The acute formation of thrombus after atherosclerotic plaque rupture has been well recognized as the cause of unstable angina, myocardial infarction, transient ischemic attacks, and stroke (1, 2). Platelets and fibrin are the major components of all thrombi involved in the development and progression of atherosclerotic disease (3). MRI has shown promise in thrombus detection in both animals and humans (4), such as direct thrombus imaging based on the T1-shortening properties of endogenous methemogobin in venous thrombi (5) and enhancing the contrast between the myocardium and intracardiac by conventional gadolinium chelates (6). However, thrombosis is a dynamic process in which the thrombus material of different ages forms a layered structure due to successive mural deposition (7). MR signal of thrombi is complicated by the presence of platelets, fibrin, and red blood cells in the clots (7). Accurate thrombus age definition and detection of old and organized thrombi remain difficult. Since fibrin is abundant in all types of thrombi, including arterial, venous, acute, and chronic, fibrin-targeted contrast agents can be used to differentiate between layers of fibrin deposits in all types of thrombi and in superimposed thrombosis associated with plaque (3). The low concentration of fibrin present in plasma minimizes spurious background imaging signal (3).
Fibrin is formed after thrombin cleavage of fibrinopeptide A from fibrinogen Aα-chains, followed by polymerization and cross-linkage to form thick fibrin bundles and complex branched clot network (8). 4GdPeptide is a gadolinium based contrast agent designed to bind to fibrin (7). 4GdPeptide comprises a small peptide of 11 amino acids and two gadolinium chelates such as gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) or gadolinium-1,4,7,10-tetraazcyclododecane-N,N’,N”,N”’-tetraacetate (Gd-DOTA) attached to each terminal (7, 9). Gd-DOTA has an in vitro stability five orders of magnitude greater than that of Gd-DTPA (10). This greater stability reduces the in vivo toxicity caused by the dissociation of free Gd(III) in the metabolic process (10). The small peptide contains one intramolecular disulfur bond, and binds to fibrin selectively and reversibly (9, 11). The binding to fibrin generates a field dependent paramagnetic enhancement effect (PRE) due to the increase of the effective rotation correlation time τR (12). No interactions and competitive binding with other proteins such as fibrinogen or collagen have been noted in both in vitro or in vivo (11). 4GdPeptide can penetrate through thrombi to bind fibrin in depth via passive diffusion; and distinguish between occlusive and non-occlusive arterial thrombi or between thrombi of different sizes and ages (11). Early-phase clinical studies (phase I and II) are currently testing the safety of 4GdPeptide in humans (11).