US5407657A — Hybrid magnetic resonance contrast agents

Claim 1

Independent Claim 65 words

A hybrid, copolymeric magnetic-resonance-imaging contrast agent comprising: at least one chelating unit monomer; at least one free radical monomer linked to said at least one chelating unit monomer; and at least one paramagnetic ion combined with at least one of said at least one chelating unit monomer; wherein said chelating unit monomer is a polynitrilo chelating agent and said free radical monomer is a nitroxide.

Claim 2

Dependent Claim 65 words

A hybrid, copolymeric magnetic-resonance-imaging contrast agent comprising: at least one chelating unit monomer; at least one free radical monomer linked to said at least one chelating unit monomer; and at least one paramagnetic ion combined with at least one of said at least one chelating unit monomer; wherein said chelating unit monomer is a polynitrilo chelating agent and said free radical monomer is a nitroxide.

Claim 3

Dependent Claim 173 words

The contrast agent of claim 1, having the following structure: ##STR36## wherein Ch is a polynitrilo chelating unit monomer, L is a linker monomer, FR is a nitroxide free radical monomer, and M is a paramagnetic ion; wherein q=1 to 10,000; wherein, within each of the q polymeric groups ##STR37## independently, p=0 to 10,000 and p'=0 to 10,000; wherein, within each of the p oligomeric groups ##STR38## independently, n=0 to 10,000 and j=0 to 10,000; for each group of paramagnetic ions ##STR39## chelated by each of the n chelating unit monomers --Ch-- in the p oligomeric groups, independently, k=0 to 2; and for each group of free radical monomers ##STR40## linked to each of the j linker monomers --L-- in the p oligomeric groups, independently, m=0 to 2; and wherein, within each of the p' oligomeric groups ##STR41## independently, n=0 to 10,000 and m=0 to 10,000; and for each group of paramagnetic ions ##STR42## chelated by each of the n chelating unit monomers --Ch-- in the p' oligomeric groups, independently, k=0 to 2.

Claim 4

Dependent Claim 51 words

The contrast agent of claim 1, wherein each polynitrilo chelating agent comprises at least one COOH, COOR 1 , or COZ group; each R 1 being, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group or an anhydride; and each Z being, independently, Cl, Br, or I.

Claim 5

Dependent Claim 42 words

The contrast agent of claim 3, wherein at least one of said C1-C20 alkyl or cycloalkyl group is substituted with at least one moiety selected from the group of OH, NH 2 , SH, COOH, and PO 4 , or mixtures thereof.

Claim 6

Dependent Claim 18 words

The contrast agent of claim 3, wherein each R 1 is, independently, a polyhydroxy-substituted alkyl or cycloalkyl group.

Claim 7

Dependent Claim 30 words

The contrast agent of claim 5, wherein said polyhydroxy-substituted alkyl or cycloalkyl group is selected from the group consisting of sugar alcohols, monosaccharides, polysaccharides, and synthetic polymers, or mixtures thereof.

Claim 8

Dependent Claim 57 words

The contrast agent of claim 1, wherein each polynitrilo chelating unit monomer consists, independently, of a chelating agent selected from the group consisting of ethylenediamine tetraacetic acid; diethylenetriamine pentaacetic acid; 1,5-di-methoxyethylene-iminocarbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5,-triazapentane; 1,5-di-α,-dihydroxypropeneimino-carbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5-triazapentane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid; 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid; hydroxybenzyl-ethylenediamine diacetic acid; N,N'-bis(pyridoxyl-5-phosphate)ethylenediamine-N,N'-diacetic acid; 1,4,7-triazacyclononane-N,N',N"-triacetic acid; 1-oxa-4,7,10-triazacyclododecane-triacetic acid; 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; triethylenetetraamine hexaacetic acid; 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; and anhydrides thereof.

Claim 9

Dependent Claim 25 words

The contrast agent of claim 1, wherein each free radical monomer is selected from the group consisting of heterocyclic nitroxide monomers and non-heterocyclic nitroxide monomers.

Claim 10

Dependent Claim 104 words

The contrast agent of claim 8, wherein said heterocyclic nitroxide monomers have the following general structure: ##STR43## wherein a five member ring is pyrrolidine, oxazolidine, imidazolidine, or thiazolidine; a six member ring is piperidine; and each of Ra, Rb, Rc and Rd is, independently, a C1-C20 alkyl or cycloalkyl group, said alkyl or cycloalkyl group being interrupted or terminated with OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 11

Dependent Claim 22 words

The contrast agent of claim 8, wherein said non-heterocyclic nitroxide monomers are selected from the group consisting of diphenylnitroxide and di-tert-butyl nitroxide.

Claim 12

Dependent Claim 81 words

The contrast agent of claim 1, wherein each nitroxide free radical monomer is selected from the group consisting of 2,2,6,6-tetramethylpiperidine-1-oxyl; 2,2,4,4-tetramethyl-pyrrolidine-1-oxyl; 2,2,4,4-tetramethyl-imidazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-thiazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-oxazolidine-3-oxyl; 2,2,6,6-tetramethylpyrimidine-1-oxyl; diphenyl-nitroxide; and di-tert-butylnitroxide; and wherein each nitroxide may have one or more OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 13

Dependent Claim 36 words

The contrast agent of claim 1, wherein each nitroxide free radical monomer is a monofunctionalized compound selected from the group consisting of 1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl acrylate; 4-(iodomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperdinyl-1-oxy; 4-(bromomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperidinyl-1-oxy; 3-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-chlorocarbonyl-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-aminomethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxymethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 3-chloroformyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; and 3-thiocabamoylmethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy.

Claim 14

Dependent Claim 36 words

The contrast agent of claim 1, wherein each nitroxide free radical monomer is a difunctionalized compound selected from the group consisting of cis-1-oxyl-2,2,5,5-tetramethylpyrrolidine; trans-1-oxyl-2,2,5,5-tetramethylpyrrolidine; 3-amino-4-aminomethylene-2,2,5,5-tetramethylpyrrolidine; cis-2,5-dimethyl-2(aminomethyl)-5-(2-carboxyethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(methoxycarbonylmethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(2-hydroxyhexyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(2-carboxyethyl)-pyrrolidinyl-1-oxy; cis-2,5-dimethyl-2,5-bis(2-hydroxy-5-methylphenyl)-tetrahydroxypyrrol-1-oxy; 3-amino-4-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 2,5-di-tertbutyl-3,4-diethyloxycarbonyl-pyrrol-1-oxyl; and 1,4-bis(4-hydroxy-2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)-butane.

Claim 15

Dependent Claim 21 words

The contrast agent of claim 1, wherein each paramagnetic ion is selected from the group consisting of transition and lanthanide elements.

Claim 16

Dependent Claim 31 words

The contrast agent of claim 1, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III), Dy(III), Yb(III), and Ho(III).

Claim 17

Dependent Claim 21 words

The contrast agent of claim 1, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II) and Fe(III).

Claim 18

Dependent Claim 127 words

The contrast agent of claim 2, wherein each linker monomer has the following general structure: X.sub.1 [(CHR.sub.2).sub.m --CHR.sub.2 --Y].sub.n --G.sub.q --(CHR.sub.2).sub.m' --CHR.sub.2 --X.sub.2 wherein each R 2 is, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group; X 1 and X 2 are, independently, OH, NH 2 , NHR 1 , COOH, COOR 1 , SH, Z or NCS; Y is O, NH, NR 1 , S or CO; each R 1 is, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride; each Z is, independently, Cl, Br, or I; G is a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group, a saccharide, a peptide or a polysulfide; and m, m', n, and q are, independently, 0 to 10,000.

Claim 19

Dependent Claim 43 words

The contrast agent of claim 17, wherein each linker monomer is, independently, a polyamino linker monomer selected from the group consisting of 1,2-diaminoethane, 13-diaminopropane, 1,4-diaminobutane, 1,5-diamino-3-(2-aminoethyl)-pentane, N,N'-dimethyl-1,2-diaminoethane, N,N'-dimethyl-1,3-diaminopropane, 2-hydroxy-1,3-diaminopropane, 2-amino-1,3-diaminopropane, 2,3-diamino-1,4-butanediol, 1,4-diamino-2,3-butane diol, 1,4-diaminocyclohexane, 1,4-phenylenediamine, 1,1,1-tris(aminomethyl)ethane, 2,2',2"-tris-aminoethylamine, tris(aminomethylene)methane, diethylenetriamine, triethylenetetraamine, 1,3,5-triaminocyclohexane, and 1,3,5-triaminobenzene.

Claim 20

Dependent Claim 36 words

The contrast agent of claim 17, wherein each linker monomer is a polyhydroxy linker monomer selected from the group consisting of 2,2-dimethyl-1,3-propanediol, tris-(2-hydroxyethyl)amine, 1,1,1-tris-(hyroxymethylene)ethane, glycerine, erythritol, sugar alcohols, polyethyleneglycol, w-amino-polyethyleneglycol, N-substituted-w-aminopolyethyleneglycol, w-thiol-polyethyleneglycol, polysulfide-blocked polyethyleneglycol, and polyethylene-imine.

Claim 21

Dependent Claim 21 words

The contrast agent of claim 17, wherein each linker monomer is selected from the group consisting of ethylenedioxydiethylamine, N,N'-bis-dihydroxypropylethylenedioxydiethylamine, and ethylenedioxydiethylmercaptane.

Claim 22

Dependent Claim 52 words

The contrast agent of claim 2, wherein each polynitrilo chelating unit monomer comprises at least one COOH, COOR 1 , or COZ group; each R 1 being, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group or an anhydride; and each Z being, independently, Cl, Br, or I.

Claim 23

Dependent Claim 42 words

The contrast agent of claim 21, wherein at least one of said C1-C20 alkyl or cycloalkyl group is substituted with at least one moiety selected from the group of OH, NH 2 , SH, COOH, and PO 4 , or mixtures thereof.

Claim 24

Dependent Claim 18 words

The contrast agent of claim 21, wherein each R 1 is, independently, a polyhydroxy-substituted alkyl or cycloalkyl group.

Claim 25

Dependent Claim 27 words

The contrast agent of claim 23, wherein said polyhydroxy-substituted alkyl or cycloalkyl group is selected from the group consisting of sugar alcohols, monosaccharides, polysaccharides, and synthetic polymers.

Claim 26

Dependent Claim 57 words

The contrast agent of claim 2, wherein each polynitrilo chelating unit monomer consists, independently, of a chelating agent selected from the group consisting of ethylenediamine tetraacetic acid; diethylenetriamine pentaacetic acid; 1,5-di-methoxyethylene-iminocarbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5,-triazapentane; 1,5-di-α,-dihydroxypropeneimino-carbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5-triazapentane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid; 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid; hydroxybenzyl-ethylenediamine diacetic acid; N,N'-bis(pyridoxyl-5-phosphate)ethylenediamine-N,N'-diacetic acid; 1,4,7-triazacyclononane-N,N',N"-triacetic acid; 1-oxa-4,7,10-triazacyclododecane-triacetic acid; 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; triethylenetetraamine hexaacetic acid; 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; and anhydrides thereof.

Claim 27

Dependent Claim 26 words

The contrast agent of claim 2, wherein each free radical monomer, independently, is selected from the group consisting of heterocyclic nitroxide monomers and non-heterocyclic nitroxide monomers.

Claim 28

Dependent Claim 104 words

The contrast agent of claim 26, wherein said heterocyclic nitroxide monomers have the following general structure: ##STR44## wherein a five member ring is pyrrolidine, oxazolidine, imidazolidine, or thiazolidine; a six member ring is piperidine; and each of Ra, Rb, Rc and Rd is, independently, a C1-C20 alkyl or cycloalkyl group, said alkyl or cycloalkyl group being interrupted or terminated with OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 29

Dependent Claim 22 words

The contrast agent of claim 26, wherein said non-heterocyclic nitroxide monomers are selected from the group consisting of diphenylnitroxide and di-tert-butyl nitroxide.

Claim 30

Dependent Claim 82 words

The contrast agent of claim 2, wherein each nitroxide free radical monomer is, independently, selected from the group consisting of 2,2,6,6-tetramethylpiperidine-1-oxyl; 2,2,4,4-tetramethyl-pyrrolidine-1-oxyl; 2,2,4,4-tetramethylimidazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-thiazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-oxazolidine-3-oxyl; 2,2,6,6-tetramethylpyrimidine-1-oxyl; diphenyl-nitroxide; and di-tertbutylnitroxide; and wherein each nitroxide may have one or more OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 31

Dependent Claim 37 words

The contrast agent of claim 2, wherein each nitroxide free radical monomer is, independently, a monofunctionalized compound selected from the group consisting of 1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl acrylate; 4-(iodomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperdinyl-1-oxy; 4-(bromomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperidinyl-1-oxy; 3-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-chlorocarbonyl-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-aminomethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxymethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxyl; 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 3-chloroformyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; and 3-thiocabamoylmethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy.

Claim 32

Dependent Claim 37 words

The contrast agent of claim 2, wherein each nitroxide free radical monomer is, independently, a difunctionalized compound selected from the group consisting of cis-1-oxyl-2,2,5,5-tetramethylpyrrolidine; trans-1-oxyl-2,2,5,5-tetramethylpyrrolidine; 3-amino-4-aminomethylene-2,2,5,5-tetramethylpyrrolidine; cis-2,5-dimethyl-2(aminomethyl)-5-(2-carboxyethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(methoxycarbonylmethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(2-hydroxyhexyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(2-carboxyethyl)-pyrrolidinyl-1-oxy; cis-2,5-dimethyl-2,5-bis(2-hydroxy-5-methylphenyl)-tetrahydroxypyrrol-1-oxy; 3-amino-4-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 2,5-di-tert-butyl-3,4-diethyloxycarbonyl-pyrrol-1-oxyl; and 1,4-bis(4-hydroxy-2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)-butane.

Claim 33

Dependent Claim 21 words

The contrast agent of claim 2, wherein each paramagnetic ion is selected from the group consisting of transition and lanthanide elements.

Claim 34

Dependent Claim 31 words

The contrast agent of claim 2, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III), Dy(III), Yb(III), and Ho(III).

Claim 35

Dependent Claim 21 words

The contrast agent of claim 2, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II) and Fe(III).

Claim 36

Dependent Claim 166 words

The contrast agent of claim 1, having the following structure: ##STR45## wherein Ch is a polynitrilo chelating unit monomer, L is a linker monomer, FR is a nitroxide free radical monomer, and M is a paramagnetic ion; wherein, independently, p=1 to 10,000 and p'=1 to 10,000; wherein, within each of the p oligomeric groups ##STR46## independently, n=0 to 10,000 and j=0 to 10,000; for each group of paramagnetic ions ##STR47## chelated by each of the n chelating unit monomers --Ch-- in each of the p oligomeric groups, independently, k=0 to 2; and for each group of free radical monomers ##STR48## linked to each of the j linker monomers --L-- in each of the oligomeric groups, independently, m=0 to 2; and wherein, within each of the p' oligomeric groups ##STR49## independently, n=0 to 10,000 and m=0 to 10,000; and for each group of paramagnetic ions ##STR50## chelated by each of the n chelating unit monomers --Ch-- in each of the p' oligomeric groups, independently, k=0 to 2.

Claim 37

Dependent Claim 127 words

The contrast agent of claim 35, wherein each linker monomer has the following general structure: X.sub.1 [(CHR.sub.2).sub.m --CHR.sub.2 --Y].sub.n --G.sub.q --(CHR.sub.2).sub.m' --CHR.sub.2 --X.sub.2 wherein each R 2 is, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group; X 1 and X 2 are, independently, OH, NH 2 , NHR 1 , COOH, COOR 1 , SH, Z or NCS; Y is O, NH, NR 1 , S or CO; each R 1 is, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride; each Z is, independently, Cl, Br, or I; G is a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group, a saccharide, a peptide or a polysulfide; and m, m', n, and q are, independently, 0 to 10,000.

Claim 38

Dependent Claim 43 words

The contrast agent of claim 36, wherein each linker monomer is, independently, a polyamino linker monomer selected from the group consisting of 1,2-diaminoethane, 13-diaminopropane, 1,4-diaminobutane, 1,5-diamino-3-(2-aminoethyl)-pentane, N,N'-dimethyl-1,2-diaminoethane, N,N'-dimethyl-1,3-diaminopropane, 2-hydroxy-1,3-diaminopropane, 2-amino-1,3-diaminopropane, 2,3-diamino-1,4-butanediol, 1,4-diamino-2,3-butane diol, 1,4-diaminocyclohexane, 1,4-phenylenediamine, 1,1,1-tris-(aminomethyl)ethane, 2,2',2"-tris-aminoethylamine, tris-(aminomethylene)methane, diethylenetriamine, triethylenetetraamine, 1,3,5-triaminocyclohexane, and 1,3,5-triaminobenzene.

Claim 39

Dependent Claim 36 words

The contrast agent of claim 36, wherein each linker monomer is a polyhydroxy linker monomer selected from the group consisting of 2,2-dimethyl-1,3-propanediol, tris-(2-hydroxyethyl)amine, 1,1,1-tris-(hyroxymethylene)ethane, glycerine, erythritol, sugar alcohols, polyethyleneglycol, w-amino-polyethyleneglycol, N-substituted-w-aminopolyethyleneglycol, w-thiol-polyethyleneglycol, polysulfide-blocked polyethyleneglycol, and polyethylene-imine.

Claim 40

Dependent Claim 21 words

The contrast agent of claim 36, wherein each linker monomer is selected from the group consisting of ethylenedioxydiethylamine, N,N'-bis-dihydroxypropylethylenedioxydiethylamine, and ethylenedioxydiethylmercaptane.

Claim 41

Dependent Claim 52 words

The contrast agent of claim 35, wherein each polynitrilo chelating unit monomer comprises at least one COOH, COOR 1 , or COZ group; each R 1 being independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group or an anhydride; and each Z being, independently, Cl, Br, or I.

Claim 42

Dependent Claim 42 words

The contrast agent of claim 40, wherein at least one of said C1-C20 alkyl or cycloalkyl group is substituted with at least one moiety selected from the group of OH, NH 2 , SH, COOH, and PO 4 , or mixtures thereof.

Claim 43

Dependent Claim 18 words

The contrast agent of claim 40, wherein each R 1 is, independently, a polyhydroxy-substituted alkyl or cycloalkyl group.

Claim 44

Dependent Claim 27 words

The contrast agent of claim 42, wherein said polyhydroxy-substituted alkyl or cycloalkyl group is selected from the group consisting of sugar alcohols, monosaccharides, polysaccharides, and synthetic polymers.

Claim 45

Dependent Claim 57 words

The contrast agent of claim 35, wherein each polynitrilo chelating unit monomer consists, independently, of a chelating agent selected from the group consisting of ethylenediamine tetraacetic acid; diethylenetriamine pentaacetic acid; 1,5-di-methoxyethylene-iminocarbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5,-triazapentane; 1,5-di-α,-dihydroxypropeneimino-carbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5-triazapentane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid; 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid; hydroxybenzyl-ethylenediamine diacetic acid; N,N'-bis(pyridoxyl-5-phosphate)ethylenediamine-N,N'-diacetic acid; 1,4,7-triazacyclononane-N,N',N"-triacetic acid; 1-oxa-4,7,10-triazacyclododecane-triacetic acid; 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; triethylenetetraamine hexaacetic acid; 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; and anhydrides thereof.

Claim 46

Dependent Claim 26 words

The contrast agent of claim 35, wherein each free radical monomer, independently, is selected from the group consisting of heterocyclic nitroxide monomers and non-heterocyclic nitroxide monomers.

Claim 47

Dependent Claim 104 words

The contrast agent of claim 45, wherein said heterocyclic nitroxide monomers have the following general structure: ##STR51## wherein a five member ring is pyrrolidine, oxazolidine, imidazolidine, or thiazolidine; a six member ring is piperidine; and each of Ra, Rb, Rc and Rd is, independently, a C1-C20 alkyl or cycloalkyl group, said alkyl or cycloalkyl group being interrupted or terminated with OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 48

Dependent Claim 22 words

The contrast agent of claim 45, wherein said non-heterocyclic nitroxide monomers are selected from the group consisting of diphenylnitroxide and di-tert-butyl nitroxide.

Claim 49

Dependent Claim 82 words

The contrast agent of claim 35, wherein each nitroxide free radical monomer is, independently, selected from the group consisting of 2,2,6,6-tetramethylpiperidine-1-oxyl; 2,2,4,4-tetramethyl-pyrrolidine-1-oxyl; 2,2,4,4-tetramethylimidazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-thiazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-oxazolidine-3-oxyl; 2,2,6,6-tetramethylpyrimidine-1-oxyl; diphenyl-nitroxide; and di-tertbutylnitroxide; and wherein each nitroxide may have one or more OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 50

Dependent Claim 37 words

The contrast agent of claim 35, wherein each nitroxide free radical monomer is, independently, a monofunctionalized compound selected from the group consisting of 1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl acrylate; 4-(iodomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperdinyl-1-oxy; 4-(bromomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperidinyl-1-oxy; 3-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-chlorocarbonyl-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-aminomethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxymethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxyl; 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 3-chloroformyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; and 3-thiocabamoylmethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy.

Claim 51

Dependent Claim 37 words

The contrast agent of claim 35, wherein each nitroxide free radical monomer is, independently, a difunctionalized compound selected from the group consisting of cis-1-oxyl-2,2,5,5-tetramethylpyrrolidine; trans-1-oxyl-2,2,5,5-tetramethylpyrrolidine; 3-amino-4-aminomethylene-2,2,5,5-tetramethylpyrrolidine; cis-2,5-dimethyl-2(aminomethyl)-5-(2-carboxyethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(methoxycarbonylmethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(2-hydroxyhexyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(2-carboxyethyl)-pyrrolidinyl-1-oxy; cis-2,5-dimethyl-2,5-bis(2-hydroxy-5-methylphenyl)-tetrahydroxypyrrol-1-oxy; 3-amino-4-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 2,5-di-tert-butyl-3,4-diethyloxycarbonyl-pyrrol-1-oxyl; and 1,4-bis(4-hydroxy-2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)-butane.

Claim 52

Dependent Claim 21 words

The contrast agent of claim 35, wherein each paramagnetic ion is selected from the group consisting of transition and lanthanide elements.

Claim 53

Dependent Claim 31 words

The contrast agent of claim 35, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III), Dy(III), Yb(III), and Ho(III).

Claim 54

Dependent Claim 21 words

The contrast agent of claim 35, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II) and Fe(III).

Claim 55

Dependent Claim 115 words

The contrast agent of claim 1, having the following structure: ##STR52## wherein Ch is a polynitrilo chelating unit monomer, L is a linker monomer, FR is a nitroxide free radical monomer, and M is a paramagnetic ion; wherein p=1 to 10,000; and wherein, within each of the p oligomeric groups ##STR53## independently, n=0 to 10,000 and j=0 to 10,000; for each group of paramagnetic ions ##STR54## chelated by each of the n chelating unit monomers --Ch-- in each of the p oligomeric groups, independently, k=0 to 2; and for each group of free radical monomers ##STR55## linked to each of the j linker monomers --L-- in each of the oligomeric groups, independently, m=0 to 2.

Claim 56

Dependent Claim 127 words

The contrast agent of claim 54, wherein each linker monomer has the following general structure: X.sub.1 [(CHR.sub.2).sub.m --CHR.sub.2 --Y].sub.n --G.sub.q --(CHR.sub.2).sub.m' --CHR.sub.2 --X.sub.2 wherein each R 1 is, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group; X 1 and X 2 are, independently, OH, NH 2 , NHR 1 , COOH, COOR 1 , SH, Z or NCS; Y is O, NH, NR 1 , S or CO; each R 1 is, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride; each Z is, independently, Cl, Br, or I; G is a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group, a saccharide, a peptide or a polysulfide; and m, m', n, and q are, independently, 0 to 10,000.

Claim 57

Dependent Claim 43 words

The contrast agent of claim 55, wherein each linker monomer is, independently, a polyamino linker monomer selected from the group consisting of 1,2-diaminoethane, 13-diaminopropane, 1,4-diaminobutane, 1,5-diamino-3-(2-aminoethyl)-pentane, N,N'-dimethyl-1,2-diaminoethane, N,N'-dimethyl-1,3-diaminopropane, 2-hydroxy-1,3-diaminopropane, 2-amino-1,3-diaminopropane, 2,3-diamino-1,4-butanediol, 1,4-diamino-2,3-butane diol, 1,4-diaminocyclohexane, 1,4-phenylenediamine, 1,1,1-tris-(aminomethyl)ethane, 2,2',2"-tris-aminoethylamine, tris-(aminomethylene)methane, diethylenetriamine, triethylenetetraamine, 1,3,5-triaminocyclohexane, and 1,3,5-triaminobenzene.

Claim 58

Dependent Claim 36 words

The contrast agent of claim 55, wherein each linker monomer is a polyhydroxy linker monomer selected from the group consisting of 2,2-dimethyl-1,3-propanediol, tris-(2-hydroxyethyl)amine, 1,1,1-tris-(hyroxymethylene)ethane, glycerine, erythritol, sugar alcohols, polyethyleneglycol, w-amino-polyethyleneglycol, N-substituted-w-aminopolyethyleneglycol, w-thiol-polyethyleneglycol, polysulfide-blocked polyethyleneglycol, and polyethylene-imine.

Claim 59

Dependent Claim 21 words

The contrast agent of claim 55, wherein each linker monomer is selected from the group consisting of ethylenedioxydiethylamine, N,N'-bis-dihydroxypropylethylenedioxydiethylamine, and ethylenedioxydiethylmercaptane.

Claim 60

Dependent Claim 52 words

The contrast agent of claim 54, wherein each polynitrilo chelating unit monomer comprises at least one COOH, COOR 1 , or COZ group; each R 1 being, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group or an anhydride; and each Z being, independently, Cl, Br, or I.

Claim 61

Dependent Claim 42 words

The contrast agent of claim 59, wherein at least one of said C1-C20 alkyl or cycloalkyl group is substituted with at least one moiety selected from the group of OH, NH 2 , SH, COOH, and PO 4 , or mixtures thereof.

Claim 62

Dependent Claim 18 words

The contrast agent of claim 59, wherein each R 1 is, independently, a polyhydroxy-substituted alkyl or cycloalkyl group.

Claim 63

Dependent Claim 27 words

The contrast agent of claim 61, wherein said polyhydroxy-substituted alkyl or cycloalkyl group is selected from the group consisting of sugar alcohols, monosaccharides, polysaccharides, and synthetic polymers.

Claim 64

Dependent Claim 57 words

The contrast agent of claim 54, wherein each polynitrilo chelating unit monomer consists, independently, of a chelating agent selected from the group consisting of ethylenediamine tetraacetic acid; diethylenetriamine pentaacetic acid; 1,5-di-methoxyethylene-iminocarbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5,-triazapentane; 1,5-di-α,-dihydroxypropeneimino-carbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5-triazapentane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid; 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid; hydroxybenzyl-ethylenediamine diacetic acid; N,N'-bis(pyridoxyl-5-phosphate)ethylenediamine-N,N'-diacetic acid; 1,4,7-triazacyclononane-N,N',N"-triacetic acid; 1-oxa-4,7,10-triazacyclododecane-triacetic acid; 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; triethylenetetraamine hexaacetic acid; 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; and anhydrides thereof.

Claim 65

Dependent Claim 26 words

The contrast agent of claim 54, wherein each free radical monomer, independently, is selected from the group consisting of heterocyclic nitroxide monomers and non-heterocyclic nitroxide monomers.

Claim 66

Dependent Claim 104 words

The contrast agent of claim 64, wherein said heterocyclic nitroxide monomers have the following general structure: ##STR56## wherein a five member ring is pyrrolidine, oxazolidine, imidazolidine, or thiazolidine; a six member ring is piperidine; and each of Ra, Rb, Rc and Rd is, independently, a C1-C20 alkyl or cycloalkyl group, said alkyl or cycloalkyl group being interrupted or terminated with OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 67

Dependent Claim 22 words

The contrast agent of claim 64, wherein said non-heterocyclic nitroxide monomers are selected from the group consisting of diphenylnitroxide and di-tert-butyl nitroxide.

Claim 68

Dependent Claim 82 words

The contrast agent of claim 54, wherein each nitroxide free radical monomer is, independently, selected from the group consisting of 2,2,6,6-tetramethylpiperidine-1-oxyl; 2,2,4,4-tetramethyl-pyrrolidine-1-oxyl; 2,2,4,4-tetramethylimidazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-thiazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-oxazolidine-3-oxyl; 2,2,6,6-tetramethylpyrimidine-1-oxyl; diphenyl-nitroxide; and di-tertbutylnitroxide; and wherein each nitroxide may have one or more OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 69

Dependent Claim 37 words

The contrast agent of claim 54, wherein each nitroxide free radical monomer is, independently, a monofunctionalized compound selected from the group consisting of 1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl acrylate; 4-(iodomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperdinyl-1-oxy; 4-(bromomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperidinyl-1-oxy; 3-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-chlorocarbonyl-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-aminomethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxymethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxyl; 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 3-chloroformyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; and 3-thiocabamoylmethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy.

Claim 70

Dependent Claim 37 words

The contrast agent of claim 54, wherein each nitroxide free radical monomer is, independently, a difunctionalized compound selected from the group consisting of cis-1-oxyl-2,2,5,5-tetramethylpyrrolidine; trans-1-oxyl-2,2,5,5-tetramethylpyrrolidine; 3-amino-4-aminomethylene-2,2,5,5-tetramethylpyrrolidine; cis-2,5-dimethyl-2(aminomethyl)-5-(2-carboxyethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(methoxycarbonylmethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(2-hydroxyhexyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(2-carboxyethyl)-pyrrolidinyl-1-oxy; cis-2,5-dimethyl-2,5-bis(2-hydroxy-5-methylphenyl)-tetrahydroxypyrrol-1-oxy; 3-amino-4-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 2,5-di-tert-butyl-3,4-diethyloxycarbonyl-pyrrol-1-oxyl; and 1,4-bis(4-hydroxy-2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)-butane.

Claim 71

Dependent Claim 21 words

The contrast agent of claim 54, wherein each paramagnetic ion is selected from the group consisting of transition and lanthanide elements.

Claim 72

Dependent Claim 31 words

The contrast agent of claim 54, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III), Dy(III), Yb(III), and Ho(III).

Claim 73

Dependent Claim 21 words

The contrast agent of claim 54, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II) and Fe(III).

Claim 74

Dependent Claim 83 words

The contrast agent of claim 1, having the following structure: ##STR57## wherein Ch is a polynitrilo chelating unit monomer, FR is a nitroxide free radical monomer, and M is a paramagnetic ion; wherein p'=1 to 10,000; and wherein, within each of the p' oligomeric groups ##STR58## independently, n=0 to 10,000 and m=0 to 10,000; and for each group of paramagnetic ions ##STR59## chelated by each of the n chelating unit monomers --Ch-- in each of the p' oligomeric groups, independently, k=0 to 2.

Claim 75

Dependent Claim 52 words

The contrast agent of claim 73, wherein each polynitrilo chelating unit monomer comprises at least one COOH, COOR 1 , or COZ group; each R 1 being, independently, a C1-C20 substituted or unsubstituted, saturated or unsaturated, alkyl or cycloalkyl group or an anhydride; and each Z being, independently, Cl, Br, or I.

Claim 76

Dependent Claim 42 words

The contrast agent of claim 74, wherein at least one of said C1-C20 alkyl or cycloalkyl group is substituted with at least one moiety selected from the group of OH, NH 2 , SH, COOH, and PO 4 , or mixtures thereof.

Claim 77

Dependent Claim 18 words

The contrast agent of claim 74, wherein each R 1 is, independently, a polyhydroxy-substituted alkyl or cycloalkyl group.

Claim 78

Dependent Claim 27 words

The contrast agent of claim 76, wherein said polyhydroxy-substituted alkyl or cycloalkyl group is selected from the group consisting of sugar alcohols, monosaccharides, polysaccharides, and synthetic polymers.

Claim 79

Dependent Claim 57 words

The contrast agent of claim 73, wherein each polynitrilo chelating unit monomer consists, independently, of a chelating agent selected from the group consisting of ethylenediamine tetraacetic acid; diethylenetriamine pentaacetic acid; 1,5-di-methoxyethylene-iminocarbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5,-triazapentane; 1,5-di-α,dihydroxypropeneimino-carbonyl-methylene-1,3,5-tricarboxymethylene-1,3,5-triazapentane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid; 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoic acid; hydroxybenzyl-ethylenediamine diacetic acid; N,N'-bis(pyridoxyl-5-phosphate)ethylenediamine-N,N'-diacetic acid; 1,4,7-triazacyclononane-N,N',N"-triacetic acid; 1-oxa-4,7,10-triazacyclododecane-triacetic acid; 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; triethylenetetraamine hexaacetic acid; 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid; and anhydrides thereof.

Claim 80

Dependent Claim 26 words

The contrast agent of claim 73, wherein each free radical monomer, independently, is selected from the group consisting of heterocyclic nitroxide monomers and non-heterocyclic nitroxide monomers.

Claim 81

Dependent Claim 104 words

The contrast agent of claim 79, wherein said heterocyclic nitroxide monomers have the following general structure: ##STR60## wherein a five member ring is pyrrolidine, oxazolidine, imidazolidine, or thiazolidine; a six member ring is piperidine; and each of Ra, Rb, Rc and Rd is, independently, a C1-C20 alkyl or cycloalkyl group, said alkyl or cycloalkyl group being interrupted or terminated with OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 2 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 82

Dependent Claim 22 words

The contrast agent of claim 79, wherein said non-heterocyclic nitroxide monomers are selected from the group consisting of diphenylnitroxide and di-tert-butyl nitroxide.

Claim 83

Dependent Claim 82 words

The contrast agent of claim 73, wherein each nitroxide free radical monomer is, independently, selected from the group consisting of 2,2,6,6-tetramethylpiperidine-1-oxyl; 2,2,4,4-tetramethyl-pyrrolidine-1-oxyl; 2,2,4,4-tetramethylimidazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-thiazolidine-3-oxyl; 2,2,4,4-tetramethyl-1,3-oxazolidine-3-oxyl; 2,2,6,6-tetramethylpyrimidine-1-oxyl; diphenyl-nitroxide; and di-tertbutylnitroxide; and wherein each nitroxide may have one or more OH, SH, NH 2 , NHR 1 , COOH, COOR 1 , NCS, COCHCH 1 , or COZ, each R 1 being, independently, a C1-C20 substituted or unsubstituted alkyl or cycloalkyl group or an anhydride, and each Z being, independently, Cl, Br, or I.

Claim 84

Dependent Claim 37 words

The contrast agent of claim 73, wherein each nitroxide free radical monomer is, independently, a monofunctionalized compound selected from the group consisting of 1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl acrylate; 4-(iodomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperdinyl-1-oxy; 4-(bromomethylenecarbonylimino)-2,2,6,6-tetramethyl-piperidinyl-1-oxy; 3-carboxy-2,2,5,5-tetramethylpyrolidinyl-1-oxy; 3-chlorocarbonyl-2,2,5,5-tetramethylpyrrolfdinyl-1-oxy; 3-aminomethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 3-hydroxymethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxyl; 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 3-chloroformyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; and 3-thiocabamoylmethylene-2,2,5,5-tetramethylpyrrolidinyl-1-oxy.

Claim 85

Dependent Claim 37 words

The contrast agent of claim 73, wherein each nitroxide free radical monomer is, independently, a difunctionalized compound selected from the group consisting of cis-1-oxyl-2,2,5,5-tetramethylpyrrolidine; trans-1-oxyl-2,2,5,5-tetramethylpyrrolidine; 3-amino-4-aminomethylene-2,2,5,5-tetramethylpyrrolidine; cis-2,5-dimethyl-2(aminomethyl)-5-(2-carboxyethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(methoxycarbonylmethyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2-(hydroxymethyl)-5-(2-hydroxyhexyl)-tetrahydropyrrole-1-oxyl; cis-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(3-hydroxypropyl)-pyrrolidinyl-1-oxy; trans-2,5-dimethyl-2,5-bis(2-carboxyethyl)-pyrrolidinyl-1-oxy; cis-2,5-dimethyl-2,5-bis(2-hydroxy-5-methylphenyl)-tetrahydroxypyrrol-1-oxy; 3-amino-4-carboxy-2,2,5,5-tetramethylpyrrolidinyl-1-oxy; 2,5-di-tert-butyl-3,4-diethyloxycarbonyl-pyrrol-1-oxyl; and 1,4-bis(4-hydroxy-2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)-butane.

Claim 86

Dependent Claim 21 words

The contrast agent of claim 73, wherein each paramagnetic ion is selected from the group consisting of transition and lanthanide elements.

Claim 87

Dependent Claim 31 words

The contrast agent of claim 73, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III), Dy(III), Yb(III), and Ho(III).

Claim 88

Dependent Claim 21 words

The contrast agent of claim 73, wherein each paramagnetic ion is selected from the group consisting of Gd(III), Mn(II) and Fe(III).

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1998-04-17	1998-10-17	1999-04-18	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2002-04-17	2002-10-17	2003-04-18	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2006-04-17	2006-10-17	2007-04-18	$7700.00	Window Closed / Lapsed

Hybrid magnetic resonance contrast agents

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