EP-2104R: a fibrin-specific gadolinium-Based MRI contrast agent for detection of thrombus

K Overoye-Chan, S Koerner, RJ Looby… - Journal of the …, 2008 - ACS Publications
K Overoye-Chan, S Koerner, RJ Looby, AF Kolodziej, SG Zech, Q Deng, JM Chasse…
Journal of the American Chemical Society, 2008ACS Publications
Thrombus (blood clot) is implicated in a number of life threatening diseases, eg, heart attack,
stroke, pulmonary embolism. EP-2104R is an MRI contrast agent designed to detect
thrombus by binding to the protein fibrin, present in all thrombi. EP-2104R comprises an 11
amino acid peptide derivatized with 2 GdDOTA-like moieties at both the C-and N-terminus of
the peptide (4 Gd in total). EP-2104R was synthesized by a mixture of solid phase and
solution techniques. The La (III) analogue was characterized by and 1D and 2D NMR …
Thrombus (blood clot) is implicated in a number of life threatening diseases, e.g., heart attack, stroke, pulmonary embolism. EP-2104R is an MRI contrast agent designed to detect thrombus by binding to the protein fibrin, present in all thrombi. EP-2104R comprises an 11 amino acid peptide derivatized with 2 GdDOTA-like moieties at both the C- and N-terminus of the peptide (4 Gd in total). EP-2104R was synthesized by a mixture of solid phase and solution techniques. The La(III) analogue was characterized by and 1D and 2D NMR spectroscopy and was found to have the expected structure. EP-2104R was found to be significantly more inert to Gd(III) loss than commercial contrast agents. At the most extreme conditions tested (pH 3, 60 °C, 96 hrs), less than 10% of Gd was removed from EP-2104R by a challenge with a DTPA based ligand, while the commercial contrast agents equilibrated within minutes to hours. EP-2104R binds equally to two sites on human fibrin (Kd = 1.7 ± 0.5 µM) and has a similar affinity to mouse, rat, rabbit, pig, and dog fibrin. EP-2104R has excellent specificity for fibrin over fibrinogen (over 100-fold) and for fibrin over serum albumin (over 1000-fold). The relaxivity of EP-2104R bound to fibrin at 37 °C and 1.4 T was 71.4 mM−1 s−1 per molecule of EP-2104R (17.4 per Gd), about 25 times higher than that of GdDOTA measured under the same conditions. Strong fibrin binding, fibrin selectivity, and high molecular relaxivity enable EP-2104R to detect blood clots in vivo.
ACS Publications