Fibrin imaging
Fibrin is another crucial target
that is frequently used for molecular imaging of thrombosis. Botnaret al. developed a novel fibrin-binding gadolinium-labelled
peptide (EP-1873) for MRI of thrombosis and tested this in an
experimental rabbit model of plaque rupture (Botnar et al., 2004). This
probe was further optimised (EP-2104R) and successfully validated for
MRI-based diagnosis of coronary thrombosis and PE (Spuentrup et al.,
2005a, 2005b; Overoye-Chan et al., 2008). In another study using a
murine model of venous thrombosis in the inferior vena cava, Andia et
al. demonstrated the maximal increased of signal at day 7 of thrombosis
and gradual reduction from day 10 onwards (Andia et al., 2014). After
radiolabelling 64Cu with EP-2104R, the construct was
injected into a rat model of crush injury-induced thrombosis. A clear
increase in uptake of radioactivity was observed in the location of the
thrombi via PET imaging (Ay et al., 2014). Furthermore, the
administration of fibrinolytic therapy resulted in a loss of
radioactivity signal, indicating that the thrombi have been
thrombolysed, indicating the suitability of this imaging approach for
the monitoring of success or failure of thombolytic therapy (Ay et al.,
2014). Bimodal imaging performed with 64Cu
radiolabeled EP-2104R provided direct visualisation of thrombi via PET
and MRI (Uppal et al., 2011). This method also allowed the detection of
multisite thrombi located in the carotid artery and the femoral vein in
a rat model via a whole-body PET scan (Blasi et al., 2015). In another
study, EP-2104R was radiolabelled with 68Ga or111In, whereas a non-binding control was radiolabeled
with 64Cu, for multimodal SPECT/PET/CT imaging
(Oliveira et al., 2015). 125I-fibrinogen was injected
prior to ferric chloride induced thrombosis of the common carotid
artery. Multimodal imaging showed a hot spot corresponding to the125I-fibrinogen labelled thrombi with fibrin-targeted68Ga or 111In isotopes, but not the
non-binding radioisotopes (Oliveira et al., 2015).
Using EP-2104R, Hara et al.
synthesised a fibrin-binding peptide (FTP11) conjugated to a
near-infrared dye and demonstrated successful in vivo optical
imaging of thrombi in a jugular DVT murine model (Figure 18) (Hara et
al., 2012). Using the same construct, the group further demonstrated
successful imaging of fibrin deposition on stents that were implanted in
rabbits using invasive optical coherence tomography (Figure 19) (Hara et
al., 2015). EP-2104R has also been evaluated in Phase II trials, where
molecular MRI was performed on patients who were previously diagnosed
with thrombosis in the arteries, veins and/or the heart (Spuentrup et
al., 2008; Vymazal et al., 2009). Nevertheless, none of these imaging
products has reached approval for clinical use (Lanza et al., 2019).