Nuclear magnetic resonance contrast compositions

Abstract: A nuclear magnetic resonance contrast composition which comprises a tetraazamacrocyclic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4 ; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6. The nuclear magnetic resonance contrast compositions are particularly suitable for liver imaging in a subject.

Description: Field of the Invention The present invention relates to compositions and methods for enhancing contrast in imaging internal structures and functions of living subjects. Imaging Modalities Imaging of internal structures and functions of living subjects may be accomplished by applying electromagnetic radiation from external sources (as in conventional x-rays and computerized axial tomography) or internal sources (as in PET or positron emission tomography and radionuclide scans). Use of ionizing radiation is avoided in imaging with nuclear magnetic resonance (NMR) and untrasonography, making these methods advantageous for many applications. Whatever the imaging modality, consideration is given to means of increasing image contrast through localization of contrast agents in the region to be imaged. Such agents are frequently metals which emit, absorb, or scatter energy or, as in the case with NMR agents, increase the image signal strength locally. For best effect, agents must be localized. This may be accomplished, for example, by direct injection of contrast agent (as in myelograms or retrograde urethrograms), through metabolic uptake of an agent (as in PET), and by conjugation of contrast agents with monoclonal antibodies which tend to accumulate in certain tissues. The latter process in particular has been used in NMR image enhancement with chelated metal ions. Though well known, the process has several shortcomings: 1 - preparation of the antibody is complex; 2 - diminished immunoreactivity of the antibody occurs following conjugation; 3 - there is limited uptake of the conjugate by the target tissue; and 4 - there may be unfavorable interactions between the chelated ion and the antibody. Because of the advantages of NMR imaging (good resolution and avoidance of ionizing radiation), an NMR contrast agent capable of greater localization would be clinically important. Such an agent would offer significant advantages over contrast agents of the prior art. NMR Contrast Agents The quality of the images obtained from an NMR scan is based on two properties: the proton densities of the various tissues and differences in proton relaxation rates. The proton density of tissues cannot be readily altered. Proton relaxation rates can be adjusted by adding a paramagnetic relaxation agent, more commonly known as a "contrast agent." Contrast agents enhance the contrast in NMR images between magnetically similar but histologically dissimilar tissues. Gadolinium, which has strong paramagnetic properties because of its seven unpaired electrons, has been tested as a contrast agent. It has a large magnetic moment which efficiently relaxes magnetic nuclei and increases tissue contrast in the region of the gadolinium. One drawback of gadolinium as a contrast agent is its toxicity to animals, although a possible remedy for this problem is incorporation of gadolinium in a compound that would pass through the body and be excreted without releasing toxic gadolinium ions. Unfortunately, the rare earth elements (including gadolinium) do not form stable covalent bonds with organic molecules, so such molecules can decompose in vivo and release the toxic ions. Thus, there is a need for effective contrast agents which avoid the toxicity problems inherent in using gadolinium or another metal ion. Further, it is desirable that a contrast agent control or influence the distribution of chelated ions in the body. An even more desirable approach to the site-specific delivery of metal ions would be through use of stable chelates having inherent affinity for various tissue types. Inherent tissue affinity built into the organic chelating agent through modifications in both ionic charge and degree of lipophilic character would offer substantial advantages over currently available agents. WO92/08725 discloses polyazamacrocylic compounds for the complexation of metal ions which are useful for enhancing a magnetic resonance image of a subject. The compounds are of the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = y; y is 3 or 4; R is (CH 2 ) z P(=0)R 1 R 2 ; R 1 is R 3 or OR 3 where R 3 is alkyl, cycloalkyl or aryl; R 2 is H, alkyl or where R 4 is alkyl, cycloalkyl or aryl; and z is 1 to 3. Specifically disclosed is the compound where x is 2, y is 4 and R is (CH 2 ) 2 P(=O)R 1 R 2 where z is 1, R 1 is OH and R 2 is C 2 H 5 referred to as DOTEP herein. SUMMARY OF THE INVENTION The present invention relates to a series of new phosphorous-containing tetraazamacrocyclic chelators which have inherent affinity for certain tissues. Following intravascular injection, chelates comprising these compositions preferentially accumulate in certain tissues, depending on the time after injection. In particular, 1,4,7,10 tetraazacyciododecane-1,4,7,10-tetra(methylenephosphonate nonobutyl ester) has a high affinity for liver tissue and the gastrointestinal tract (in that order). Chelates comprising this agent are thus suitable for liver imaging because of the lipophilic character imparted by the ester functionality. Such agents are not metabolized, and eventually pass out of the body via the urine of faeces. Accordingly, in one aspect the present invention provides a nuclear magnetic resonance contrast composition which comprises a tetraazamacrocyclic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6. In a further aspect the present invention provides a tetraazamacrocylic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6 for use in increasing the contrast of nuclear magnetic resonance images in liver imaging in a subject. In a still further aspect the present invention provides use of a tetraazamacrocylic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; y is 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6 for the manufacture of a medicament for enhancing nuclear magnetic resonance contrast in liver imaging in a subject. While the monobutyl ester above appears well adapted for liver imaging, analogous alkyl esters have also been considered. Monopentyl esters are nearly as good for liver imaging, but monooctyl esters have the disadvantage of very low aqueous solubility. Monopropyl esters, on the other hand, may be used for liver imaging but are less efficient because a substantial portion of the agent is rapidly lost to the kidneys; monoisopropyl esters would behave similarly. Hence, the most preferred embodiment is that described above with monobutyl esters. For use with NMR, the compositions of the present invention must be chelated with a metallic element. While the element is preferably of the rare-earth series (preferably gadolinium), those skilled in the art will recognize that other metallic ions might also be useful for imaging. For example, other metal chelates ( e.g. , chelates of radionuclides or heavy metals) may be used for imaging by scintigraphy, x-radiation, and analogous imaging methods where changes in local tissue parameters can increase image contrast. Chelators of the present invention have the formula where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4 R is (CH 2 ) z P(=0)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is butyl, pentyl or hexyl; and z is 1 to 3. This compound is complexed with a metal to be a polyazamacrocyclic compound-metal complex having the formula where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4 R is (CH 2 ) Z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is butyl, pentyl or hexyl; z is 1 to 3; r is 2 or 3; and M is a metal ion. The x is preferably 2, although 3 is feasible under many circumstances. Combinations of p 2(s) and q 3(s) for x are of course readily produced but the total of p + q must be 4 for the number of units in the polyaza macrocycle. H or CH 3 for R 1 are believed equivalent in use. In a preferred embodiment of the metal complex, p is 1 and q is 3, p is 2 and q is 2 or p is 3 and 1 is 1 and z is most preferably 1. In a more preferred embodiment x is 2, z is 1, R 1 is H and R 2 is butyl. The M +r is preferably a paramagnetic lanthanide, although other divalent or trivalent metal ions, including radionuclides and heavy metals, may also be so complexed. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 scnematically illustrates the structure of DOTEP. Figure 2 schematically illustrates the structure of DOTPMB. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLE 1 (Comparative) Tetraazamacrocyclic compounds DOTEP Synthesis DOTEP, shown in Figure 1, was prepared as follows. 2 ml of dichloroethylphosphine was slowly mixed with ice to form the corresponding ethylphosphinic acid. After warming to room temperature, 390 mg of 1,4,7,10-tetraazacyclododecane tetrahydrochloride (cyclen.4HCl) (Parrish Chem. Co., Ogden, Utah) was added and the mixture heated to boiling under a nitrogen atmosphere. A solution containing 157 mg of paraformaldehyde dissolved in 10 ml of 6M HCl was added at a rate of 0.5 ml/hr, while the mixture continued to reflux. The final mixture was refluxed an additional 4 hours then cooled to room temperature. This solution was concentrated under vacuum to a viscous oil, redissolved into 6 ml of water and loaded onto a DOWEX 50Wx4 (hydrogen form) cation exchange column (7.5 ml bed volume). The column was washed to neutrality with water and the product eluted with 60 ml of 0.66 M HCl. The fractions containing DOTEP were combined, evaporated, redissolved in absolute ethanol and evaporated to a white solid. This solid was dispersed into anhydrous ether, filtered off, pre-dried under nitrogen and dried under vacuum at 60-70°C to yield a white, very hygroscopic solid (360 mg, 44% yield). This solid was stored in sealed ampoules. Elemental analysis and potentiometry shows the solid to be DOTEP.2HCl EXAMPLE 2 Tetraazamacrocyclic compounds DOTP Dibutyl Ester Synthesis Tetraaza-12-crown-4·4HCl (1 g, 3.14x10 -3 mol) was dissolved in water and the pH adjusted to 9.0 using 1M NaOH. The solvent was evaporated and the residue dried under vacuum for 1 hour. Formaldehyde (6.6 mL of 37% solution, 7.15 g, 0.24 mol) was added and the solution stirred for 30 minutes at room temperature. Dibutyl phosphite (5.10 mL of 96% purity, 0.025 mol) was then added and the reaction mixture stirred for 15 hours at room temperature (dipentyl and dihexyl phosphite are so used to produce dipentyl and dihexyl esters respectively). The resulting mixture consisted of two layers. The bottom layer was mostly excess formaldehyde, as indicated by 13 C NMR. The upper layer contained the product and excess phosphite. This layer was separated, concentrated and dried under vacuum for 1 hour. The resulting syrup was loaded onto a silica-gel column (2.5 x 11 cm). The excess phosphite was washed away with methylene chloride (250 mL). The product was eluted with 5% methanol in methylene chloride. 20 mL fractions were collected and monitored by TLC. The fractions containing the product were combined, concentrated, and dried under vacuum,. A pale yellow oil was obtained in 75% yield (2.34 g). 1 H NMR (CDCl 3 ) ; 0.87 (t, J=7.3, 6H), 1.33 (m, J=7.3, 4H), 1.60 (p, J=7.3, 4H), 3.18 (br s, 4H), 3.39 (d, J=8.5, 2H), 4.03 (m, J=7.3, 6.1, 4H). 13 C NMR (CDCl 3 ): 11.3 (s), 16.5 (s), 30.3 (d, J=5.9), 47.3 (d, J=148), 50.0 (br s), 63.8 (d, J=7.3). EXAMPLE 3 Tetraazamacrocyclic compounds DOTP Monobutyl Ester (DOTPMB) Synthesis The dibutyl ester was suspended in 1M KOH (20 mL). The mixture was stirred at 85°C for 17 hours and then at 106°C for 9 hours. The solvent was evaporated and the sample dried under vacuum for 1 hour. Methylene chloride (40 mL) was then added and the remaining solid KOH crushed as much as possible. The solvent was again evaporated and this procedure repeated another two times. The solvent was evaporated and the residue dissolved in methanol (60 mL). The mixture was filtered and then concentrated to a syrup under vacuum. Methylene chloride (80 mL) was added and the mixture filtered. The solvent was evaporated and the residue dried under vacuum to yield a white solid in 71% yield. 13 C NMR (D 2 O; ref. dioxane at 67.0 ppm): 13.5, 18.9, 32.9 (d, J=5.9), 50.7 (d, J=140.6), 51.5 (br s), 64.6 (d, J=5.9). EXAMPLE 4 Biodistribution of Gd-DOTPMB Complexation and Biodistribution A complex of DOTPMB (Figure 2) and Gd complex (0.012M based on metal, 2:1 ligand/metal ratio) was prepared and spiked with tracer quantities of Gd-159. Complexation was determined to be greater than 99% by standard analytical methods described in earlier reports. Two Sprague-Dawley rats were then injected with the complex at a 0.05 mmol/kg level. The animals were sacrificed after 30 minutes and dissected for biodistribution data (Tables I and II); actual counts obtained from various tissues are shown in Table II. At the end of this time period, an average of 58% of the injected dose was found in small intestine (see entry for SM INTES in Table I). A similar experiment performed with a third rat yielded 52% in small intestine (Tables III and IV); actual counts obtained from various tissues are shown in Table IV. The bulk of the remaining activity in each case was eliminated via the renal system (Tables II and IV). In order for localization to occur in the small intestine, the complex must first pass through the liver. Thus, since liver activity at the 30 minute time point (1%) was minimal (see e.g. , Table I), the peak of liver localization passed within the prior 30 minutes. This is evident in an example of biodistribution 15 minutes after administration of chelated tracer, which is documented in Tables VIII and IX. Although by 15 minutes the peak of liver localization had passed for mouse 1, with 4% in the liver and 88% in the small intestine, mouse 2 still had a significant liver concentration (66%) at the 15 minute point. These animal models suggest that imaging within 15 minutes after administration of chelated tracer will be necessary for best definition of the liver. The following test description supports that conclusion. Higher doses would, of course, lengthen the time of liver localization at concentrations sufficient to substantially enhance liver imaging. Gamma Imaging of DOTPMB A Sm(153)-DOTPMB complex was prepared as described above for gamma imaging of a Sprague-Dawley rat. Images were acquired at one minute intervals over a 16-minute period. The image sequence revealed concentration of the chelate in liver within one minute following injection. The complex is then rapidly transported from the liver to the stomach and small intestine. Tables V, VI and VII contain data taken at 1 hour, 24 hours and 72 hours after injection, showing movement of the agent from stomach and intestine to feces. TIME: 30 Minute Biodistribution DATE 8/6/91 LIGAND DOTPMB-K, METAL Gd-159, COMMENTS 99% Complexation 4:1, LIG:MET Molar Ratio, (Metal = 3X10-4M) %DOSE/GRAM RAT 1 RAT 2 AVERAGE +/- WEIGHT 216.72 228.17 222.45 8.096 BONE 0.019 0.006 0.01 0.009 TAIL 0.077 0.068 0.07 0.007 LIVER 0.114 0.069 0.09 0.032 KIDNEY 0.169 0.126 0.15 0.031 SPLEEN 0.011 0.021 0.02 0.007 MUSCLE 0.007 0.005 0.01 0.001 BLOOD 0.021 0.017 0.02 0.003 HEART 0.014 0.000 0.01 0.010 LUNG 0.126 0.023 0.07 0.073 BRAIN 0.002 0.003 0.00 0.000 0.000 = NO ACTIVITY DETECTED DOSE BONE 0.281 0.106 0.193 0.124 TAIL 0.212 0.191 0.201 0.015 LIVER 1.234 0.755 0.994 0.339 KIDNEY 0.392 0.299 0.346 0.066 SPLEEN 0.009 0.011 0.010 0.002 MUSCLE 0.658 0.506 0.582 0.108 BLOOD 0.299 0.250 0.274 0.035 HEART 0.011 0.000 0.006 0.008 LUNG 0.158 0.029 0.094 0.091 BRAIN 0.004 0.004 0.004 0.001 STOMACH 0.574 0.530 0.552 0.031 SM INTES 80.304 36.405 58.354 31.041 LG INTES 0.591 0.433 0.512 0.112 (see legend for Table I) DATA COUNTS ORGAN N ENTER WT BCKG COR %DOSE/G % DOSE 1 Std A X Rat 1 Wt 0 1 Std B X 216.72 0 2 414838 Std C av 414404.5 414405 3 480 Bone 0.60 47 1.87E-02 2.81E-01 4 1311 Tail 2.74 878 7.73E-02 2.12E-01 5 5546 Liver 10.86 5113 1.14E-01 1.23E+00 6 2058 Kidney 2.32 1625 1.69E-01 3.92E-01 7 469 Spleen 0.75 36 1.14E-02 8.57E-03 8 478 Muscle 1.52 45 7.06E-03 6.58E-01 9 576 Blood 1.62 143 2.12E-02 2.99E-01 10 481 Heart 0.82 48 1.40E-02 1.15E-02 11 1088 Lung 1.25 655 1.26E-01 1.58E-01 12 449 Brain 1.62 16 2.31E-03 3.74E-03 13 2811 Stomach 2378 5.74E-01 14 333215 Sm Intes 332782 8.03E+01 15 2883 Lg Intes 2450 5.91E-01 16 150310 Urine 149877 3.62E+01 17 400 Urine 0 0.00E+00 18 428 Urine 0 0.00E+00 19 443 BKG 228.17 WT Rat 2 20 451 Bone 0.67 18 6.30E-03 1.06E-01 21 1225 Tail 2.82 792 6.77E-02 1.91E-01 22 3561 Liver 10.96 3128 6.89E-02 7.55E-01 23 1674 Kidney 2.38 1241 1.26E-01 2.99E-01 24 480 Spleen 0.53 47 2.12E0-02 1.12E-02 25 469 Muscle 1.66 36 5.16E-03 5.06E-01 26 559 Blood 1.80 126 1.68E-02 2.50E-01 27 430 Heart 0.85 0 0.00E+00 0.00E+00 28 554 Lung 1.28 121 2.27E-02 2.91E-02 29 452 Brain 1.55 19 2.88E-03 4.46E-03 30 2629 Stomach 2196 5.30E-01 151297 Sm Intes 150864 3.64E+01 2229 Lg Intes 1796 4.33E-01 116731 Urine 116298 2.81E+01 901 Urine 468 1.13E-01 423 Urine 0 0.00E+00 424 BKG 0 BKG AVG = 434 TIME: 30 Minute Biodistribution DATE 8/6/91 LIGAND DOTPMB-K, METAL Gd-159, COMMENTS 99% Complexation 4:1, LIG:MET Molar Ratio, (Metal = 3x10-4M) %DOSE/GRAM RAT 3 WEIGHT: 235.14 Bone 0.006 Tail 0.013 Liver 0.016 Kidney 0.121 Spleen 0.000 Muscle 0.000 Blood 0.000 Heart 0.000 Lung 0.009 Brain 0.004 0.000 = No Activity Detected Bone 0.109 Tail 0.038 Liver 0.196 Kidney 0.303 Spleen 0.000 Muscle 0.026 Blood 0.000 Heart 0.000 Lung 0.012 Brain 0.005 Stomach 0.012 Sm Intes 51.549 Lg Intes 2.232 (see legend for Table III) DATA COUNTS ORGAN N ENTER WT BCKG COR %DOSE/G % DOSE 1 Std A X Rat 1 Wt 0 1 Std B X 235.14 0 2 414367 Std C av 413946 413946 3 439 Bone 0.69 18 6.30E-03 1.09E.01 4 578 Tail 2.95 157 1.29E-02 3.79E-02 5 1232 Liver 11.96 811 1.64E-02 1.96E-01 6 1675 Kidney 2.51 1254 1.21E-01 3.03E-01 7 418 Spleen 0.66 0 0.00E+00 0.00E+00 8 423 Muscle 1.91 2 2.53E-04 2.56E-02 9 412 Blood 1.84 0 0.00E+00 0.00E+00 10 417 Heart 0.85 0 0.00E+00 0.00E+00 11 470 Lung 1.25 49 9.47E-03 1.18E-02 12 442 Brain 1.28 21 3.96E-03 5.07E-03 13 470 Stomach 49 1.18E-02 14 213806 Sm Intes 213385 5.15E+01 15 9661 Lg Intes 9240 2.23E+00 16 102818 Urine 102397 2.47E+01 17 12520 Urine 12099 2.92E+00 18 447 Urine 26 6.28E-03 19 421 BKG BKG AVG = 421 One Hour Biodistribution, Imaged Rat TIME: One Hour biodistribution DATE 8/8/91 LIGAND DOTPMB-K, D. METAL Sm=153 COMMENTS 99% Complex 4:1, LIG:MET Molar Ratio (Metal = 3X10-4M) % DOSE/GRAM % DOSE WEIGHT: 263.82 Bone 0.004 0.067 Tail 0.038 0.093 Liver 0.014 0.144 Kidney 0.084 0.245 Spleen 0.016 0.011 Muscle 0.001 0.078 Blood 0.001 0.019 Stomach 45.144 Smll Int 31.408 Lrg Int 0.003 24 Hour Biodistribution, Imaged Rat TIME: 24 Hour biodistribution DATE 8/8/91 LIGAND DOTPMB-K METAL Sm=153 COMMENTS 99% Complex 4:1, LIG:MET Molar Ratio (Metal = 3X10-4M) % DOSE/GRAM % DOSE WEIGHT: 263.82 Bone 0.008 0.146 Tail 0.015 0.036 Liver 0.010 0.106 Kidney 0.154 0.451 Spleen 0.029 0.020 Muscle 0.017 1.883 Blood 0.000 0.004 Stomach 0.053 Smll Int 2.109 Smll Int 19.611 Lrg Int 8.351 Feces 35.981 Urine 2.799 Paper 0.126 Rat Injected: 8/8/91 TIME: 72 hour biodistribution DATE 8/12/91 LIGAND DOTPMB-K METAL Sm=153 COMMENTS 99% Complex 4:1, LIG:MET Molar Ratio (Metal = 3X10-4M) % DOSE/GRAM % DOSE WEIGHT: 269.58 Bone 0.014 0.219 Tail 0.002 0.005 Liver 0.002 0.030 Kidney 0.019 0.054 Spleen 0.000 0.000 Muscle 0.000 0.000 Blood 0.000 0.000 Feces 5.832 Feces 5.467 Feces 2.464 Urine 0.077 Bladder 0.242 (Comparative) File=BTY15STD Summary Standardized Data Mouse #2 (15 minute biodistribution), 99% complex, 25.0 UL dose Ca added to complex at 1;1 molar, lig: Ca DATE 10/30/91 LIGAND DOTPME-K METAL Sm-15 COMMENTS #08-07-91 2:1, Lig:Met Molar Ratio, (Metal=3x10-4M), pH 7-=8 %DOSE/GRAM MOUSE 1 MOUSE 2 AVERAGE WEIGHT 15.854 10.702 13.278 BONE 0.171 3.169 1.670 TAIL 1.374 83.296 42.335 LIVER 3.979 66.441 35.210 KIDNEY 0.889 14.568 7.728 SPLEEN 1.260 0.831 1.046 MUSCLE 0.173 1.437 0.805 BLOOD 43.105 3.743 23.424 HEART 0.472 2.418 1.445 LUNG 0.697 2.735 1.716 BRAIN 0.023 0.139 0.081 TUMOR 0.648 4.844 2.746 STOMACH 14.272 4.343 9.308 SMALL INT. 88.504 40.343 64.423 LARGE INT. 3.320 2.298 2.809 URINE 0.000 0.000 0.000 BODY 1 0.408 1.637 1.022 BODY 2 0.148 5.594 2.871 *MOUSE 2 DID NOT BECOME ACTIVE AFTER ANESTHESIA, HOWEVER ALIVE*** (Comparative) %DOSE MOUSE 1 MOUSE 2 BONE 0.149 2.100 LIVER 3.379 37.732 KIDNEY 0.199 3.610 SPLEEN 0.095 0.039 MUSCLE 1.179 6.615 BLOOD 44.420 2.604 HEART 0.033 0.157 LUNG 0.090 0.210 BRAIN 0.010 0.054 TUMOR 0.062 0.237 STOMACH 3.565 0.586 SMALL INT. 86.734 27.837 LARGE INT. 2.994 1.145 URINE 12.857 0.007 BODY 1 2.294 6.890 BODY 2 0.585 17.147

Claims: A nuclear magnetic resonance contrast composition which comprises a tetraazamacrocyclic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6. A composition as claimed in claim 1 where x is 2. A composition as claimed in claim 1 where p is 1 and q is 3, p is 2 and q is 2, or p is 3 and q is 1. A composition as claimed in claim 1 where z is 1. A composition as claimed in any one of the preceding claims wherein R 2 is C 4 H 9 . A composition as claimed in any one of the preceding claims wherein the lanthanide is gadolinium. A tetraazamacrocyclic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6 for use in increasing the contrast of nuclear magnetic resonance images in liver imaging in a subject. A tetraazamacrocyclic compound - metal complex as claimed in claim 7 where x is 2. A tetraazamacrocyclic compound - metal complex as claimed in claim 7 where p is 1 and q is 3, p is 2 and q is 2, or p is 3 and q is 1. A tetraazamacrocyclic compound - metal complex as claimed in claim 7 where z is 1. A tetraazamacrocyclic compound - metal complex as claimed in any one of claims 7 to 10 where R 2 is C 4 H 9 . A tetraazamacrocyclic compound - metal complex as claimed in any one of claims 7 to 11 where the lanthanide is gadolinium. Use of a tetraazamacrocyclic compound - paramagnetic lanthanide complex having the formula: where x is 2, 3 or a combination of p 2(s) and q 3(s) where p + q = 4; y is 4; R is (CH 2 ) z P(=O)OR 1 OR 2 ; R 1 is H or CH 3 ; R 2 is C n H 1+2n ; z is 1 to 3; r is 2 or 3; M is a paramagnetic lanthanide; and n is 4 to 6 for the manufacture of a medicament for enhancing nuclear magnetic resonance contrast in liver imaging in a subject. The use as claimed in claim 13 where x is 2. The use as claimed in claim 13 where p is 1 and q is 3, p is 2 and q is 2, or p is 3 and q is 1. The use as claimed in claim 13 where z is 1. The use as claimed in any one of claims 13 to 16 where R 2 is C 4 H 9 . The use as claimed in any one of claims 13 to 17 wherein the lanthanide is gadolinium.

Inventors: KIEFER GARRY E, SHERRY ALLAN DEAN, KIEFER, GARRY E., SHERRY, ALLAN DEAN
Applicants: DOW CHEMICAL CO, UNIV TEXAS, BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM, THE DOW CHEMICAL COMPANY
Application year: 1993
Main classification: C07F9
IPC codes: C07F9, A61K49, C07D257