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US4899755A
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US
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Hepatobiliary NMR contrast agents
Assignee: General Hospital Corp
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Filing: 1985-05-08
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Granted: 1990-02-13
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Expires: 2005-05-08
Abstract
Abstract A method of altering proton NMR relaxation times in the liver or bile duct of a human patient involving administering to the patient an agent characterized in that it is taken up preferentially by human hepatocytes, compared to human reticuloendothelial cells, and it contains a paramagnetic substance capable of altering the proton NMR relaxation times in the hepatocytes.
Inventors
- 👤 Randall B. Lauffer
- 👤 Thomas J. Brady
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 11:48
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/06
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
151 words
A method of altering proton NMR relaxation times in the liver or bile duct of a human patient comprising administering to said patient an agent characterized in that it is taken up preferentially by human hepatocytes, compared to human reticuloendothelial cells, it contains a complex of a paramagnetic substance capable of altering said proton NMR relaxation times in said hepatocytes, and an organic chelating ligand, said complex having a formation constant of at least 10 15 M 1 , a solubility to at least 1.0 mM concentration in normal saline, a molecular weight greater than 250, and a charge of an absolute value of 2 or less, said organic chelating ligand containing at least one aryl ring, and said paramagnetic substance being selected from the group consisting of gadolinium (III), iron (III), manganese (II), manganese (III), chromium (III), copper (II), dysprosium (III), terbium (III), holmium (III), erbium (III) and europium (III).
Claim 2
Independent Claim
151 words
A method of altering proton NMR relaxation times in the liver or bile duct of a human patient comprising administering to said patient an agent characterized in that it is taken up preferentially by human hepatocytes, compared to human reticuloendothelial cells, it contains a complex of a paramagnetic substance capable of altering said proton NMR relaxation times in said hepatocytes, and an organic chelating ligand, said complex having a formation constant of at least 10 15 M 1 , a solubility to at least 1.0 mM concentration in normal saline, a molecular weight greater than 250, and a charge of an absolute value of 2 or less, said organic chelating ligand containing at least one aryl ring, and said paramagnetic substance being selected from the group consisting of gadolinium (III), iron (III), manganese (II), manganese (III), chromium (III), copper (II), dysprosium (III), terbium (III), holmium (III), erbium (III) and europium (III).
Claim 3
Dependent Claim
19 words
The method of claim 1, further comprising, following said administration of said agent, subjecting said patient to NMR imaging.
Claim 4
Dependent Claim
33 words
The method of claim 1 wherein said paramagnetic substance is further characterized in that it contains at least 1 unpaired electron and it has a magnetic moment of at least 1.7 Bohr magneton.
Claim 5
Dependent Claim
15 words
The method of claim 3 wherein said paramagnetic substance contains at least 5 unpaired electrons.
Claim 6
Dependent Claim
13 words
The method of claim 4 wherein said paramagnetic substance contains 7 unpaired electrons.
Claim 7
Dependent Claim
37 words
The method of claim 1 wherein said complex is further characterized in that its lipophilicity is sufficiently high to cause it to be taken up in greater amount by normally functioning human hepatocytes than by hepatocarcinoma cells.
Claim 8
Dependent Claim
14 words
The method of claim 1 wherein said complex contains at least one halogen atom.
Claim 9
Dependent Claim
17 words
The method of claim 1 wherein said complex has an LD 50 of at least 0.05 mmol/kg.
Claim 10
Dependent Claim
15 words
The method of claim 1 wherein said complex contains zero open sites for water coordination.
Claim 11
Dependent Claim
17 words
The method of claim 1 wherein said complex contain one or more open sites for water coordination.
Claim 12
Dependent Claim
22 words
The method of claim 1 wherein said agent is further characterized in that it exhibits an octanol:water coefficient of at least 0.005.
Claim 13
Dependent Claim
22 words
The method of claim 11 wherein said agent is further characterized in that it exhibits an octanol:water coefficient of at least 0.01.
Claim 14
Dependent Claim
32 words
The method of claim 1 wherein said agent is further characterized in that at least 15% of said agent binds to 4.5% human serum albumin at a concentration of 0.2 mM agent.
Claim 15
Dependent Claim
25 words
The method of claim 13 wherein at least 50% of said agent binds to 4.5% human serum albumin at a concentration of 0.2 mM agent.
Claim 16
Dependent Claim
27 words
The method of claim 1 wherein the in vitro relaxivity in saline of said agent at 20 MHz is at least 5 s -1 mM -1 .
Claim 17
Dependent Claim
19 words
The method of claim 15 wherein said in vitro relaxivity is at least 1.0 s -1 mM -1 .
Claim 18
Dependent Claim
25 words
The method of claim 1 wherein the in vivo relaxivity in liver tissue of said agent is at least 1.0 s -1 (μmol/g) -1 .
Claim 19
Dependent Claim
26 words
The method of claim 1 wherein said organic chelating ligand is a macrocyclic compound containing at least 3 carbon atoms and at least two hetero atoms.
Claim 20
Dependent Claim
55 words
The method of claim 18 wherein said macrocyclic compound has the formula ##STR14## where A is ##STR15## X is 0 or 1, and each R 1 , R 2 , R 3 and R 4 , independently, is ethyl, propyl, or ##STR16## provided that when A is ##STR17## at least one group must be ##STR18##
Claim 21
Dependent Claim
22 words
The method of claim 19 wherein said macrocyclic compound is a derivative of 1,4,7,10-tetraazacyclotetradecane-1,4,7,10-tetraacetic acid which contains at least one aryl ring.
Claim 22
Dependent Claim
16 words
The method of claim 1 wherein said organic chelating ligand is benzodiethylenetriamine or a derivative thereof.
Claim 23
Dependent Claim
18 words
The method of claim 1 wherein said organic chelating ligand is bis-2 (hydroxybenzyl)-ethylene-diamineacetic acid or a derivative thereof.
Claim 24
Dependent Claim
16 words
The method of claim 1 wherein said organic chelating ligand is ethylenebis-(2-hydroxyphenylglycine) or a derivative thereof.
Claim 25
Dependent Claim
24 words
The method of claim 23 wherein said derivative is substituted at the 5-position on its phenyl rings with Cl, Br, Me, t-Bu, or sec-Bu.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1993-02-12 | 1993-08-14 | 1994-02-13 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1997-02-12 | 1997-08-14 | 1998-02-13 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2001-02-12 | 2001-08-14 | 2002-02-13 | $7700.00 | Window Closed / Lapsed |