DETECTION OF HIGH-RISK UNSTABLE ATHEROSCLEROTIC PLAQUE
The technology relates to a method for detecting high-risk unstable atherosclerotic plaque in a subject, the method comprising: a) administering to the subject a magnetic resonance imaging (MRI) contrast agent capable of being activated by myeloperoxidase (MPO) in atherosclerotic plaque; b) allowing the contrast agent to be activated by myeloperoxidase in atherosclerotic plaque; c) obtaining an image of the atherosclerotic plaque from the subject using such molecular MRI, wherein enhanced imaging is indicative of unstable plaque. In some embodiments an MPO inhibitor is administered to a subject identified as having a high-risk unstable atherosclerotic plaque.
1 . A method for detecting unstable atherosclerotic plaque in a subject, the method comprising:
a) administering to the subject a magnetic resonance imaging (MRI) contrast agent capable of being activated by myeloperoxidase (MPO) in atherosclerotic plaque;
b) allowing the contrast agent to be activated by myeloperoxidase in atherosclerotic plaque;
c) obtaining an enhanced image of the atherosclerotic plaque from the subject using MRI;
d) determining from the enhanced imaging one or more of;
ΔCNR,
thickness of a fibrous cap associated with the atherosclerotic plaque; and
fibrous cap:lesion ratio,
wherein a ΔCNR, cap thickness or cap:lesion ratio within a predetermined range indicates that the atherosclerotic plaque is unstable.
2 . The method according to claim 1 , wherein ΔCNR is determined from the enhanced imaging.
3 . The method according to claim 1 , wherein the predetermined range for ΔCNR is from about 1 to about 80.
4 . The method according to claim 3 wherein the wherein the predetermined range for ΔCNR is from about 10 to about 30.
5 . The method according to claim 1 , wherein the predetermined range for cap thickness is from about 0.01 μm to about 65 μm.
6 . The method according to claim 1 , wherein the predetermined range for cap:lesion ratio is from about 10 to about 20.
7 . The method of claim 1 , wherein the predetermined range for ΔCNR is from about 10 to about 30, the predetermined range for cap thickness is from about 0.01 μm to about 65 μm, and the predetermined range for cap:lesion ratio is from about 10 to about 20.
8 . The method according to claim 1 , wherein the MRI contrast agent is a gadolinium(III) chelate.
9 . The method according to claim 8 , wherein the gadolinium(III) chelate is selected from bis-5HT-DTPA-Gd (MPO-Gd), mono-5HT-DTPA-Gd, bis-o-dianisidine-DTPA-Gd, mono-o-dianisidine-DTPA-Gd, mono-(5-hydroxytryptophan)-DTPA, (mono-HTrp-DTPA), and bis-(5-hydroxytryptophan)-DTPA, (bis-HTrp-DTPA).
10 . The method according to claim 9 , wherein the gadolinium(III) chelate is bis-5HT-DTPA-Gd.
11 . The method according to claim 1 , further comprising:
e) administering to a subject identified as having unstable atherosclerotic plaque, a therapeutically effective amount of a myeloperoxidase inhibitor to stabilise the unstable atherosclerotic plaque.
12 . The method according to claim 11 wherein the stabilisation of the unstable atherosclerotic plaque is characterised by at least one of an increase in fibrous cap thickness an improved ΔCNR, and an increase in the cap:lesion ratio.
13 . The method according to claim 12 wherein the increase in fibrous cap thickness is at least 50%
14 . The method according to claim 11 wherein the myeloperoxidase inhibitor is selected from the group consisting of AZM198, 3-isobutyl-2-thioxo-7H-purin-6-one, 3-[(4-fluorophenyl)methyl]-2-thioxo-7H-purin-6-one, 3-(tetrahydrofuran-2-ylmethyl)-2-thioxo-7H-purin-6-one, 3-[[(2R)-tetrahydrofuran-2-yl]methyl]-2-thioxo-7H-purin-6-one, and 3-(2-methoxyethyl)-2-thioxo-7H-purin-6-one, AZD3241, 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide, and PF-1355.
15 . The method of according to claim 1 , wherein the subject is a human.