regulated saline solutions, either with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions can be formulated in the form of an ointment such as petrolatum. For administration by inhalation or nasal spray, the pharmaceutical compositions of the present invention are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared in the form of saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional dispersing or solubilizing agents. The dosage depends on the sensitivity of the imaging instrumentation for diagnosis, as well as the composition of the contrast agent. For example, for imaging by MRI, a contrast agent containing a highly paramagnetic substance, for example gadolinium (III), generally requires a lower dosage than a contrast agent containing a paramagnetic substance with a lower magnetic pulse, for example iron (III). Preferably, the dosage will be within the range of from about 0.001 to 1 mmol / kg body weight per day of the active metal-ligand complex. More preferably, the dosage will be within the range of about 0.005 and about 0.05 mmol / kg of body weight per day. It should be understood, however, that a specific dosage regimen for any particular patient will also depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, diet of excretion, the combination of drugs and the opinion of the attending physician. If the application of the present invention is carried out by means of MRI imaging, after administration of the appropriate dosage of the contrast agent, MRI imaging is performed. The choice of pulse sequence (investment recovery, IR; SE rotation echo, echo plane, EPI, TOF flight time, turbo-flash; Gradient echo, GE) and the values of the imaging parameters (echo time, TE, inversion time, TI, repetition time, RT, angle of rotation, etc.), will be governed by the diagnostic information sought . In general, if we want to obtain weighted images T- | , the TE should be less than 30 milliseconds) or the minimum value) to maximize the weight of T. Conversely, if you want to measure T2, then the TE should be greater than 30 milliseconds to minimize the competitive T effects. Ti and T2 will remain approximately the same for both TI and TR weighted images; they will remain approximately equal for both weighted images T-j and T2; TI and TR are generally of the order of approximately 5-1000 and 2-1000 milliseconds, respectively. The MRI contrast agents of the present invention are useful for general image formation, for decomposition of the blood-brain barrier, and other lesions. In addition, they are very useful for examining perfusion, that is, blood flow to and from tissues (heart, brain, legs, lungs, kidneys, tumors, etc.), and blood vessels (MR angiography). In addition, agents can be used to improve signal changes in the brain during cognitive events (functional MRI). It has been contemplated that the contrast agents of the present invention can also be used to enhance X-ray imaging, as well as ultrasound and light imaging. In these cases, the doses of agent will be approximately equal to those of MRI (0.001 -10 mmol / kg). For nuclear imaging, however, the doses will be trace levels. For all these techniques, the use and administration of the contrast agents and the regulation in the machines for the formation of images, is known or employs commonly accepted principles. In order that the present invention may be better understood, the following examples are provided.

EXAMPLES Experimental Unless otherwise indicated, all the materials mentioned were obtained from commercial suppliers and were used without further purification. THF was distilled from potassium kez benzophenone immediately before use. Methylene chloride was distilled over calcium hydride. All column chromatography was carried out, under nitrogen by the evaporation method described by Still, with silica gel (230-400 mesh, EM separation). All reactions were monitored by thin layer chromatography (TLC) carried out on silica gel supported on aluminum, in 0.2 mm plates of F254, (EM separation), and the compounds were visualized under UV light (254 nm) , Ninhydrin-Plus reagent or Dragendorff reagent (both from Alltech) subsequent to heating. Routine proton NMR spectra were recorded at 300 MHZ in CDCL3 with TMS as internal standard, except for the spectra recorded in D2O. Coupling constants (J) are indicated in Hertz (Hz). The 31 P NMR spectra were obtained at 121.4 MHZ.

Preparation of the Phosphoramidite Intermediate A. Serine Ethylenediamine Amide. Serine methyl ester hydrochloride (36.03 g, 232 mmol) was dissolved in 400 ml of diethylenediamine and stirred at room temperature for 16 hours. The ethyldendiamine was removed by evaporation under reduced pressure. The residue was dissolved in 80 ml of 4 N NaOH and concentrated under reduced pressure. This material was dissolved in methanol (150 ml), filtered and concentrated twice. This residue was suspended in methylene chloride (150 ml) and methanol (5-10 ml) and added with heating until the oily residue dissolved. The solution was dried over NaS? 4, filtered through Celite and concentrated. The viscous oily product was obtained without further purification.

B. 2-Hydroxymethyl diethylenetriamine tri-hydrate The crude amide (<239 mmol) was dissolved in 100 ml of THF. The stirred solution, borane THF (150 mL, 1.0 M) was slowly added. Subsequently the reaction was refluxed, under Ar for 16 hours. The excess borane was cooled by the careful addition of 250 ml of methanol at a temperature of 0 ° C. The reaction mixture was concentrated under reduced pressure. Concentrated HCl (100 ml) was slowly added, with cooling and the solution was then refluxed for 24 hours. The product mixture was concentrated under reduced pressure and crystallized from MeOH / EtOH. This produced 39.92 g of white solid (71% methyl ester).

C. Ester 1-hydroxymethyl-DTPA-penta-t-butyl ester (1) To a solution of hydroxymethyl diethylenetriamine trichlorhydrate (30.25 g, 124.70 mmol) and diisopropylamine (218 ml, 1.25 mol) in 300 ml. of dry DMF at room temperature under N2, t-butyl bromoacetate (16 ml, 0.78 mol) was added and stirred for 24 hours at room temperature. The solvents were then evaporated in vacuo and the residue was dissolved in EtOAc and extracted with H2O, NaHCO3 (sat), H2O and NaCl (sat). The residue was purified by silica gel column chromatography (CHCl3 only-CHCl3: MeOH = 100: 1) to obtain the pure product (oil) 70, 12 g, 81.7%) Rf (CHCl3 MeOH = 10: 1 ) 0.54, (ether: hexanes = 2: 1) 0.23 1 H-NMR (CDCl 3) d 1.44 (brs, 45H), 2.44-3.06 (m, gH, 3.24 and 3.29 (each d, each IH, J = 16.8), 3.34-3.58 (m, 10H), 3.66 (dd, 1 H, J = 11, 2 5.3), 4 , 20-4.70 (br, 1 H).

D. Phosphoramidite Intermediate (2) To a stirred solution of the penta-5-butyl ester (1) (12.88 g, 18.72 mmol) in CH2Cl2 est. (100 ml), 2-cyanoethyl N, N-diisopropylchlorophosphoramide (5.92 g, 25 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the solution was diluted with 100 ml of CH 2 Cl 2, and washed with an ice-cold solution of 10% NaHC 3 (100 ml), H 2 O (100 ml), and brine. (100 ml) and dried over MgSO The organic layer was evaporated to yield a crude product in the form of a light yellow oil (2). This crude oil can be used for the next coupling reaction without further purification. Examples 1 to 6 given below show the synthesis of some of the preferred contrast agents of the present invention, according to the following generalized scheme: Synthesis of Phosphodiester Ligands Example 1 Preparation of MS-315 - (2) (3a) - (4a) -5 (a) A, N-octyloxy phosphate (3a) Prepared from an intermediate of crude soforamidite (2) (prepared from 4.40 g, 6.40 mmol of 1-hydroxymethyl-DTPA-penta-t-butyl ester (1) by the same procedure described for (3d) and purified by gel column chromatography silica (CHCl3 / MeOH) [2.71 g, 44.7% total yield of (2)]. Rf (CHCl3: MeOH = 10: 1) 0.33.

B. N-octyl phosphate diester (4a) Prepared from phosphate (3a) (2.70 g, 2.84 mmol) by the same procedure described for (4e (2.17 g, 85.1%).

C MS-315 (5a) The solution of (4a) (2.16 g, 2.42 mmol) in trifluoroacetic acid (20 ml) was allowed to stand at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved with 5 mil of H2O. The solution was purified with reverse phase silica gel column C g (pre-loaded cartridge 'Sep-Pak, aters) (H2O only -CH3CN: H2O = 1: 4) to produce the pure product (5a) (1 , 13 g, 76.2%). 31 P-NMR (D20) d2.3.

Example 2 Preparation of MS-317 - (2) - (3) - (4b) - (5b) A. 5-Phenyl-1 -pentyloxy phosphate (3b) Prepared from a crude phosphoramidite intermediate (2) (prepared from 2.72 g, 3.96 mmol of 1-hydroxy-DTPA-pebta-t-butyl ester (1)) by the same procedure described for (3d), except that the crude product (3b), it was used for the next reaction without silica gel column chromatography (4.28 g of crude). R f (CHCl 3: MeOH = 10: 1) 0.26.

B, 5-phenyl-1 -pentyl phosphodiester (4b). Prepared from phosphate (3b) by the same procedure described for (4e), except that the crude product was purified by chromatography with Sephadex LH 20 (2.72). g of crude). Rf (CHCl3: MeOH = 10: 1) 0.1.1.

C, MS-317 (5b) Prepared from the crude (4b) (2.72 g), by the same procedure described for (5a) [1, 12 g, 43.5% of total yield from the intermediate of phosphoramidite (2)]. 31 P-NMR (D2O) d0, 1.

Example 3 Preparation of MS-322 - (2) - (3c) - (4c) - (5c) A. 2- (4-biphenylyl) -1-ethoxy phosphate (3 c) Prepared from a phosphoramidite intermediate purified (2) (3.50 g, 3.87 mmol) by the same procedure described for (3d), except that the crude product (3c) was used for the next reaction without chromatography on silica gel colomna.

B. 2- (4-Biphenylyl) -1-ethyl phosphodiester Prepared from phosphate (3c) by the same procedure described for (4e), except that the crude product was purified by chromatography with Sephadex LH 20 (2.34) g of crude).

C. MS-322 (5c) Prepared from the crude (4c) (2.34 g), by the same procedure described for (5a) [1, 15 g, 43.5% of total yield from the intermediate of phosphoramidite (2) j. 31 P-NMR (D2O) d3.7.

Example 4 Preparation of MS-323 - (2) - (3d) - (4d) - (5d) A. 10-Phenyl-1-decanoxy phosphate (3d) To a purified phosphoramidite (2) (15.20 g, 16.81 mmol) in CH3CN dest. (50 ml), 10-phenyl-1-decanol (9.00 g, 38.39 mmol) and 1 H-tetrazole (2.36 g, 33.79 mmol) in CH3CN dist. (50 ml). T-Butyl hydroperoxide (90%, 2.33 mL, 21.00 mmol) was added and reacted and left for 1 hour at room temperature. The solvent was concentrated in vacuo (ca 10 ml) and the residue was partitioned between AcOEt and H2O. The organic layer was washed with H 2 O and NaCl (sat.), Dried over MgSO 4 and evaporated. • The residue was purified with silica gel column chromatography (hexanes only -hexanes: ether = 1: 1 and then CHCl3: MeOH = 100: 1-50: 1), to produce the product (3d) (14, 12). g, 79.7%), Rf (CHCl3: MeOH = 10: 1) 0.35.

B. 10-Phenyl-1-decanyl phosphodiester (4d) Prepared from the phosphate (3d) (12.27 g, 1 1, 65 mmol), by the same procedure for (4e) (10.52 g, 90.3%). Rf (CHCl3: MeOH = 10: 1) 0.15.

C. MS-325 (5d) The mixture of (4d) (10.50 g, 10.50 mmol) in CHCl (vestigial metal quality, 15 ml) and ether (15 ml) was stirred at room temperature during the overnight and the ether was evaporated in vacuo. It was added to the resulting aqueous layer (pH <; O) CNHOH to adjust the pH to 1, 6. The precipitated white solid was collected by filtration and washed with diluted HCl solution (pH 2.5 3 times, 100 ml each time) and ether (3 times, 200 ml each time). The white solid was dried under vacuum for 24 hours at room temperature to yield the pure product (5d) (6.80 g, 90.0%). 31 P-NMR (D2O + NaOD, Ph = 13.5) d4, 9.

Example 5 Preparation of Ms-e325 - (2) - (3e) - (4e) - (5e) A. 4.4'-Diphenylcyclohexyloxyphosphate (3e) Prepared from a purified phosphoramidite intermediate (2) (4.52) g, 5.00 mmol) by the same procedure described for (3d), except that in the silica gel column chromatography the solvents (CH2Cl2 only - CH2Cl2: MeOH = 100; 1 (2.97 g, 4%). Rf (CHCl 3: MeOH = 10: 1) 0.47.

B. 4,4-Diphenylcyclohexyl Phosphodiester (4e) The solution of (3e) (2.14 g, 2.00 mmol) in NH3_-MeOH 2N (30 mL) was stirred at room temperature for 5 hours. The residue was evaporated and the residue (4e) (2.00 g, 98.3%) was used for the next reaction without further purification Rf (CHCl3: MeOH = 10: 1) 0.12.

C. MS-325 (5e) The mixture of (4b) (2.00 g, 1.96 mmol) in CHCl (vestigial metal grade, 5 ml) and ether (5 ml) was stirred at room temperature during the night. The solvents were removed by evaporation and the residue was triturated with H 2 O (5 times, 10 ml at a time) and ether (5 times, 50 ml at a time). The solid product was dried under pumping at room temperature for 24 hours to produce the pure product (5b) (1, 18) g, 81.5%). 31 p. MN (D20 + NaOD, pH = 13.5) d-0, 3.

Example 6 Preparation of MS-328 - (2) - (3f) - (4f) - (5f) A. 4,4-bis (4-methoxyphenyl) pentyl phosphate (3f) Prepared from 32.5 g ( 36 mmol) of crude phosphoramidite (2) and 4,4-bis (4-methoxyphenyl) pentanol (21.06 g, 70 mmol) by the procedure described for (3d). Chromatography was carried out in 50% EtOAc / hexane to yield 18.27 g of a yellow oil which was highly contaminated with the starting alcohol. Rf (50% EtOAc / hex) 0.4.

B. 4,4-bis (4-methoxy-phenyl) -pentyl phosphodiester (4f) A solution of (3f) (18.27 g) was prepared by the same procedure described for (4e) (17.26 g).

C MS-328 (50 Prepared from (4f) (17.26 g) by the procedure described for (5a), obtaining 4.88 g of a white solid (4.87 mmol, 13% yield from phosphoramidite) 3, P-NMR (D2O) d2.3.

Example 7 In situ formulation of the N-methyl-glucamine salt of the gadolinium complex of 5a (MS-315) (200mM, 5ml). Gadolinium oxide (Gd2γ3) was weighed in a test tube (0, 181 g 0.5 mmol), of compound (5a) (92% by weight, 0.703 g, 1.05 mmol) and (N-methyl-glucamine (NMG) (4.1 g, 3.6 mmol). deionized water (3.5 ml), and the mixture was stirred at a temperature of 95 ° C for 7 hours, after which the solution was cooled to room temperature and the volume was adjusted to 5.0 ml with deionized water. The solution was filtered through a 2 x 10-6 m filter (2 microns), to produce an aqueous solution of the titled compound.

Example 8 In situ formulation of the N-methyl glucamine salt. of the gadolinium complex of 5b (MS-317) (200mM, 4ml). Gadolinium oxide (Gd2? 3) (0.145 g, 0.4 mmol), of compound (5b) (81% by weight, 0.706 g, 0.84 mmol) were weighed into a test tube, and N methyl glucamine (NMG) (0.60 g, 8.0 mmol). Deionized water (3ml) was added, and the mixture was stirred at a temperature of 95 ° C for 6 hours, after which the solution was cooled to room temperature and the volume was adjusted to 4.0 ml with deionized water. The solution was filtered through a 2 x 10"6 m (2 micron) filter to produce an aqueous solution of the titled compound.

EXAMPLE 9 In situ formulation of the N-methyl-glucamine salt of the gadolinium complex of 5c (MS-322) (200 mM, 4mL), were weighed in a test tube, gadolinium oxide (Gd2? 3) (0). , 145 g, 0.4 mmol), compound (5c) (79% by weight, 0.779 g, 0.84 mmol) and N-methyl-glucamine (NMG) (0.61 g, 3.1 mmol). Deionized water (3 ml) was added, and the mixture was stirred at a temperature of 95 ° C for 6 hours, after which the solution was cooled to room temperature, and the volume was adjusted to 4.0 ml with deionized water. . The solution was filtered through a 2 x 10"6 m (2 micron) filter to produce an aqueous solution of the titled compound.

Example 10 In situ formulation of the N-methyl glucamine salt of the gadolinium complex of 5e (MS-325) (200 mM, 5mL). Weighed in a test tube, gadolinium oxide (Gd2? 3) (0.181 g, 0.5 mmol), compound (5e) (95% by weight, 0.820 g, 1.05 mmol) and N-methyl-glucamine (NMG) (0.68 g, 3.5 mmol). Deionized water (3.5 ml) was added, and the mixture was stirred at a temperature of 95 ° C for 6 hours, after which the solution was cooled to room temperature and the volume was adjusted to 5.0 ml with water deionized. The solution was filtered through a 2 x 10"6 m (2 micron) filter to produce an aqueous solution of the titled compound.

Example 1 1 In situ formulation of the N-methyl-glucamine salt of the gadolinium complex of 5f (MS-328) (200 mM, 5 mL) Weighed in a test tube, gadolinium oxide (Gd2? 3) (0, 181 g, 0.5 mmol), compound (5e) (97% by weight, 0.850 g, 1.05 mmol) and N-methyl-glucamine (NMG) (0.62 g, 3.2 mmol). Deionized water (3.5 ml) was added, and the mixture was stirred at a temperature of 95 ° C for 6 hours after which, the solution was cooled to room temperature and the volume was adjusted to 5.0 ml with disinfected water, The solution was filtered through a 2 x 10-6 m (2 micron) filter to produce an aqueous solution of the titled compound.

Example 12 Preparation of the N-methyl-glucamine salt of the gadolinium complex of 5b (MS-317). Gadolinium oxide (Gd2? 3) (0.50 g, 1.38 mmoi) was weighed into a test tube. ), compound (5b) (87% by weight, 1.87 g, 2.5 mmol) and N-methyl-glucamine (NMG) (1.53 g, 7.8 mmol). Deionized water (8 ml) was added and the mixture was stirred at a temperature of 95 ° C for 6 hours, after which the solution was cooled to room temperature and the volume was adjusted to 9.0 ml with deionized water. The solution was loaded onto a 10-g Sep-Pak column and eluted with water, the solvent was evaporated under reduced pressure, and the glassy white solid was dried under high vacuum for 48 hours. Yield: 3.50 g (2.48 mmol, 99%). Anal. Cale, for (NMG +) 3 [Gd (5e5") (H2O)] (C47Hg GdN6? 3oP): C, 40.08; h, 6.51; n, 5.97; gD.1.1, 16. Found : C, 4.24, H, 6.69, N, 5.88, Gd, 10.1 1.

Example 13 Preparation of the N-methyl-glucamine salt of the gadolinium complex of 5d (MS-323) Weigh into a 50 ml round bottom flask, gadolinium chloride hexahydrate (CDCI3 ° 6H2O) (2.1 1 g, 5.68 mmol), compound (5d) (74% by weight, 5.82 g, 5.98 mmol) and N-methyl-glucamine (NMG) (6.06 g, 31 mmol). Deionized water (16 ml) was added and the mixture was stirred at a temperature of 95 ° C for 4 hours and cooled to room temperature. The solution was loaded onto a column (C-18 (200 g) and eluted with a 1: 1 mixture of water-ethanol.The solvent was evaporated under reduced pressure, and the white, vitreous solid Yield: 8.0 g, (5.41 mmol, 95%) Anal.Cal, for (NMG +) 3 [Gd (5d5 -) (H2O) J (C52Hl ?? GdN6? 3? P): C, 42.27 h, 5 , 82; n, 5.69; Gd, 10.64, Found: C 42.04, H, 7.03, N, 5.83, Gd, 9.55.

Example 14 The following contrast agent has a binding to HSA of more than 95%.

W-323 It is shown to have a conc-AUC (for 0 to 10 minutes) of 100%, or greater than that of the following analog:

Claims (102)

1. R E I V I N D I C C O N E S 1. A contrast agent for diagnostic imaging characterized in that it comprises: a) an image enhancing portion (IEM); b) a plasma protein binding portion (PPBM); and c) a prolongation portion of the half-life in the blood (BHEM), said contrast agent demonstrating at least a binding of approximately 10% to plasma proteins and, in a rat plasma pharmacokinetic experiment, an area below of the plasma concentration curve versus time from 0 to 10 minutes, which is at least approximately 20% greater than that observed for the combination of IEM and PPBM alone without BHEM.
2. 2, The contrast agent as described in Claim 1, further characterized in that the image enhancing portion is selected from the group consisting of organic molecules, metal ions, salts or chelates, particles, iron particles, or labeled peptides, proteins, polymers or liposomes.
3. 3. The contractor's agent as described in the Claim 1, further characterized in that the image enhancing portion is a physiologically compatible iron particle, or a metal chelate compound consisting of one or more cyclic or non-cyclic organic chelating agents in complex, with one or more i < í > paramagnetic metal with atomic numbers of 21 -29, 42, 44, or 57-834. The contrast agent as described in Claim 1, further characterized in that the image enhancing portion is an organic iodinated molecule or a physiologically compatible metal chelate compound consisting of one or more cyclic or non-cyclic organic chelating agents in complex with one or more metal ions with atomic numbers from 57 to 83. 5. The contrast agent as described in Claim 1, further characterized in that the image enhancing portion consists of bubbles filled with gas, or particles or a physiologically compatible metal chelate compound, consisting of one or more cyclic organic chelating agents. or non-cyclic in complex with one more metal ions with atomic numbers of 21 -29, 42, 44, or 57-83. 6. The contrast agent as described in Claim 1, further characterized in that the image enhancing portion consists of a radioactive molecule. 7. The contrast agent as described in Claim 1, further characterized in that the image enhancing portion is a physiologically compatible metal chelate compound, which consists of one or more cyclic or non-cyclic organic chelating agents complexed with one or more Metallic elements with numbers of 27, 29, 31, 43, 47, 49, 75, 79, 82 or 83. 8. The contrast agent as described in Claim 1, further characterized in that the image enhancing portion is a physiologically compatible metal chelate compound, which consists of one or more cyclic or non-cyclic organic chelating agents complexed with Tc-99m. 9. The contrast agent as described in claim 1, further characterized in that the image enhancing portion is an organic or inorganic colorant. 10. The contrast agent as described in Claim 1, further characterized in that the plasma protein binding portion binds with human serum albumin. 11. The contrast agent as described in Claim 10, further characterized in that the plasma protein binding moiety comprises an aliphatic group and / or at least one aryl ring. 12. The contrast agent as described in Claim 10, further characterized in that the plasma protein binding moiety comprises a peptide containing hydrophobic amino acid residues and / or substituents, with or without hydrophobic or hydrophilic termination groups. The contrast agent as described in Claim 10, further characterized in that the protein-binding portion of the plasma contains at least one aryl ring. 14. The contrast agent as described in Claim 10, further characterized in that the protein-binding portion of the plasma contains at least two aryl rings rigidly held in non-planar form. 1.5. The contrast agent as described in Claim 1, characterized in that the prolongation portion of the half-life in the blood has one or more negative total or partial charges in aqueous solution at a physiological pH in which the negative charge can not be partially or totally neutralized, by covalent binding or covalent coordinate to the image enhancing portion. 16. The contrast agent as described in Claim 1, further characterized in that said contrast agent demonstrates at least about 50% plasma protein binding. 17. The contrast agent as described in Claim 1, further characterized in that said contrast agent demonstrates at least about 80% binding to the plasma proteins. 18. The contrast agent as described in claim 1, further characterized in that said contrast agent demonstrates at least about 95% binding to plasma proteins. 19. The contrast agent as described in Claims 1, 16, 17 or 18 further characterized in that said contrast agent demonstrates, in a pharmacokinetic experiment in rat plasma, an area below the plasma concentration curve versus time, from 0 to 10 minutes which is at least approximately '40% higher, than that observed for the combination of only IEM and POBM without BHEM. 20. The contrast agent as described in Claims 1, 16, 17 or 18, further characterized in that said contrast agent demonstrates, in a pharmacokinetic experiment in rat plasma, an area below the plasma concentration curve versus time, from 0 to 10 minutes which is at least approximately 70% higher than that observed for the combination of only IEM and PPBM without BHEM. 21. The contrast agent as described in Claims 1 16, 17 or 18, further characterized in that said contrast agent, demonstrates in a rat plasma pharmacokinetic experiment, an area below the plasma concentration versus time curve, from 0 to 10 minutes which is approximately 100% higher than what is observed for the combination of only IEM and PPBM without BHEM. 22. The contrast agent as described in Claims 1, 16, 17 or 18, further characterized in that said contrast agent, demonstrates in a rat plasma pharmacokinetic experiment, an area below the plasma concentration versus time curve, from 0 to 10 minutes which is from about 20% up to approximately 100% greater than that observed for the combination of only IEM and PPBM without BHEM. 23. The contrast agent as described in Claims 1, 16, 17 or 18, further characterized in that said contrast agent demonstrates in a rat plasma pharmacokinetic experiment, an area below the plasma concentration versus time curve, from 0 to 10 minutes which is from about 40% up to approximately 100% greater than that observed for the combination of only IEM and PPBM without BHEM. 24. The contrast agent as described in Claims 1, 16, 17 or 18, further characterized in that said contrast agent, demonstrates in a rat plasma pharmacokinetic experiment, an area below the plasma concentration versus time curve, from 0 to 10 minutes which is therefore less from approximately 70% to approximately 100% greater than that observed for the combination of only IEM and PPBM without BHEM. The contrast agent as described in Claim 1, 16, 17 or 18, further characterized in that said contrast agent, demonstrates in a pharmacokinetic experiment in rat plasma, an area below the plasma concentration curve versus time, or from 0 to 10 minutes which is at least approximately 100% greater than that observed for the combination of only IEM and PPBM without BHEM. 26. The contrast agent as described in Claims 1, 16, 17 or 18, further characterized in that it comprises a portion directed to a target, which allows to direct the contrast agent to a selected biological component. 27, The contrast agent as described in Claim 26, further characterized in that the targeted portion is selected from the group consisting of lipophilic substances, receptor ligands, and antibodies. 28, A method for prolonging the half-life in the blood, in a contrast agent for diagnostic imaging, comprising an image enhancing portion and a plasma protein binding portion, and which demonstrates at least approximately 10% binding to plasma protein layers, further characterized in that it comprises the step of incorporating to the contrast agent, a prolongation portion of the half-life in the blood at a position within the agent such that it does not reduce the binding of the plasma contrast agent, and which demonstrates in a rat plasma pharmacokinetic experiment, an area below the plasma concentration versus time curve, from 0 to 10 minutes, which is at least about 20% greater than the which is observed for the combination of the image enhancing portion and the protein binding portion of the plasma, alone, without the prolongation portion of the half-life in the blood. 29. The method as described in claim 28, further characterized in that the prolongation portion of the half-life in the blood, possesses one or more negative total or partial charges in aqueous solution at physiological pH, and in which the charge or Negative charges can not be partially or totally neutralized by covalent binding or coordinated covalent binding with the image enhancing portion. 30. The method as described in Claim 28, further characterized in that the area under the plasma concentration curve versus time from 0 to 10 minutes, of the contrast agent is at least about 40% greater than that of the it is observed for the combination of the image enhancing portion and the plasma protein binding portion alone, without the prolongation portion of the half-life in the blood. 31. The method as described in Claim 28 further characterized in that the area below the plasma concentration curve versus time from 0 to 10 minutes, of the contrast agent, is at least about 70% greater than that which it is observed for the combination of the image enhancing portion, and the protein-binding portion of the plasma alone, without the prolongation portion of the half-life in the blood. 32. The method as described in Claim 28 further characterized in that the area below the plasma concentration curve versus the 0 to 10 minute time of the contrast agent is at least about 100% greater than that which it is observed for the combination of the image enhancing portion and the plasma protein binding portion alone, without the prolongation portion of the half-life in the blood. 33. The method as described in Claim 28 further characterized in that the area under the plasma concentration versus time curve of the contrast agent is from about 20% to about 100% greater than that observed for the combination of the image enhancer portion and the protein-binding portion of the plasma alone, without the prolonging portion of the half-life in the blood. 34. The method as described in Claim 28, further characterized in that the area below the plasma concentration versus time curve of the contrast agent is from about 40% to about 100% greater than that which is observe for the combination of the image enhancing portion and the plasma protein binding portion alone, without the prolonged portion of the half-life in the blood. 35. The method as described in claim further characterized in that the area under the plasma concentration curve versus the time of the contrast agent is from about 70% to about 100% greater than what is observed for the combination of the enhancing portion of imag the protein-binding portion of the plasma alone, without the life-prolonging agent measured in the blood. 36. The method as described in claim further characterized in that the area under the plasma concentration curve versus the time 0 to 10 minutes of the contrast agent, at least about 100% greater than that obse the combination of the image enhancer portion and the per-ligand portion to the plasma protein alone, without the long-acting half-life in the blood. 37. A contrast agent for diagnostic imaging, further characterized by comprising the following form IEM - [(L) m -. { (BHEM) S - (PPBM) O} p] q where IEM is an image enhancing portion, L is a binding portion, BHEM is a prolongation portion of the half-life in blood, which has two or more electropositive hydrogen atoms two or more pairs of electrons alone, which can not be partially fully neutralized by coordinated covalent or covalent binding IEM, and is selected from the group consisting of sulfone, urea, urea, amine, sulfonamide, carbamate, peptide, ester, carbonate, acetals Y! Y3-Z-Y < I or the ester forms Y2"R; where Z = P, W, Mo, or S Y1,? 2 = O or S Y3, Y * = O, s or R2 = H, C1.6 alkyl are not present or are not present. PPBM is a plasma protein binding portion comprising at least seven carbon atoms, m can be equal to 0-4, s, o and p may be the same or different, and equal to 1 -4, and q is at least one 38. The contrast agent as described in Claim 37 further characterized because the BHEM is 1 Y3-Z-Y4 or the ester forms t Y2-R2 where Z = P, W, Mo, or S? 1, Y2 = O or S? 3_? 4 so, S or are not present R2 = H, alkyl of Ci .go are not present. 39. The contrast agent as described in Claim 37, further characterized in that BHEM is phosphate or the ester forms thereof. 40. The contrast agent as described in Claim 37, further characterized in that PPBM comprises at least 13 carbon atoms. 41. The contrast agent as described in Claim 37, further characterized in that PPBM comprises at least 18 carbon atoms, 42. The contrast agent as described in Claim 37, further characterized in that PPBM has a contribution of the logarithm P of at least 2.0. 43. The contrast agent as described in Claim 37, further characterized in that PPBM has a contribution of logarithm P of at least 3.0. 44. The contrast agent as described in Claim 37, further characterized in that PPBM has a contribution of logarithm P of at least 4.0. 45. A contrast agent for diagnostic imaging, further characterized in that it comprises the following formula: IEM - [(PPBM) 0 (BHEM) s] r where IEM, is an image enhancing portion, BHEM is a prolonged portion of the half-life in the blood, which has two or more electropositive hydrogen atoms, or two or more pairs of single electrons that can not be partially or totally neutralized by covalent or coordinated covalent bonds to the IEM, and is selected from the group consisting of sulfone, urea, thio-urea, amine, sulfonamide, carbamame, peptides, ester, carbonate, acetals and YJ II Y3-Z-Y 'or the ester forms I Y2-R2 wherein Z = P, W, Mo Y1, Y2 to O or S Y3, Y4 s O, S or R2 = H, Ci.g alkyl are not present or are not present. PPBM is a ligand portion of the plasma protein comprising at least seven carbon atoms, they may be the same or different and they are equal to 1 -4 and r is at least 1. 46. The contrast agent as described in the Claim 45, further characterized in that the BHEM portion is Y1 Y3- Z-Y < or the ester forms, I Y2-R2 where Z = P, W, Mo Y1, Y2 = O or S Y3, Y4 = O, S or are not present. R2 = H, C_6 alkyl or are not present. 47. The contrast agent as described in Claim 45, further characterized in that BHEM is phosphate or the ester forms thereof, 48. The contrast agent as described in Claim 45, further characterized in that PPBM comprises at least minus 13 carbon atoms. 49. The contrast agent as described in Claim 45, further characterized in that PPBM comprises at least 18 carbon atoms. 50. The contrast agent as described in Claim 45, further characterized in that PPBM has a contribution of logarithm P of at least 2.0. 51. The contrast agent as described in Claim 45, further characterized in that PPBM has a contribution of logarithm P of at least 3.0. 52. The contrast agent as described in Claim 45, further characterized in that PPBM has a contribution of logarithm P of at least 4.0. 53. A contrast agent for diagnostic imaging, further characterized by comprising the following formula: IEM - (PPBM) 0 (L) m - (BHEM) S wherein IEM, is an image enhancing portion, L is a binding portion, BHEM is a prolongation portion of the half-life in the blood, which has two or more electropositive hydrogen atoms or two or more pairs of electrons alone, which can not be partially or totally neutralized by covalent bonds or covalent bonds coordinated to the IEM, and is selected from the group consisting of sulfone, urea, thio-urea, amine, sulfonamide, carbamate, peptides, ester, carbonate, acetals and SO3 or their ester forms and Y1 Y3 Z-Y < or the ester forms I Y2-R, where Z = P, W, Mo, O or S Y1, Y2 = O or S Y3, Y4 = O, S or are not present R2 = H, alkyl of C «6 or are not present, PPBM is a binding portion of plasma protein comprising at least seven carbon atoms, m may be equal to 0-4, but may be the same or different, or equal to 1 -4. 54. The contrast agent as described in Claim 53, further characterized because BHEM is Y1 3 II? "Z? ~ Y or the ester forms, Y2-R, where Z = P, W, Mo, OS Y1, Y = 0 or S Y3, Y4 = O, S or are not present R2 = H, C alkyl or are not present 55. The contrast agent as described in Claim 53, further characterized in that BHEM is phosphate or its ester forms. 56. The contrast agent as described in Claim 53, further characterized in that PPBM comprises at least 13 carbon atoms. 57. The contrast agent as described in Claim 53, further characterized in that PPBM comprises at least 18 carbon atoms. 58. The contrast agent as described in Claim 53, further characterized in that PPBM has a contribution of logarithm P of at least 2.0. 59. The contrast agent as described in Claim 53, further characterized in that PPBM has a »contribution of the logarithm P of at least 3.0. 60. The contrast agent as described in Claim 53. further characterized in that PPBM has the contribution of logarithm P of at least 4.0. 61. A contrast agent for diagnostic imaging, further characterized in that it comprises: M wherein M is a metal ion with an atomic number of 21-R-R1 and R15, they can be the same or different and are selected from the group consisting of H, PPBM, BHEM and alkyl of C1 -6. with the proviso that at least one of R -R11 or R6 > is PPBM, with the additional condition that at least one of R -Rn or Rie be BHEM, R12-R13 and R 14 may be the same or different, and be selected from the group consisting of 0 and N (H) R17, R15 = H, CH2CH (OH) CH3, hydroxy alkyl or CH (R16) COR? 2, R17 = H or C-alkyl? _6, BHEM is a prolonged portion of the half-life in the blood that has two or more electropositive hydrogen atoms or two or more pairs of electrons alone, which can not be partially or totally neutralized by covalent bonds or covalent bonds coordinated to the IEM and is selected from the group consisting of sulfone, urea, thio-urea-amine, sulfonamide, carbamate, peptide, ester, carbonate, acetals, COO- or ester forms, SO3- or ester forms and: Y1 • 3 II Y -Z-Y4 0 | as ester forms, Y2-R2 where Z = P, W, Mo, O S? 1,? 2 = O or S Y3, Y4 = O, S O are not present. R2 = H, C alkyl? If or not they are present, PPBM is a ligand portion of the plasma protein, comprising at least seven carbon atoms. 62. The contrast agent as described in Claim 61, further characterized in that M is selected from the group consisting of Gd (lll), Fe (lll), Mn (ll), Mn (lll), Cr (lll) , Cu (lll), Dy (lll), Tb (lll), Ho (lll), Er (lll) and Eu (lll). 63. The contrast agent as described in Claim 62, further characterized in that M is Gd (III). 64. The contrast agent as described in any of Claims 61 to 63, further characterized in that BHEM is selected from the group of COO "or ester forms, SO3" or ester forms ? or the ester forms, I * Y; -R, where Z = P, W, mO, O s Y "!, Y2 = O or S Y3, Y4 = O, S or are not present. R2 = H, alkyl C. The contrast agent as described in any of Claims 61 to 63, further characterized in that PPBM comprises at least 13 carbon atoms. contrast as described in any of Claims 61 to 63, further characterized in that PPBM comprises at least 18 carbon atoms .. 67. The contrast agent as described in any of the Claims of the 61 to the 63, further characterized in that PPBM has a contribution of logarithm P of at least 2.0 68. The contrast agent as described in any of Claims 61 to 63, further characterized in that PPBM has a contribution from logarithm P of at least 3.0 69. The contrast agent as described in either of Claims 61 to 63, further characterized in that PPBM has a contribution of logarithm P of at least 4.0. 70. A compound characterized by the formula: M-3? 71. A compound characterized by the formula: M-317 72. A compound characterized by the formula: KS-322 3. A compound characterized by the formula: M-323 74. A compound characterized by the formula: MS-325 75. A compound characterized by the formula: IO-32I 76. A compound characterized by the formula: 15 20 77. A compound characterized by the formula: 78. A compound characterized by the formula: 79. A compound characterized by the formula: 80. A compound characterized by the formula: A compound characterized by the formula: HS-32C 82. A compound characterized by the formula: Hß-327 83. A compound characterized by the formula: in which PPBM is a binding portion of the plasma protein, which comprises at least seven carbon atoms, and n can be equal to 1 -4. 84. A compound characterized by the formula: in which PPBM, is a binding portion of the plasma protein, which comprises at least seven carbon atoms and can not be equal to 1 -4. 85, A compound characterized by the formula: where n can be equal to 1 -4. 86. A compound characterized by the formula: where n can be equal to 1-4. 87. A compound characterized by the formula: where n can be equal to 1-4 88. A compound characterized by the formula: where n can be equal to 1 -4. 89. A compound characterized by the formula: where n can be equal to 1 -4. 90. A compound characterized by the formula: wherein R comprises an aliphatic group and / or at least 1 aryl ring. 91. The compound as described in Claim 90, further characterized in that R comprises a peptide, which contains hydrophobic amino acid residues and / or substituents with or without hydrophobic or hydrophilic termination groups. 92. A compound characterized by the formula: wherein R, comprises an aliphatic group and / or at least 1 aryl ring, 93, The compound as described in Claim 90, further characterized in that R comprises a peptide, which contains hydrophobic aminino acid residues and / or substituents with or without hydrophobic or hydrophilic termination groups. 94. A method for MRI imaging of a biological component, further characterized in that it comprises the step of administering a diagnostically effective amount of a contrast agent, according to any one of Claims 1, 37, 45, 53, or 61 . 95. A method for ultrasound imaging of a biological component, which comprises the step of administering a diagnostically effective amount of a contrast agent, according to any one of Claims 1, 37, 45, 53, or 61. 96. A X-ray imaging method of a biological component which comprises the step of administering a diagnostically effective amount of a contrast agent, according to any one of Claims 1, 37, 45, 53, or 61. 97. A method for the formation of nuclear radiopharmaceutical images of a biological component, which comprises the step of administering a diagnostically effective amount of a contrast agent, according to any of Claims 1, 37, 45, 53, or 61. 98. A method for ultraviolet / visible / infrared light imaging of a biological component further characterized in that it comprises the step of administering a diagnostically effective amount of a contrast agent according to any one of Claims 1, 37, 45, 53. or 61. 99. A composition pharmaceutically characterized in that it comprises a contrast agent, according to any one of Claims 1, 37, 45, 53, or 61 and a carrier, adjuvant or vehicle. 100. The pharmaceutical composition according to Claim 99, further characterized in that it comprises a free organic ligand or a pharmaceutically acceptable salt thereof. 101. The pharmaceutical composition as described in Claim 99, characterized in that it further comprises a free organic ligand or calcium, sodium or meglumine salts, or a combination thereof. 102. A method for administering a contrast agent, according to any of Claims 1, 37, 45, 53 or 61, further characterized by comprising the steps of: a) drawing blood from a patient in a syringe containing the contrast agent , b) mixing the blood and the contrast agent in the syringe, c) and injecting the mixture back into the patient. ABSTRACT OF THE INVENTION The present invention relates to contrast agents for image formation for diagnosis with prolonged retention in the blood. In particular, the present invention relates to novel compounds that are characterized by an image enhancing portion (IEM); a protein binding portion of the plasma (PPBM); and a prolonged portion of the half-life in the blood (BHEM). The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using the compounds and compositions for prolonging the half-life in the blood and to enhance the contrast in diagnostic imaging.