WO1995020353A1

WO1995020353A1 - Functionalized aza-bimacrocyclic ligands for imaging applications

Info

Publication number: WO1995020353A1
Application number: PCT/US1995/001172
Authority: WO
Inventors: T. Jeffrey Dunn; Dennis A. Moore; Rebecca A. Wallace
Original assignee: Mallinckrodt Medical, Inc.
Priority date: 1994-01-28
Filing date: 1995-01-26
Publication date: 1995-08-03
Also published as: AU1694895A

Abstract

The present invention provides new and structurally diverse compositions comprising compounds of general formula (I), wherein A is N-G or P-G; B is N or P; C is N-G, P-G or -[CH(R7)]q-; D is N or P; E is N-F or P-F; F is -[CH(R8)]p-N(G)2 or -[CH(R8)]p-P(G)2; G is -[CH(R9)]r-X or -[CH(R9)]s-N[CH(R10)t-X]2; X is -CO2H, -OPO3H2, -PO3H2, -SO3H, -SH, -OH, or -CONHOH; R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 may be the same or different and are hydrogen, C1-8 alkyl, or C6-10 aryl, optionally substituted by one or more hydroxy, C1-8 alkyl, C1-8 hydroxyalkyl, C1-8 alkoxy, C6-10 aryl, C6-10 hydroxyaryl, C6-10 aryloxy, -CO2R11, -CONR12R13, or -NR14R15 groups; R11, R12, R13, R14 and R15 may be the same or different and are hydrogen, C1-8 alkyl, C1-8 hydroxyalkyl, or C1-8 alkoxyalkyl; R14 and R15 may form a 5 or 6 membered carbocyclic ring optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, l, m, n, p, q, r, s and t may be the same or different and are zero to about 5. Methods for imaging using compositions of the invention are also provided.

Description

FUNCTIONALIZED AZA-BIMACROCYCLIC LIGANDS

FOR IMAGING APPLICATIONS

FTELD OF THE INVENTION

This invention relates to magnetic resonance imaging (MRI) , X-ray imaging, and radiopharmaceuticals. More particularly the invention relates to methods and compositions for enhancing MRI, X-ray imaging, and radiopharmaceuticals. BACKGROUND OF THE INVENTION

The use of contrast agents in diagnostic medicine is rapidly growing. In X-ray diagnostics, for example, increased contrast of internal organs, such as the kidneys, the urinary tract, the digestive tract, the vascular system of the heart: (angiography), and so forth is obtained by administering a contrast agent which is substantially radiopaque. In

conventional proton MRI diagnostics, increased contrast of internal organs and tissues may be obtained by administering compositions containing paramagnetic metal species which increase the relaxivity of surrounding protons. In ultrasound diagnostics, improved contrast is obtained by administering compositions having acoustic impedances different than that of blood and other tissues.

The recently developed technique of MRI encompasses the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with

excellent resolution of soft tissue detail. As currently used, the images produced constitute a map of the proton density distribution, the relaxation times, or both, in organs and tissues. The technique of MRI is advantageously noninvasive as it avoids the use of ionizing radiation.

While the phenomenon of NMR was discovered in 1945, it is only recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature, 242, 190-191

[1973]). The fundamental lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. In addition to standard scan planes (axial, coronal, and sagittal), oblique scan planes can also be selected.

With an MRI experiment, the nuclei under study in a sample (e.g. protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei, as they relax, subsequently emit RF at a sharp resonance frequency. The resonance frequency of the nuclei depends on the applied magnetic field.

According to known principles, nuclei with appropriate spin, when placed in an applied magnetic field (B, expressed generally in units of gauss or Tesla [10⁴ gauss]) align in the direction of the field. In the case of protons, these nuclei precess at a frequency, f, of 42.6 MHz, at a field strength of 1 Tesla. At this frequency, an RF pulse of radiation will excite the nuclei and can be considered to tip the net magnetization out of the field direction, the extent of this rotation being deteimined by the pulse duration and energy. After the RF pulse, the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency. The decay of the emitted radiation is characterized by two relaxation times, i.e., T₁, the spin- lattice relaxation time or longitudinal relaxation time, that is, the time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T₂, the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. These relaxation times have been established for various fluids, organs and tissues in different species of mammals. In MRI, scanning planes and slice thicknesses can be selected. This selection permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in MRI equipment promotes high reliability. It is believed that MRI has a greater potential than CT for the selective examination of tissue

characteristics in view of the fact that in CT, X-ray

attenuation coefficients alone determine image contrast, whereas at least five separate variables (T₁, T₂, proton density, pulse sequence and flow) may contribute to the MRI signal.

By reason of its sensitivity to subtle physicochemical differences between organs and/or tissues, it is believed that MRI may be capable of differentiating different tissue types and in detecting diseases which induce

physicochemical changes that may not be detected by X-ray or CT which are only sensitive to differences in the electron density of tissue. As noted above, two of the principal imaging

parameters are the relaxation times, T₁ and T₂. For protons (or other appropriate nuclei), these relaxation times are influenced by the environment of the nuclei, (e.g.,

viscosity, temperature, and the like). These two relaxation phenomena are essentially mechanisms whereby the initially imparted radio-frequency energy is dissipated to the

surrounding environment. The rate of this energy loss or relaxation can be influenced by certain other nuclei which are paramagnetic. Chemical compounds incorporating these

paramagnetic nuclei may substantially alter the T₁ and T₂ values for nearby protons. The extent of the paramagnetic effect of a given chemical compound is a function of the environment. In general, paramagnetic species such as ions of elements with atomic numbers of 22 to 29, 42 to 44 and 58 to 70 have been found effective as MRI image contrasting agents. Examples of suitable ions include chromium(III),

manganese(II), manganese(III), iron(II), iron(III),

cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III), and ytterbium(III). Because of their very strong magnetic moments, gadolinium(III),

terbium(III), dysprosium(III), holmium(III) and erbium(III) are preferred. Gadolinium(III) ions have been particularly preferred as MRI contrasting agents.

Typically, paramagnetic ions have been administered in the form of complexes with organic complexing agents. Such complexes provide the paramagnetic ions in a soluble, nontoxic form, and facilitate their rapid clearence from the body following the imaging procedure. Gries et al., U.S. Patent 4,647,447, disclose complexes of various paramagnetic ions with conventional aminocarboxylic acid complexing agents. A preferred complex disclosed by Gries et al. is the complex of gadolinium(III) with diethylenetriamine-pentaacetic acid

( "DTPA").

Paramagnetic ions, such as gadolinium(III), have been found to form strong complexes with DTPA, ethylenediamine-tetraacetic acid ("EDTA"), and with tetraazacyclododecane-N,N',N",N"'-tetraacetic acid ("DOTA"). These complexes do not dissociate substantially in physiological aqueous fluids. The gadolinium complex of DTPA has a net charge of -2, whereas the gadolinium complex of EDTA or DOTA has a net charge of -1, and both are generally administered as soluble salts. Typical salts are sodium and N-methylglucamine. The administration of salts is attended by certain disadvantages. These salts can raise the in vivo ion concentration and cause localized disturbances in osmolality, which in turn, can lead to edema and other undesirable reactions.

Efforts have been made to design new ionic and neutral paramagnetic metal complexes which avoid or minimize the above mentioned disadvantages. In general, this goal can be achieved by converting one or more of the free carboxylic acid groups of the complexing agent to neutral, non-ionizable groups. For example, S.C. Quay, in U.S. Patents 4,687,658 and 4,687,659, discloses alkylester and alkylamide derivatives, respectively, of DTPA complexes. Similarly, published Dean et al., U.S. Patent Number 4,826,673 discloses mono- and

polyhydroxyalkylamide derivatives of DTPA and their use as complexing agents for paramagnetic ions. It can also be achieved by covalent attachment of organic cations to the complexing agent in such a manner that the sum of positive and negative charges in the resulting metal complex is zero.

The nature of additional substituents in the complexing agent can have a significant impact on tissue specificity. Hydrophilic complexes tend to concentrate in the interstitial fluids, whereas lipophilic complexes tend to associate with cells. Thus, differences in hydrophilicity can lead to different applications of the compounds. See, for example, Weinmann et al., AJR, 142, 679 (Mar. 1984) and

Brasch, et al., AJR, 142, 625 (Mar. 1984). Finally, toxicity of paramagnetic metal complexes is greatly affected by the nature of the complexing agents. In vivo release of free metal ions from the complex is a major cause of toxicity. Four principal factors are important in the design of chelates for making paramagnetic metal complexes that are highly stable in vivo and less toxic. The first three factors are thermodynamic in nature whereas the fourth involves chelate kinetics. The first factor is the

theriTodynamic stability constant of the metal-ligand. The thermodynamic stability constant indicates the affinity that the totally unprotonated ligand has for a metal. The second factor is the conditional stability constant which takes into account the pH and is important when considering stability under physiological pH. The selectivity of the ligand for the paramagnetic metal over other endogenous metal ions such as zinc, iron, magnesium and calcium is the third factor. In addition to the three thermodynamic considerations, complexes with structural features that make in vivo transmetallation reactions much slower than their clearance rates would be predicted to have low toxicities. Therefore, in vivo reaction kinetics are a major factor in the design of stable complexes. See, for example, Cacheris et al., Magnetic Resonance Imaging, 8:467 (1990) and Oksendal, et al., JMRI. 3:157 (1993).

A need continues to exist for new and structurally diverse compounds for use as imaging agents and

radiopharmaceuticals. There is a further need to develop highly stable complexes with good relaxivity and osmolar characteristics. SUMMARY OF THE INVENTION

The present invention provides new and structurally diverse compositions comprising compounds of the general formula:

Wherein A is N-G or P-G; B is N or P; C is N-G, P-G or - [CH(R₇)]_q-; D is N or P; E is N-F or P-F; F is - [CH(R₈)]_p-N(G)₂ or -[CH(R₈)]_p-P(G)₂; G is -[CH(R₉)]_r-X or -[CH(R₉)]_s-N[CH(R₁₀)_t-X]₂; X is -CO₂H, -OPO₃H₂, -PO₃H₂, -SO₃H, -SH, -OH, or -CONHOH;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀ may be the same or different and are hydrogen, C_1-8 alkyl, or C_6-10 aryl, optionally substituted by one or more hydroxy, C_1-8 alkyl, C_1-8

hydroxyalkyl, C_1-8 alkoxy, C_6-10 aryl, C_6-10 hydroxyaryl, C_6-10 aryloxy, -CC₂R₁₁, -CONR₁₂R₁₃, or -NR₁₄R₁₅ groups; R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ may be the same or different and are hydrogen, C_1-8 alkyl, C_1-8 hydroxyalkyl, or C_1-8 alkoxyalkyl;

R₁₄ and R₁₅ may form a 5 or 6 membered carbocyclic ring

optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, l, m, n, p, q, r, s and t may be the same or different and are zero to about 5.

Also provided are compositions comprising complexes of the compounds with metal ions of the general formula

Wherein A is N-G or P-G; B is N or P; C is N-G, P-G or - [CH(R₇)]_q-; D is N or P; E is N-G, P-G, N-F, or P-F; F is - [CH(R₈]_p-P(G)₂ or -[CH(R₈)]_p-P(G)₂; G is -[CH(R₉)]_r-X or - [CH(R₉)]_s-N[CH(R₁₀)_t-X]₂; X is CO₂M, -OPO₃HM, -PO₃HM, -SO₃M, -SM, -OM, or -CONHOM; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ may be the same or different and are hydrogen, C_1-8 alkyl, or C_6-10 aryl, optionally substituted by one or more hydroxy, C_1-8 alkyl, C_1-8 hydroxyalkyl, C_1-8 hydroxyalkyl, C_1-8 alkoxy, C_6-10 aryl, C_6-10 hydroxyaryl, C_6-10aryloxy, -CO₂R₁₁, -CONR₁₂R_13; or - NR₁₄R₁₅ groups; R₁₁, R₁₂,

R₁₃, R₁₄, and R₁₅ may be the same or different and are hydrogen, C_1-8 alkyl, C_1-8 hydroxyalkyl, or C_1-8 alkoxyalkyl; R₁₄ and R₁₅ may form a 5 or 6 membered carbocyclic ring optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, l, m, n, p, q, r, s and t may be the same or different and are zero to about 5; and M is a metal ion equivalent and/or a physiologically acceptable cation of an organic base. Compositions comprising the above formulas wherein M is a radioactive metal ion, a paramagnetic ion, or a metal ion capable of absorbing x-rays are also provided for use as radiopharmaceuticals, magnetic resonance imaging, and x-ray contrast agents, respectively.

Diagnostic compositions comprising the compounds of the invention are also provided. Methods of performing diagnostic procedures with compositions of the invention are also disclosed. The methods comprise administering to a patient an effective amount of the compositions of the invention and optionally subjecting the patient to an imaging procedure of imaging. DETAILED DESCRIPTION

The compositions of the invention are suitable for use with a variety of modalities including x-rays, magnetic resonance imaging and radiopharmaceuticals.

The functionality of the R groups of the compositions of the invention afford the additional capability of

derivatization to biomolecules and synthetic polymers.

Biomolecule refers to all natural and synthetic molecules that play a role in biological systems. Biomolecules include hormones, amino acids, peptides, peptidomimetics, proteins, deoxyribonucleic acid (DNA) ribonucleic acid (RNA), lipids, albumins, polyclonal antibodies, receptor molecules, receptor binding molecules, monoclonal antibodies and aptamers.

Specific examples of biomolecules include insulins,

prostaglandins, growth factors, liposomes and nucleic acid probes. Examples of synthetic polymers include polylysine, arborols, dendrimers, and cyclodextrins. The advantages of using biomolecules include enhanced tissue targeting through specificity and delivery. Coupling of the chelating moieties to biomolecules can be accomplished by several known methods (e.g., Krejcarek and Tucker Biochem. Biophys. Res. Comm, 30, 581 (1977); Hnatowich, et al. Science, 220, 613 (1983). For exairple, a reactive moiety present in one of the R groups is coupled with a second reactive group located on the

biomolecule. Typically, a nucleophilic group is reacted with an electrophilic group to form a covalent bond between the biomolecule and the chelate. Examples of nucleophilic groups include amines, anilines, alcohols, phenols, thiols and hydrazines. Electrophilic group examples include halides, disulfides, epoxides, maleimides, acid chlorides, anhydrides, mixed anhydrides, activated esters, imidates, isocyanates and isothiocyanates. And finally, the compositions of the invention should provide the additional advantage of being kinetically inert. Examples of suitable alkyl groups for use with the invention include methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, heptyl and octyl. Suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy and octoxy. Hydroxyalkyl groups suitable for use with the

invention include both mono and poly hydroxyalkyls such as hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, tris(hydroxymethyl)methyl and 2-hydroxy-1-hydroxymethyl-ethyl. Suitable alkoxyalkyl groups include methoxymethyl, 2,3-dimethoxypropyl, tris

(methoxymethyl)methyl, and 2-methoxy-1-methoxymethyl-ethyl.

Examples of suitable compounds of the invention are 4-[N, N-bis(carboxymethyl)aminoethyl]-10-carboxymethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; 4, 10, 15- tris(carboxymethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane; 4-[N,N-bis(mercaptoethyl)aminoethyl]-10-mercaptoethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; 4,10,15-tris(mercaptoethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane; 4-[N,N- bis(sulfonomethyl)aminoethyl]-10-sulfonomethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; and 4, 10, 15-tris(phosphonomethyl-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane.

Complexes of the novel ligands or compounds of the invention with one or more central metal ions or metal ion equivalents such as paramagnetic metals praseodymium(III), neodymium(III), samarium(III), ytterbium(III) terbium(III), dysprosium(III), holmium(III), erbium(III), iron(II),

iron(III), manganese(II), manganese(III), gadolinium(III), chromium(III), cobalt(II) and nickel(II) are useful for enhancing magnetic resonance images. While such metal ions are themselves paramagnetic in nature and capable of altering the magnetic resonance signal characteristics of body tissues, organs or fluids, they may exhibit significant toxicity when administered in the form of ionic salts. However, novel complexes of the invention are relatively or substantially nontoxic and therefore useful for enhancing magnetic resonance images by favorably altering relaxation times T₁ and T₂ and affording improved contrast between normal and diseased tissues or organs.

The preferred complexes of the invention are those formed from the above ligands and iron(II), iron(III), manganese(II), manganese(III) and gadolinium(III) as the central metal ion or ions. Depending upon the particular ligand employed and the particular central metal ion used, the complexes formed may be neutral, ionic, cationic, or zwitterionic in nature, or they may be negatively charged. The neutral complexes are

generally preferred and generally appear to exhibit relatively lower toxicity as compared to ionic or negatively charged complexes. The negatively charged complexes formed by the ligands and central metal ions enumerated above may be further coπplexed with one or more cations of an inorganic or organic base which are physiologically tolerated. Exarrples of cations for further complexing include sodium, potassium, calcium, and salts of N-methylglucamine, and diethanolamine. Examples of preferred compounds of the invention and one or more central metal ions (i.e., complexes) include

gadolinium(III)-4-N, N'[bis(carboxymethyl)aminoethyl]-10-carboxymethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane;

gadolinium(III)-4,10,15-tris(carboxymethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane; iron(III)

-4-[N,N-bis(mercaptoethyl)aminoethyl]-10-mercaptoethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; iron(III)-4,10,15-tris(mercaptoethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]

heptadecane; dysprosium(III)-4-[N,N-bis(sulfonomethyl)aminoethyl]-10-sulfonomethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; and dysprosium(III)-4,10,15-tris(phosphonomethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane. In addition to their utility in magnetic resonance imaging procedures, the compositions of the invention can also be employed for delivery of either radiopharmaceuticals or heavy metals for x-ray contrast into the body. For use in diagnostic and therapeutic radiopharmaceuticals the complexed metal ion must be radioactive. Radioisotopes of the elements technetium, rhenium, indium, gallium, copper, yttrium,

samarium and holmium are suitable. For use as X-ray contrast applications the complexed metal ion must be able to absorb adequate amounts of the X-rays. These metal ions are

generally refered to as radioopaque. Suitable elements for use as the radioopaque metal ion include lead, bismuth, gadolinium, dysprosium, holmium and praseodymium.

Exarrples of preferred compounds for radiopharmaceuticals are holmium(III)-4-[N,N-bis(carboxymethyl)aminoethyl]-10- carboxymethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; indium(III)-4,10,15-tris(carboxymethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane; technetium(III)-4-[N,N-bis(mercaptoethyl)aminoethyl]-10-mercaptoethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; gallium(III)-4,10,15-tris(mercaptoethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane citrate; yttrium(III)-4- [N,N-bis(sulfonomethyl)aminoethyl]-10-sulfonomethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; and samarium(III)-4,10,15-tris(phosphonomethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane.

Exarrples of preferred compounds for x-ray contrast are lutetium(III)-4-[N,N-bis(carboxymethyl)aminoethyl]-10-carboxymethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; lutetium(III)-4,10,15-tris(carboxymethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane; bismuth(III)-4-[N,N-bis(mercaptoethyl)aminoethyl]-10-mercaptoethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; lead(TV)-4,10,15-tris(mercaptoethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane citrate; holmium(III)-4- [N,N-bis(sulfonomethyl)aminoethyl]-10-sulfonomethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane; and holmium(III)-4,10,15-tris(phosphonomoethyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane.

The compositions of the invention can be formulated into therapeutic or diagnostic compositions for enteral or

parenteral administration. These compositions contain an effective amount of the paramagnetic ion complex along with conventional pharmaceutical carriers and excipients

appropriate for the type of administration contemplated. For example, parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to about 1.0M of a paramagnetic ion complex according to this invention. Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration. Preferred parenteral formulations have a concentration of paramagnetic ion complex of about 0.1M to about 0.5M. Such solutions also may contain

pharmaceutically acceptable buffers and, optionally,

electrolytes such as sodium chloride. The compositions may advantageously contain a slight excess (e.g., from about 0.01 to about 15.0 mole % excess) of a complexing agent or its complex with a physiologically acceptable, non-toxic cation. Such physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zinc ions, salts of n-methylglucamine and diethanolamine, and the like.

Generally, calcium ions are preferred.

Formulations for enteral administration may vary widely, as is well-known in the art. In general, such formulations are liquids which include an effective amount of the

paramagnetic ion complex in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.

The diagnostic compositions are administered in doses effective to achieve the desired enhancement of the image. Such doses may vary widely, depending upon the particular paramagnetic ion complex errployed, the organs or tissues which are the subject of the imaging procedure, the imaging

procedure, the imaging equipment being used, and the like. In general, parenteral dosages will range from about 0.001 to about 1.0 mMol of paramagnetic ion complex per kg of patient body weight. Preferred parenteral dosages range from about 0.01 to about 0.5mMol of paramagnetic ion complex per kg of patient body weight. Enteral dosages generally range from about 0.5 to about 100 mMol, preferably from about 1.0 to about 20 mMol, more preferably from about 1.0 to about 10.0 mMol of paramagnetic ion complex per kg of patient body weight.

The diagnostic compositions of the invention are used in the conventional manner. The compositions may be administered to a patient, typically a warm-blooded animal, either

systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.

Protocols for imaging and instrument procedures are found in texts such as Stark, D.D.; Bradley, W.G. Magnetic Resonance Imaging; Mosby Year Book: St. Louis, MO, 1992.

Radiopharmaceutical Imaging Procedures are found in Fred A. Mettler, Jr., M.D., M.P.H., Milton J. Guiberteau, M.D., Essentials of Nuclear Medicine Imaging. Grune and Stratton, Inc., New York, NY 1983) and E. Edmund Kim, M.S., M.D. and Thomas P. Haynie, M.D., (MacMillan Publishing Co. Inc., New York, NY 1987).

X-ray contrast Imaging Procedures are found in Albert A. Moss, M.D., Gordon Gamsu, M.D., and Harry K. Genant, M.D., Computed Tomography of the Body. (W.B. Saunders Company, Philadelphia, Pennsylvania 1992) and M. Sovak, Editor,

Radiocontrast Agents. (Springer-Verlag, Berlin 1984).

The following exarrples illustrate the specific

embodiments of the invention described in this document. As would be apparent to skilled artisans, various changes and modifications are possible and are contemplated within the scope of the invention described. EXAMPLES

Example 1

Synthesis of 4-[N,N-bis(carboxymethyl)aminoethyl]-10-carboxy-methyl-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane.

To a stirred solution consisting of 10.0g (0.166mole, 11.2mL) ethylenediamine, 50.4g (0.498mole, 69.4mL) triethylamine and 250 mL dichloromethane is added, dropwise, a solution of 73.3g (0.365mole) 2-trimethylsilylethylsulfonyl chloride (Weinreb, S.M.; Demko, D.M.; Lessen, T.A.; Lett. (1986) 27, 2099.) in 150 mL dichloromethane. When the addition is complete, the mixture is placed in seperatory funnel and washed with 2x500mL 1.0N HCl, and 2×500mL 1.0N NaOH. The organic layer is collected and dried with MgSO₄. After the drying agent is removed by filtration, the solvent is evaporated and the dry white solid remaining crystallized from boiling methanol containing 10% water. The clear colorless crystals which form are dried in air. Yield of 1,4-bis(trimethylsilylethylsulfonyl)-1,4-diazabutane, 43.2g (67.0% based on ethylenediamine). Melting point 166-7C. Identity and purity of of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis. A solution containing 18.2g (0.173mole) diethanolamine and 150 mL (1.08mole, 108.9g) triethylamine in 500 mL dichloromethane is cooled in an ice-water bath. To this solution is added a solution containing 108.6g (0.570mole)p-toluene-sulfonyl chloride in 200 mL dichloromethane. The rate of addition is such that the temperature of the reaction mixture does not exceed 5C. When the addition is complete, the mixture is stored in 2L flask fitted with a CaCl₂ drying tube in a 0C refrigerator overnight. The cold solution is filtered to remove the large amount of crystals which form (HNEt₃+Cl-) and concentrated by evaporation in vacuo to a thick oil. The oil is shaken with 1000g ice and water and the precipitate which forms is collected by filtration. The solid is dissolved in 300mL fresh dichloromethane and washed in 3×150mL 1.0N HCl. The organic layer is collected and dried with MgSO₄. After removing the drying agent by filtration the solvent is removed by evaporation and the oil which forms is dissolved in a minimum of boiling methanol/ethyl acetate (20:1), ca. 250mL. Upon cooling, crystals of 1,4,7-tris(p-toluenesulfonyl)-4-aza-1,7-dioxoheptane are formed. Yield 83.0g (98.2%) based on diethanolamine). Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis.

A solution containing 18.2g (0.173mole) diethanolamine and 150mL (1.08mole, 108.9g) triethylamine in 500mL

dichloromethane is cooled in an ice-water bath. To this solution is added a solution containing 114.4g (0.570mole) 2-trimethyl-silylethylsulfonyl chloride in 200mL

dichloromethane. The rate of addition is such that the temperature of the reaction mixture does not exceed 5C. When the addition is complete, the mixture is stored in 2L flask fitted with a CaCl₂ drying tube in a 0C refrigerator overnight. The cold solution is filtered to remove the large amount of crystals which form (HNEt₃+Cl-) and concentrated by evaporation in vacuo to a thick oil. The oil is shaken with 1000g ice and water and the precipitate which forms is collected by

filtration. The solid is dissolved in 300mL fresh

dichloromethane and washed with 3×150mL 1.0N HCl. The organic layer is collected and dried with MgSO₄. After removing the drying agent by filtration the solvent is removed by

evaporation and the oil which forms dissolved in a minimum of boiling methanol/ethyl acetate (20:1), ca. 250mL. Upon cooling, crystals of 1,4,7-tris(trimethylsilylethylsulfonyl)-4-aza-1,7-dioxoheptane are formed. Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis. To a slurry containing 9.06g (60% dispersion in mineral oil, 0.226mole) sodium hydride in 250mL dry dmf is added, dropwise, a solution of 40g (0.103mole) 1,4-bis(trimethylsilylethylsulfonyl)-4,7-diazabutane in 250mL dry dmf. When the addition is complete the mixture is briefly to 60C and allowed to cool to room temperature. When cool, the mixture is filtered to remove unreacted NaH and the solution returned to a reaction vessel. The solution is heated, under dry air, to 85C and a solution containing 64.3g (0.113mole) 1,4,7-tris(p-toluenesulfonyl)-4-aza-1,7-dioxoheptane in 200 mL dry dmf. is added. When the addition is corrplete, the mixture is allowed to stir overnight. After cooling the mixture to room temperature, the solvent is removed in vacuo, and the pasty solid remaining is treated with 500g ice. The resulting precipitate is collected by filtration and washed with

distilled water until the filtrate is neutral pH. The solid is pressed dry to remove most of the water present and

dissolved in a minimum amount of boiling methanol and acetone (20:1). The hot solution is quickly filtered to remove any particulates and the solution allowed to stand. Upon cooling, crystals of 1,4-bis(2-trimethylsilylethanesulfonyl)-7-(p-toluenesulfonyl)-1,4,7-triazacyclononane are deposited. Yield 41. lg (65.0%). Identity and purity of the product is

confirmed by ¹H and ¹³C nmr, and elemental analysis.

A slurry consisting of 40.0g (65.1mmoles) 1,4-bis(2-trimethylsilylethanesulfonyl)-7-(p-toluenesulfonyl)-1,4,7-triazacyclononane and 29.7g (195mmoles)CsF in 100mL dry dmf is refluxed overnight. After cooling to room temperature 50mL methanol is added and the mixture evaporated in vacuo. The residue is diluted with 50mL diethyl ether, heated briefly to reflux, filtered and allowed to stand. Upon cooling, crystals of

1-p-toluenesulfonyl-1,4,7-triazacyclononane are deposited.

Yield of 14.9g (81%). Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis.

To a slurry consisting of 14.0g (49.4mmoles) 1-p-toluenesulfonyl-l,4,7-triazacyclononane, and 35.4g (109mmoles) Cs₂CO₃ in 250mL acetonitrile is slowly added a solution of

32 .3g (54 .3mmoles) 1, 4 , 7-tris(trimethylsilylethylsulfonyl)-4-aza-1,7-dioxoheptane, in 200mL acetonitrile. When the

addition is corrplete, the mixture is heated to reflux for two hours and checked for completeness by thin layer

chromatography. The mixture is filtered to remove the bulk of the insoluble salts present, and the filtrate evaporated in vacuo. The residue is dissolved in ethyl acetate, filtered and treated with hexanes to induce crystallization of 1-p-toluenesulfonyl-7-trimethylsilylethylsulfonyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane. Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis.

A slurry consisting of 19.0g (36.8mmoles) 1-p-toluenesulfonyl-7-trimethylsilyethylsulfonyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane and 11.2g (73.7mmoles)CsF in

100mL dry dmf is refluxed overnight. After cooling to room temperature 50mL methanol is added and the mixture evaporated in vacuo. The residue is treated with 150mL ethyl acetate, filtered and evaporated. The residue is dissolved in 10OmL acetonitrile and treated with a solution consisting of 8.00g (40.5mmoles) N-tosylaziridine in 50mL acetonitrile. The mixture is allowed to stir for three hours, and the progress of the reaction is followed by thin layer chromatography.

When the reaction is corrplete, acetonitrile is removed by evaporation and the residue dissolved in a minimum of

dichloromethane. The solution is eluted through a 5×35cm column containing 500g silica gel. The chromatography is completed by elution with 3% methanol in dichloromethane. The fractions are checked by tic, and appropriately combined. A solid is isolated upon evaporation of the solvent. The solid is treated with 50mL concentrated sulfuric acid and allowed to stir overnight. The mixture is cooled to 0C and poured carefully into 500mL dry, cold diethyl ether. The white solid which forms is collected by filtration and washed with cold ether. If the precipitate is tacky, or hygroscopic, the mother liquor of the diethyl ether-sulfuric acid slurry may be decanted, leaving the tacky residue. Treatment of the

precipitate with a solution of 8.1g sodium hydroxide to 200mL methanol followed by evaporation of solvent leaves a white precipitate. The solid is slurried with 200mL dichloromethane and treated with magnesium sulfate. After removing the drying agent by filtration, the solvent is removed by evaporation to leave 1-(2-aminoethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane as a clear colorless oil. Yield 7.55g (85%). Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis.

To a solution containing 3.50g (14.5mmoles) 1-(-2-aminoethyl)-1,4,7,10-tetra-azabicyclo[5.5.2]tetradecane and 5.07g

(47.9mmoles) Na₂CO₃ in 50mL 1,2-dimethoxyethane is added, dropwise, a solution containing 7.54mL (47.9mmoles, 10.9g). benzylbromoacetate in 25mL 1,2-dimethoxyethane. When the addition is corrplete, the mixture is heated briefly to reflux, and allowed to cool to room temperature, stirring overnight. The mixture is evaporated, slurried in 25mL dichloromethane, filtered to remove the salts present and purified by flash column chromatography (1×10cm, 50:50 ethyl acetate:hexanes, applied as CH₂Cl₂ solution). The appropriate fractions are combined and the solution filtered to remove any particulates. The filtrate is evaporated in vacuo leaving 4-[N,N-bis(benzylacetato)aminoethyl]-10-benzylacetato-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane as a pale oil. Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis. A slurry consisting of 1g 5% Pd on C and 6.50g (9.48mmoles) 4- [N,N-bis(benzylacetato)aminoethyl]-10-benzylacetato-1,4,7,10-tetrabicyclo[5.5.2]tetradecane and in ethanol (95%) is shaken at 60psi H₂ overnight. The catalyst is removed by filtration and the filtrate evaporated to afford 4- [N,N-bis(carboxymethyl)aminoethyl]-10-carboxy-methyl-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane as a pale oil. Identity and purity of the product is confirmed by ¹H and ¹³C nmr, -and elemental analysis.

Example 2

Synthesis of gadolinium(III) aqua-4-[N,N-bis(acetato)aminoethyl]-10-acetato-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane.

A slurry containing 3.50g (8.42mmoles) 4-[N,N-bis(carboxymethyl)aminoethyl]-10-carboxy-methyl-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane, and 1.50g (4.14mmoles) gadolinium oxide in 100mL water is refluxed until the mixture is clarified. Water is removed by evaporation and the residue dissolved in a mixture of boiling acetonitrile:absolute ethanol: iso-propyl alcohol 3:3:4, filtered hot and allowed to stand. Upon cooling crystals of gadolinium(III) aqua-4-[N,N-bis(acetato)aminoethyl]-10-acetato-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane are deposited. Identity and purity of the product is confirmed by hplc examination and elemental analysis.

Example 3

Synthesis of 4,10,15-tris(carboxymethyl)l,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane.

To a stirred slurry consisting of 20g (41.6rrnπoles) 1,7-bis(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane (Alfeim, T.; Buoen, S.; Dale, J.; Krautwurst, K.D.; Acta Chem. Scand. (1986) B40, 40.), and29.8g (91.5mmoles) cesium carbonate in 300mL dry N,N-dimethylformamide, is added slowly a solution of 26.0g (45.8mmoles) 1,4,7-tris(p-toluenesulfonyl)-4-aza-1,7-dioxoheptane in 100mL dmf. When the addition is complete, the mixture is heated to 60C and the reaction tested for

completeness by thin layer chromatography. The mixture is concentrate under reduced pressure and the residue treated with 400g ice-water. The resulting solid is collected by filtration, washed with water until the pH of the filtrate is neutral and dried on the frit with suction. The crude solid is dissolved in ethyl acetate (250mL), and dried with MgSO₄. After the drying agent is removed by filtration, the solution is concentrated by evaporation to 75mL and treated with hexanes to affect crystallization of 4, 10, 15-tris (p-toluenesulfonyl)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane. Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis.

A solution of 16.0g (22.7mmoles) of 4, 10, 15-tris (p-toluenesulfonyl)-1,4,7,10,15-pentaazabicyclo [5.5.5] heptadecane in 50mL concentrated sulfuric acid is allowed to stir for 24 hours. The solution is cooled in an ice bath and carefully poured into 2L 0C diethyl ether

(danger! exotherm!). The resulting solid is collected by filtration and treated with a solution of 10g (0.25mole) sodium hydroxide in 200mL methanol. The mixture is evaporated and the resulting solid stirred in 100mL dichloromethane. The slurry is filtered and the solid washed with 2×100mL

dichloromethane. The filtrates are combined and treated with MgSO₄. After the drying agent is removed by filtration the solution is evaporated to give 1,4, 7,10, 15-pentaazabicyclo [5.5.5] heptadecane as an oil.

Identity and purity of the product is confirmed by ¹H and ¹³C nmr, and elemental analysis. To a 45C, stirred slurry of 4.00g (16.6mmoles) 1,4,7,10,15-pentaaza-bicyclo [5.5.5] heptadecane, and 5.80g (54.7mmoles) sodium carbonate in 200mL acetonitrile is added a solution of 12.5g (8.7mL, 54.7mmoles) benzyl 2-bromoacetate. The progress of the reaction is followed by thin layer chromatography.

When the reaction is corrplete, the mixture is filtered and the filtrate evaporated. The residue is dissolved in ethyl acetate (30mL) and crystallization of 4, 10, 15-tris(benzylacetato)-1,4,7,10,15-pentaazabicyclo[5.5.5]heptadecane is affected by addition of hexanes. Identity and purity of the product is confirmed by ^λE and ¹³C nmr, and elemental analysis.

A slurry consisting of 5.00g (7.29mmoles) 4,10,15-tris(benzylacetato)-1,4,7,10,15-pentaaza-bicyclo[5.5.5]heptadecane, and 2.50g 10% Pd on carbon in 75mL 95% ethanol is shaken for 4 hours at a pressure of 60 p.s.i. hydrogen. The mixture is filtered to remove the catalyst and the filtrate evaporated leaving 4, 10, 15-tris(acetato)-l,4,7,10,15-pentaaza-bicyclo[5.5.5]heptadecane as clear colorless oil. Identity and purity of the product is

confirmed by ¹H and ¹³C nmr, and elemental analysis.

Example 4

Synthesis of gadolinium(III) aquo-4,10,15-tris(acetato)-1,4,7,10,15-pentaaza-bicyclo[5.5.5]heptadecane.

To a solution of 2.00g (4.81 mmoles) 4, 10, 15-tris(acetato)-1,4,7,10,15-pentaaza-bicyclo[5.5.5]heptadecane in 100mL water is added 0.87g (2.40mmoles) gadolinium(III) oxide. The mixture is refluxed for 14 hours. After cooling to room temperature the mixture is filtered and the filtrate

concentrated to ca. 10mL. To this solution is added 10mL of a 50:50 iso-propyl alcohol-ethanol mixture. Upon standing overnight crystals of gadolinium(III) aquo-4,10,15- tris(acetato)-1,4,7,10,15-pentaaza-bicyclo[5.5.5]heptadecane are formed. Identity and purity of the product is confirmed by hplc examination and elemental analysis. Although the invention has been described with respect to specific modifications, the details thereof are not to be construed as limitations, for it will be apparent that various equivalents, changes and modifications may be resorted to without departing from the spirit and scope thereof, and it is understood that such equivalent embodiments are to be included therein.

Claims

CLAIMS What is claimed is:

1. A compound of the general formula:

Wherein A is N-G or P-G; B is N or P; C is N-G, P-G or - [CH(R₇)]_q-; D is N or P; E is N-F or P-F; F is - [CH(R₈) ]_P-N(G)₂ Or -[CH(R₈)]_p-P(G)₂; G is -[CH(R₉)]_r-X or - [CH (R₉) ]_s-N[CH(R₁₀)_t-X]₂; X is -CO₂H, -OPO₃H₂, -PO₃H₂, -SO₃H, -SH, -OH, or -CONHOH; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀ may be the same or different and are hydrogen, C_1-8 alkyl, or C_6-10 aryl, optionally substituted by one or more hydroxy, C_1-8 alkyl, C_1-8

hydroxyalkyl, C_1-8 alkoxy, C_6-10 aryl, C_6-10 hydroxyaryl, C_6-10 aryloxy, -CI₂R₁₁, -CONR₁₂R₁₃, or -NR₁₄R₁₅ groups; R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ may be the same or different and are hydrogen, C_1-8 alkyl, C_1-8 hydroxyalkyl, or C_1-8 alkoxyalkyl;

R₁₄ and R₁₅ may form a 5 or 6 membered carbocyclic ring

2. The corrpound of claim 1 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₈) ]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -CO₂H; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; and r is 1.

3. The compound of claim 1 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂H; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; and r is 1.

4. The compound of claim 1 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SH; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is

H; R₈ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; and r is 2.

5. The compound of claim 1 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is - [CH(R₉)]_rX; X is -SH; R₁ is H; R₂ is H; R₃ is H; R- is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; and r is 2.

6. The compound of claim 1 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p- N(G)₂; G is - [CH(R₇)]_rX; X is -SO₃H; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is O; and r is 1.

7. The compound of claim 1 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -PO₃H₂; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; and r is 1.

8. The compound of the general formula

Wherein A is N-G or P-G; B is N or P; C is N-G, P-G or -

[CH(R₇)]_q-; D is N or P; E is N-G, P-G, N-F, or P-F; F is - [CH(R₈]_p-P(G)₂ or -[CH(R₈)]_p-P(G)₂; G is -[CH(R₉)]_r-X or - [GH(R₉)]_s-N[CH(R₁₀)_t-X]₂; X is CO₂M, -OPO₃HM, -PO₃HM, -SO₃M, -SM, -OM, or -CONHOM; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ may be the same or different and are hydrogen, C_1-8 alkyl, or C_6-10 aryl, optionally substituted by one or more hydroxy, C_1-8 alkyl, C_1-8 hydroxyalkyl, C_1-8 hydroxyalkyl, C_1-8 alkoxy, C_6-10 aryl, C_6-10 hydroxyaryl, C_6-10 aryloxy, -CO₂R₁₁ , -CONR₁₂R₁₃, or - NR₁₄R₁₅ groups; R₁₁, R₁₂,

R₁₃, R₁₄, and R₁₅ may be the same or different and are hydrogen, d-β alkyl, d-β hydroxyalkyl, or C_1-8 alkoxyalkyl; R₁₄ and R₁₅ may form a 5 or 6 membered carbocyclic ring optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, l, m, n, p, q, r, s and t may be the same or different and are zero to about 5; and M is a metal ion equivalent and/or a physiologically acceptable cation of an organic base.

9. The compound of claim 8 wherein A is N-G; B is N; C is [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is gadolinium.

10. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; E is N-G; G is - [CH(R₉) ]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is gadolinium.

11. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q; D is N; E is N-F; F is - [CH(R₈)]_p-N(G)₂; G is -

[CH(R₉)]_r

X; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 2; and M is iron.

12. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -SM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2; and M is iron.

13. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p- N(G)₂; G is - [CH(R₉)]_rX; X is -SO₃M; R₁ is H; R. is H; R_ is H; R₆ is H; R₇ is H; Rg is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is dysprosium.

14. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is - [CH(R₉) ]_rX; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is

dysprosium.

15. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₈)]_p-N(G)₂; G is -

[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R_g is H; i is 1; j is 0; k is 0; 1 is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is lutetium.

16. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₆ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is lutetium.

17. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R8)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is

H; R₈ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; in is 1; n is 1; p is 2; q is 0; r is 2; and M is bismuth.

18. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is - [CH(R₉)]_rX; X is -SM; R₁ is H, R₂ is H, R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2, and M is lead.

19. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₆)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SO₃M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is

H; R₆ is H; R₉ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is holmium.

20. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₆)]--X; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is holmium.

21. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is - [CH(R₈)]_p-N(G)₂; G is - [CH(R₇)]_rX; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; Rg is H; R₆ is H; i is 1; j is 0; k is 0; 1 is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is holmium.

22. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is indium.

23. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is -

[CH(R₆)]_rX; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; 1 is 1; m is 1; n is 1; p is 2; q is 0; r is 2; and M is technetium.

24. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -SM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2; and M is gallium.

25. The compound of claim 8 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₇)]_p-N(G)₂; G is - [CH(R₆)]_rX; X is -SO₃M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; 1 is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is yttrium.

26. The compound of claim 8 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₆)]_rX; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₉ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is samarium.

27. A method of imaging comprising administering to a patient a compound of the general formula:

'B Wherein A is N-G or P-G; B is N or P; C is N-G, P-G or - [CH(R₇)]_q-; D is N or P; E is N-G, P-G, N-F, or P-F; F is - [CH(R₈]_p-P(G)₂ or -[CH(R₈)]_p-P(G)₂; G is -[CH(R₆)]_r-X or - [CH(R₉)]₈-N[CH(R₁₀)_t-X]₂; X is CO₂M, -OPO₃HM, -PO₃HM, -SO₃M, -SM, -OM, or -CONHOM; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₆, R₉ and R₁₀ may be the same or different and are hydrogen, C_1-8 alkyl, or C_6-10 aryl, optionally substituted by one or more hydroxy, C_1-8 alkyl, C_1-8 hydroxyalkyl, C_1-8 hydroxyalkyl, C_1-8 alkoxy, C_6-10 aryl, C_6-10 hydroxyaryl, C_6-10 aryloxy, -CO₂R₁₁, -CONR₁₂R₁₃, or - NR₁₄R₁₅ groups; R_11; R₁₂,

R₁₃, R₁₄, and R₁₅ may be the same or different and are hydrogen, C_1-8 alkyl, C_1-8 hydroxyalkyl, or C_1-8 alkoxyalkyl; R₁₄ and R₁₅ may form a 5 or 6 membered carbocyclic ring optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, l, m, n, p, q, r, s and t may be the same or different and are zero to about 5; and M is a metal ion equivalent and/or a physiologically acceptable cation of an organic base.

28. The method of claim 27 wherein wherein A is N-G; B is N; C is [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₆)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is gadolinium.

29. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is

gadolinium.

30. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q; D is N; E is N-F; F is -[CH(R₆)]_p-N(G)₂; G is - [CH(R₉)]_r

X; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₈ is H; R₆ is H; i is 1; j is 0; k is 0; 1 is 1; m is 1; n is 1; p is 2; q is 0; r is 2; and M is iron.

31. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -SM; R₁ is H; R₂ is

H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2; and M is iron.

32. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p- N(G)₂; G is -

[CH(R₉)]_rX; X is -SO₃M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is dysprosium.

33. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is

dysprosium.

34. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is

H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is lutetium.

35. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is lutetium.

36. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₆)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₉ is H; i is 1; j is 0; k is 0; l iis 1; m is 1; n is 1; p is 2; q is 0; r is 2; and M is bismuth.

37. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -SM; R₁ is H, R₂ is H, R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2, and M is lead.

38. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SO₃M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is holmium.

39. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₆ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is holmium.

40. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is -

[CH(R₆)]--X; X is -CO₂M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R₆ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is holmium.

41. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -CO₂M; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is indium.

42. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SM; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is H; R_g is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 2; and M is technetium.

43. The method of claim 27 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -SM; R1 is H; R2 is H; R3 is H; R4 is H; R5 is H; R6 is H; R9 is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 2; and M is gallium.

44. The method of claim 27 wherein A is N-G; B is N; C is - [CH(R₇)]_q-; D is N; E is N-F; F is -[CH(R₈)]_p-N(G)₂; G is - [CH(R₉)]_rX; X is -SO₃M; R₁ is H; R₄ is H; R₅ is H; R₆ is H; R₇ is

H; R₈ is H; R₆ is H; i is 1; j is 0; k is 0; l is 1; m is 1; n is 1; p is 2; q is 0; r is 1; and M is yttrium.

45. The method of claim 28 wherein A is N-G; B is N; C is N- G; D is N; E is N-G; G is -[CH(R₉)]_rX; X is -PO₃HM; R₁ is H; R₂ is H; R₃ is H; R₄ is H; R₅ is H; R₆ is H; R₆ is H; i is 1; j is 1; k is 1; l is 1; m is 1; n is 1; r is 1; and M is samarium.