SHAPE Society

1. 1
MR Contrast Agents for
Vulnerable Plaque Imaging
Philip Graham, PhD
EPIX Medical, Inc.
Cambridge, MA 02142

2. 2
MS-325: Vascular Contrast
Agent
• Albumin binding
•Extends plasma
t1/2
•4-10X increase
in signal
•Slows ECS
uptake
• Phase III
angiography trials
ongoing
• Hypothesis: MS-
325, an albumin-
targeted Gd
contrast agent,
highlights inflamed
vessel wall and
facilitates plaque Equilibrium Phase MS-325Arterial Phase

3. 3
Vessel Wall Enhancement with
MS-325
Courtesy of: T. Grist (University of Wisconsin, Madison, WI)

4. 4
Vessel Wall Enhancement
with MS-325
• Atherosclerosis = inflammation
• Leaky capillaries supplying vessel
wall
– Increased albumin conc. in wall
• Consistent enhancement of wall in
patients with MS-325
• Implications for stenosis
identification and quantitation (and
plaque burden)
• Enhancement may correlate with
risk of rupture
Aorta
Right Iliac
Artery
Vessel
Wall
Vessel
Wall
Courtesy of: Dr. J Maki (UW/Puget S VA)

5. 5
Arterial Phase Equilibrium Phase MS-325
Source Images - Left External Iliac Artery
Artery
Vein

6. 6
0
0.5
1
1.5
2
2.5
3
Adj to Plaque No Plaque
Wall Thickness (mm) Related to Plaque
Results
Adj to Plaque No Plaque
P < 0.01

7. 7
Pharmacological trigger
histamine = vasoconstrictor -> increases mechanical force on fibrous cap -> plaque
disruption
Russells viper venom -> triggers blood clotting cascade
fresh thrombus
lipid core?
thin fibrous cap?
fresh thrombus
vasoconstriction
pre-trigger
post-trigger disrupted plaque
T2w
Visualization of Plaque Rupture in Rabbit Model
Johnstone MT, Botnar RM, Perez AS, Stewart R, Quist W, Hamilton J, Manning
WJ. In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in a
Rabbit Model. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60.
Courtesy: Johnstone, Botnar, Manning: BIDMC

8. 8
baseline
MS-325
MS-325 improves Plaque Visualization
plaque
contrast uptake no uptake
wall
plaque
thrombus
MS-325
Post-trigger
Courtesy: Johnstone, Botnar, Manning: BIDMC

9. 9
Direct Clot Detection with Fibrin-
Targeted Contrast Agent
• Fibrin targeting lead discovered in a collaboration with
Dyax
• MR contrast agents EP-1242 and EP-1873 resulted from
extensive modifications by EPIX of the original leads
• Elimination profile similar to Magnevist®
EP-1242 Enhanced Carotid Clot in Guinea Pig
In collaboration with Z. Fayad, Ph.D., Mt. Sinai, New York

10. 10
To be annotated, final copy will be printed high definition
Post Gd-BSA (angiography)
Pre contrast
1 minute post EP-1873
36 minute post EP-1873
Jugular
thrombus
Rabbit Carotid
thrombus
Jugular
thrombus
Carotid
thrombus
In collaboration with E. Kent Yucel, Li Zhou Brigham & Women’s, Boston

11. 11
Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
aorta
thrombus
thrombus
thrombus
Botnar RM, Perez AP, Johnstone MT, Manning WJ
EP-1873 injected 75 mins after triggering

12. 12
15minbaseline 5:45h
Post EP-1873
35min post histamine
3D Inversion Sequence
fibrin

13. 13
3D Inversion Sequence
5:45h after EP-1873
QuickTime™ and a
decompressor
are needed to see this picture.

14. 14
Summary
• Fibrin-binding agent makes thrombotic consequences
of plaque rupture directly visible on standard MR scans
– Potential for assessing thromboembolic risk in a variety
of vascular beds
– Follow clot resolution after treatment administration?
• Vascular Agent MS-325 shows strong wall enhancement
because of increased capillary volume and binding to
extravasated albumin
– Low signal between wall and lumen represents
atherosclerotic plaque
– Prolonged enhancement of wall and lumen allows high
resolution measurement of plaque burden
– Potentially straightforward method of plaque
visualization and quantification
• ? Follow statin therapy progress