Magnetic resonance molecular imaging of thrombosis in an arachidonic acid mouse model using an activated platelet targeted probe.
OBJECTIVE
Atherosclerotic plaque rupture leads to acute thrombus formation and may trigger serious clinical events such as myocardial infarction or stroke. Therefore, it would be valuable to identify atherothrombosis and vulnerable plaques before the onset of such clinical events. We sought to determine whether the noninvasive in vivo visualization of activated platelets was effective when using a target-specific MRI contrast agent to identify thrombi, hallmarks of vulnerable or high-risk atherosclerotic plaques.


RESULTS
Inflammatory thrombi were induced in mice via topical application of arachidonic acid on the carotid. Thrombus formation was imaged with intravital fluorescence microscopy and molecular MRI. To accomplish the latter, a paramagnetic contrast agent (P975) that targets the glycoprotein alpha(IIb)beta(3), expressed on activated platelets, was investigated. The specificity of P975 for activated platelets was studied in vitro. In vivo, high spatial-resolution MRI was performed at baseline and longitudinally over 2 hours after injecting P975 or a nonspecific agent. The contralateral carotid, a sham surgery group, and a competitive inhibition experiment served as controls. P975 showed a good affinity for activated platelets, with an IC(50) (concentration of dose that produces 50% inhibition) value of 2.6 micromol/L. In thrombosed animals, P975 produced an immediate and sustained increase in MRI signal, whereas none of the control groups revealed any significant increase in MRI signal 2 hours after injection. More important, the competitive inhibition experiment with an alpha(IIb)beta(3) antagonist suppressed the MRI signal enhancement, which is indicative for the specificity of P975 for the activated platelets.


CONCLUSIONS
P975 allowed in vivo target-specific noninvasive MRI of activated platelets.
Klink
Ahmed
A
Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, Atran BM-24, Box 1234, One Gustave L. Levy Place, New York, NY 10029, USA.
Lancelot
Eric
E
Ballet
Sébastien
S
Vucic
Esad
E
Fabre
Jean-Etienne
JE
Gonzalez
Walter
W
Medina
Christelle
C
Corot
Claire
C
Mulder
Willem J M
WJ
Mallat
Ziad
Z
Fayad
Zahi A
ZA
D000818:Animals; D016718:Arachidonic Acid / Q000009:adverse effects*; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced* / Q000473:pathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D009928:Organ Specificity; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D015539:Platelet Activation
D003287:Contrast Media; D005456:Fluorescent Dyes; D009942:Organometallic Compounds; C548232:P975 peptide; D010456:Peptides, Cyclic; D016718:Arachidonic Acid