US2016022842A1PendingUtilityA1
Formation and uses of europium
Est. expiryMar 11, 2033(~6.6 yrs left)· nominal 20-yr term from priority
Inventors:Matthew J. Allen
A61K 49/106A61K 49/1812C07F 5/003A61K 49/101A61K 9/127
62
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Claims
Abstract
An MRI contrast composition includes a liposome and a europium metal complex disposed within the liposome. The europium metal complex includes a europium metal ion and a multi-dentate ligand selected from the group consisting of cryptands and thiacryptands and one or more counter-ions that balances a charge of the europium metal ion and the multi-dentate ligand, the europium metal ion being switchable between a 2+ and 3+ oxidation state. The contrast composition advantageously provides an oxidation-responsive dual-mode contrast agent because it would enhance either T 1 -weighted images or CEST images depending on the oxidation state of Eu.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A composition comprising:
a liposome; a europium metal complex disposed within the liposome, the europium metal complex including a europium metal ion and a multi-dentate ligand selected from the group consisting of cryptands and thiacryptands, and if necessary, counter-ions to maintain charge neutrality, the europium metal ion being switchable between a 2+ and 3+ oxidation state.
2 . The composition of claim 1 wherein the liposome includes a phospholipid.
3 . The composition of claim 2 wherein the phospholipid is a fatty acid di-esters of phosphatidylcholine, ethylphosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine or sphingomyelin.
4 . The composition of claim 2 wherein the phospholipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine.
5 . The composition of claim 1 wherein the liposome have an average diameter less than about 200 nm.
6 . The composition of claim 1 wherein the multi-dentate ligand is a substituted 2.2.2-Cryptand, a substituted 2.2.2-thiacryptand, or an unsubstituted 2.2.2-thiacryptand.
7 . The composition of claim 1 further comprising an antioxidant.
8 . The composition of claim 7 wherein the antioxidant includes a component selected from the group consisting of glutathione, 2-mercaptoethanol, dithiothreitol, S-adenosylmethionine, dithiocarbamate, dimethylsulfoxide, cysteine, methionine, cysteamine, oxo-thiazolidine-carboxylate, timonacic acid, malotilate, 1,2-dithiol 3-thione, 1,3-dithiol 2-thione, lipoamide, sulfarlem, oltipraz, taurine, N-acetylcysteine, and combinations thereof.
9 . The composition of claim 1 further comprising an additional amphiphilic compound.
10 . The composition of claim 9 wherein the additional amphiphilic compound is cholesterol.
11 . The composition of claim 1 further including a pharmaceutically acceptable aqueous carrier.
12 . The composition of claim 1 wherein the multi-dentate ligand is described by formula I:
wherein:
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently O or S;
R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 fluoroalkyl, Cl, F, Br, I, N(R) 2 , NH 2 , CH 2 CO 2 H, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom; and
R is H or C 1-12 alkyl.
13 . The composition of claim 12 wherein R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms form a phenyl group.
14 . The composition of claim 12 wherein R 1 , R 2 , and/or R 3 are each independently H, phenyl, or biphenyl.
15 . The composition of claim 1 the multi-dentate ligand has the following formula:
and
Y 1 and Y 2 are each independently O or S.
16 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
X 1 , X 2 , X 3 are independently nitro, Cl, F, Br, I, CH 3 , NH 2 , or CH 2 CO 2 H.
17 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
Y is O or S.
18 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
x, y, and z are 0, 1, 2, or 3 with the proviso that the sum of x, y, and z is 3.
19 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
x and y are 0, 1, 2, or 3 with the proviso that the sum of x and y is 3.
20 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
Y is O or S.
21 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
X is 0 to 2 and Y is 1 to 3 with the proviso that the sum of x and y is 3.
22 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
and
R, R′ are independently nitro, Cl, F, Br, I, CH 3 , NH 2 , or CH 2 CO 2 H.
23 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
Y and Z are each independently O or S; and
R is nitro, Cl, F, Br, I, CH 3 , NH 2 , or CH 2 CO 2 H.
24 . The composition of claim 1 wherein the multi-dentate ligand has the following formula:
25 . A compound having formula II:
wherein:
n, o are each independently 1 or 2;
L 1 is a multi-dentate ligand moiety that bonds to Eu;
L 2 is a multi-dentate ligand moiety that bonds to Gd;
Xp are counter-ions to maintain charge neutrality; and
Sp is a spacer moiety that provides separation between Eu and Gd.
26 . The compound of claim 25 wherein L 1 is has formula III:
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently O or S;
R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 fluoroalkyl, Cl, F, Br, I, N(R) 2 , NH 2 , CH 2 CO 2 H, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom; and
R is H or C 1-12 alkyl with the proviso that at least one R 1 , R 2 , or R 3 is a bond to Sp or has a bond to Sp.
27 . The compound of claim 25 wherein L 2 include a plurality of groups having the following formula:
28 . The compound of claim 26 wherein L 2 includes a moiety having the following formula:
29 . The compound of claim 25 having formula 5:
30 . The compound of claim 25 having the following formula:
31 . A method of magnetic resonance imaging of an organ or organ structure in a subject, the method comprising:
a) administering a liposome composition to the subject, the liposome composition comprising: a liposome; and a europium metal complex disposed within the liposome, the europium metal complex including a europium metal ion and a first multi-dentate ligand selected from the group consisting of cryptands and thiacryptands, and one or more counter-ions that balance a charge of the europium metal ion; and b) taking images of an organ in the subject by magnetic resonance imaging.
32 . The method of claim 31 wherein the magnetic resonance imaging is T 1 -weighted imaging.
33 . The method of claim 31 wherein the magnetic resonance imaging is by chemical exchange saturation transfer.
34 . A europium metal complex having formula (VIII) is provided:
wherein:
c is the charge of the combination of the europium metal atom and the multi-dentate ligand;
Xp represents a number of counter-ions necessary for charge neutrality;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently O or S;
R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 alkynyl, C 1-12 alkenyl, C 1-12 fluoroalkyl, Cl, F, Br, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom;
R is H or C 1-12 alkyl; and
R 4 , R 5 , R 6 , R 7 are each independently hydrogen, cyano, nitro, Cl, F, Br, I, CH 3 , NH 2 , C 6-15 aryl, carboxylated C 6-18 aryl, C 5-15 heteroaryl, carboxylated C 5-18 heteroaryl, C 1-12 alkyl, phenyl, carboxylated phenyl, carboxylated C 2-12 alkyl, —CO 2 H, —CH 2 CO 2 H,
and
R 8 , R 9 , R 10 , R 11 , R 12 are each independently H or CO 2 H.Join the waitlist — get patent alerts
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