US2007020185A1PendingUtilityA1
Diagnostic imaging contrast agents with extended blood retention
Assignee: EPIX PHARMACEUTICALS INC A DELPriority: Feb 1, 1995Filed: Sep 25, 2006Published: Jan 25, 2007
Est. expiryFeb 1, 2015(expired)· nominal 20-yr term from priority
A61K 49/085A61K 49/106A61K 49/0002A61K 49/10A61K 49/103C07F 9/091A61B 6/507A61K 49/00
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Claims
Abstract
The present invention relates to contrast agents for diagnostic imaging with prolonged blood retention. In particular, this invention relates to novel compounds that are characterized by an image enhancing moiety (IEM); a protein plasma binding moiety (PPBM); and a blood half-life extending moiety (BHEM). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for blood half-life extension and contrast enhancement of diagnostic imaging.
Claims
exact text as granted — not AI-modified1 . A composition of matter having the following formula:
IEM-[L m -{BHEM s -PPBM o } p ] q or a pharmaceutically acceptable salt thereof,
wherein m, s, o, p, and q are one or two;
wherein IEM is an image enhancing moiety;
wherein L is an organic linker connecting the IEM to the BHEM
wherein BHEM is a blood half-life extending moiety;
wherein PPBM is an HSA binding moiety;
wherein IEM is selected from the following:
wherein R 1 -R 11 is -[L m -{BHEM s -PPBM o } p ] q and the R 1 -R 11 groups that are not -[L m -{BHEM s -PPBM o } p ] q are hydrogen; wherein R 12 , R 13 , and R 14 can be the same or different and are selected from the group consisting of O − and NH 2 ; wherein R 15 is H, CH 2 CH(OH)CH 3 , hydroxyl alkyl, or CH 2 COR 12 ; wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); and wherein said BHEM moiety comprises an ester.
2 . The composition of claim 1 , wherein said IEM moiety is:
3 . The composition of claim 1 , wherein said composition is a pharmaceutically acceptable salt, wherein said pharmaceutically acceptable salt is selected from the group consisting of:
(a) N-methyl-D-glucamine (b) calcium, (c) sodium, and (d) mixtures thereof.
4 . The composition of claim 3 , wherein said salt is sodium.
5 . The composition of claim 3 , wherein said salt is N-methyl-glucamine.
6 . The composition of claim 3 , wherein said salt is a mixture of sodium and N-methyl-glucamine.
7 . The composition of claim 1 , wherein M is Gd(III).
8 . The composition of claim 1 , wherein said organic linker size is between 1 and 50 angstroms.
9 . The composition of claim 8 , wherein said organic linker is between 1 and 10 angstroms.
10 . The composition of claim 1 , wherein said organic linker consists of 1 to 4 —CH 2 — groups.
11 . The composition of claim 10 , wherein said organic linker is CH 2 .
12 . The composition of claim 1 , wherein said BHEM is:
wherein the wavy lines signify attachments to the linker and the PPBM.
13 . The composition of claim 1 , wherein said composition is:
14 . The composition of claim 1 , wherein said composition is:
15 . A pharmaceutical composition comprising the composition according to claim 1 and a carrier, adjuvant, or vehicle.
16 . The pharmaceutical composition of claim 15 , further comprising a free organic ligand or a pharmaceutically acceptable salt thereof.
17 . A method of MR imaging of a mammal, said method comprising the steps of:
a) administering to said mammal a composition according to claim 1; and b) subjecting said mammal to MR imaging.
18 . The method of claim 17 , wherein said mammal is a human.
19 . The method of claim 17 , wherein said MR imaging comprises imaging at least a portion of the vasculature of said mammal.
20 . The method of claim 17 , wherein a portion of said imaging occurs 10 minutes or later after administration of said composition.
21 . The method of claim 17 , wherein said composition is administered to said mammal at a concentration between 0.001 to about 1 mmol/kg body weight.
22 . The method of claim 17 , wherein said imaging of said mammal comprises imaging a tumor of said mammal.
23 . The method of claim 17 , wherein said imaging of said mammal comprises imaging the brain of said mammal.
24 . The method of claim 23 , wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.
25 . The method of claim 23 , wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.
26 . A method for examining vasculature of a tissue comprising HSA in a mammal, said method comprising:
a) administering to said mammal a composition according to claim 1; and b) obtaining an MR image of said vasculature of said tissue.
27 . The method of claim 26 , wherein said step b) comprises obtaining multiple images of said tissue.
28 . The method of claim 26 , further comprising, prior to step a), obtaining an MR image of said tissue.
29 . The method of claim 27 or 28 , further comprising comparing two or more of said images of said tissue.
30 . The method of claim 26 , wherein said mammal is a human.
31 . A method for examining perfusion in a tissue comprising HSA in a mammal, said method comprising:
a) administering to said mammal a composition according to claim 1; and b) obtaining an MR image of said tissue of said mammal.
32 . The method of claim 31 , wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.
33 . The method of claim 31 , wherein said step b) comprises obtaining multiple images of said tissue.
34 . The method of claim 31 , further comprising, prior to step a), obtaining an MR image of said tissue.
35 . The method of claim 33 or 34 , further comprising comparing two or more of said images of said tissue.
36 . The method of claim 31 , wherein said mammal is a human.
37 . The method of claim 26 or 31 , wherein said tissue comprises a stenosis.
38 . A method of monitoring a human's brain during cognitive events, said method comprising:
a) administering to said human a composition according to claim 1; and b) obtaining an MR image of said brain of said human.
39 . The method of claim 38 , wherein said step b) comprises obtaining multiple images of said brain.
40 . The method of claim 38 , further comprising, prior to step a), obtaining an MR image of said brain.
41 . The method of claim 39 or 40 , further comprising comparing two or more of said images of said brain.
42 . The method of claim 38 , 39 , or 40 , wherein said obtaining occurs during a cognitive event.
43 . The method of claim 38 , 39 , or 40 , wherein said obtaining occurs before or after a cognitive event.
44 . A method for determining blood volume in a tissue comprising HSA in a mammal, said method comprising:
a) administering to said mammal a composition according to claim 1; and b) obtaining an MR image of said tissue.
45 . The method of claim 44 , wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.
46 . The method of claim 44 , wherein said step b) comprises obtaining multiple images of said tissue.
47 . The method of claim 44 , further comprising, prior to step a), obtaining an MR image of said tissue.
48 . The method of claim 46 or 47 , further comprising comparing two or more of said images of said tissue.Cited by (0)
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