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
Jeffrey H. Maki1,2
, Gregory J. Wilson1
,
Randall B. Lauffer3
, Robert M. Weisskoff3
,
Chun Yuan2
1 - Puget Sound VAHCS, Seattle, WA
2 - University of Washington, Seattle, WA
3 - EPIX Medical, Cambridge, MA
Vessel Wall Enhancement with MS-325
MRI Facilitates Plaque Detection and
Characterization

5. 5
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)

6. 6
Arterial Phase Equilibrium Phase MS-325
Source Images - Left External Iliac Artery
Artery
Vein

7. 7
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

8. 8
Results
• Strong wall enhancement with MS-325 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 detection of plaque burden
• Potentially straightforward method of plaque
visualization and quantification
• ? Follow statin therapy

9. 9
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

10. 10
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

11. 11
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

12. 12
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, Lee Zhou (?) Brigham & Women’s, Boston

13. 13
Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
aorta
thrombus
thrombus
thrombus
Botnar RM, Perez AP, Johnstone MT, Manning WJ

14. 14
Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
Botnar RM, Perez AP, Manning WJ, Johnstone MT

15. 15
Pre contrast 10min 1.5h
Post EP-1873 (fibrin agent)
aorta
thrombus thrombus
Botnar RM, Perez AP, Manning WJ, Johnstone MT

16. 16
Summary
• Prototype clot-enhancing agents for MRI
– High binding affinity and selectivity to human fibrin
– Rapid Enhancement of arterial and venous clots
– Good in vivo clot uptake and enhancement
– No effects on clotting cascade
• 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?