US4915933A
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Mixed complexes as shift and contrast reagents in NMR imaging and spectroscopy
Assignee: University of New Mexico
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Filing: 1986-06-26
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Granted: 1990-04-10
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Expires: 2006-06-26
Abstract
Abstract Mixed anionic complexes of the type (MWmYnZp)r- wherein M is a paramagnetic ion; W, Y, and Z are each different ligands which chelate M; and m+n+p>/=2 but preferably less than 5, with the proviso that at least two different ligands W, Y, Z are present in the complex; are provided as versatile NMR contrast and shift reagents, especially for clinical diagnostic imaging and spectroscopic procedures. In an exemplary embodiment, at least one of the ligands W, Y, Z is metabolizable by the target tissue, and at least one of the ligands W, Y, Z is substantially inert; the complex is thus tailorable to improve both physiological tolerance and tissue specificity of NMR contrast and shift reagents, while maintaining excellent contrast and shift effects for reliable and accurate results.
Inventors
- 👤 Nicholas A. Matwiyoff
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-28 23:30
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/06; Y; Y10; Y10S; Y10S436/00; Y10S436/806; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
111 words
In a nuclear magnetic resonance diagnostic method of the type wherein a paramagnetic species is employed in an amount sufficient to observably alter the magnetic properties of a reference ion in vivo or in vitro, the improvement comprising employing as the paramagnetic species an anionic mixed complex of a paramagnetic ion of the formula: [M(W).sub.m (Y).sub.n (Z).sub.p ].sup.r- wherein M is a paramagnetic ion; W, Y, and Z are each a different bidentate or polydentate ligand which is a chelating agent for the ion M; m+n+p≧2 but less than 5, and no more than one of m, n, or p is zero; and the complex has an overall negative charge r-.
Claim 2
Dependent Claim
111 words
In a nuclear magnetic resonance diagnostic method of the type wherein a paramagnetic species is employed in an amount sufficient to observably alter the magnetic properties of a reference ion in vivo or in vitro, the improvement comprising employing as the paramagnetic species an anionic mixed complex of a paramagnetic ion of the formula: [M(W).sub.m (Y).sub.n (Z).sub.p ].sup.r- wherein M is a paramagnetic ion; W, Y, and Z are each a different bidentate or polydentate ligand which is a chelating agent for the ion M; m+n+p≧2 but less than 5, and no more than one of m, n, or p is zero; and the complex has an overall negative charge r-.
Claim 3
Dependent Claim
13 words
The method of claim 1, wherein the reference ion is a sodium ion.
Claim 4
Dependent Claim
26 words
The method of claim 2, wherein the paramagnetic ion M is selected from the group consisting of paramagnetic lanthanide ions, Mn(II), Mn(III), Fe(II), Cu(II) and Cr(III).
Claim 5
Dependent Claim
14 words
The method of claim 3, wherein the paramagnetic ion M is Dy(III) or Gd(III).
Claim 6
Dependent Claim
51 words
The method of claim 2, wherein each of the ligands is independently selected from the group consisting of aminecarboxylates, Schiff bases, aminecarboxylatephosphonates, porphryins, cryptates, hydroxamates, polyacetates, tetraazacyclododecanes, phosphates, phosphonates, aminephosphonates, C 3 -C 20 -peptides, amino acids, and salicylic acid, acetoacetic acid, oxalic acid, citric acid, aspartic acid and esters thereof.
Claim 7
Dependent Claim
16 words
The method of claim 2, wherein at least one of the ligands is metabolizable in vivo.
Claim 8
Dependent Claim
32 words
The method of claim 6, wherein the metabolizable ligand is pyrophosphate; tripolyphosphate; an amino acid; pyridoxal; desferrioxamine; polyglutamic acid; or acetoacetic acid, oxalic acid, citric acid, salicylic acid, or an ester thereof.
Claim 9
Dependent Claim
20 words
The method of claim 6, wherein the ligand metabolizable in vivo is preferentially metabolized by cells in a target tissue.
Claim 10
Dependent Claim
17 words
The method of claim 6, wherein at least one of the ligands is metabolically inert in vivo.
Claim 11
Dependent Claim
25 words
The method of claim 9, wherein the inert ligand is selected from the group consisting of aminecarboxylates, porphyrins, cryptates, tetraazacyclododecanes, cyclictetrapyrroles, aminecarboxylatephosphonates, aminephosphonates, and phosphates.
Claim 12
Dependent Claim
63 words
The method of claim 9, wherein the ligand metabolizable in vivo is selected from the group consisting of pyrophosphate; tripolyphosphate, amino acids, pyridoxal, desferrioxamines, polyglutamic acid, acetoacetic acid, oxalic acid, citric acid, salicylic acid, acetoacetates, oxalates, salicylates, and citrates; and the ligand metabolically inert in vivo is selected from the group consisting of aminecarboxylates, aminecarboxylatephosphonates, aminephosphonates, porphyrins, cryptates, tetraazocyclododecanes, cyclic tetrapyrroles, and phosphates.
Claim 13
Dependent Claim
13 words
The method of claim 6, wherein the metabolizable ligand is tripolyphosphate or pyrophosphate.
Claim 14
Dependent Claim
17 words
The method of claim 2, wherein at least one of the ligands is metabolically inert in vivo.
Claim 15
Dependent Claim
25 words
The method of claim 13, wherein the inert ligand is selected from the group consisting of aminecarboxylates, porphyrins, cryptates, tetraazacyclododecanes, cyclictetrapyrroles, aminecarboxylatephosphonates, aminephosphonates, and phosphates.
Claim 16
Dependent Claim
26 words
The method of claim 2, wherein at least one of the ligands is tripolyphosphate or pyrophosphate and at least one of the ligands is an aminecarboxylate.
Claim 17
Dependent Claim
16 words
The method of claim 15, wherein the aminecarboxylate is nitrilotriacetate, ethylenediaminetetraacetate, diethylenetriaminepentaacetate, or 1,4,7,10-tetraazacyclododecane-N,N',N", N'"-tetraacetic acid.
Claim 18
Dependent Claim
24 words
The method of claim 2, wherein the complex is adapted to alter the magnetic resonance properties of sodium ions or water protons in vivo.
Claim 19
Dependent Claim
11 words
The method of claim 2, wherein r is at least three.
Claim 20
Dependent Claim
23 words
The method of claim 2, wherein W is (PPP) and Y is (DTPA), m is one, n is one and p is zero.
Claim 21
Dependent Claim
22 words
The method of claim 2, wherein W is (NTA), Y is (PPP), m is one, n is one and p is zero.
Claim 22
Dependent Claim
26 words
The method of claim 2, wherein W is (NTA) or (EDTA), Y is (PP) or citrate, m is one, n is one and p is zero.
Claim 23
Dependent Claim
11 words
The method of claim 21, wherein M is Dy or Gd.
Claim 24
Dependent Claim
26 words
The method of claim 2, wherein the diagnostic method is a nuclear magnetic resonance imaging procedure, and the paramagnetic species is employed as a contrast reagent.
Claim 25
Dependent Claim
26 words
The method of claim 2, wherein the diagnostic method is a nuclear magnetic resonance spectroscopic procedure, and the paramagnetic species in employed as a shift reagent.
Claim 26
Dependent Claim
18 words
The method of claim 24, wherein the shift reagent is [Dy(DTPA) (PPP)] 6- or [Dy(ETPA) (PPP)] 6- .
Claim 27
Dependent Claim
17 words
The method of claim 24, wherein the shift reagent is [Dy(PPP) (1,4,7,10-tetraazacyclododecane-N, N', N", N'"-tetraacetate)] 6- .
Claim 28
Dependent Claim
21 words
The method of claim 2, wherein the complex is adapted to alter the magnetic resonance properties of sodium ions in vitro.
Claim 29
Dependent Claim
13 words
The method of claim 1, wherein the reference ion is a water proton.
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