Molecular Imaging Using Radiotracers

Nuclear imaging can often offer superb sensitivity in detecting pathological processes. Different types of radiotracers can theoretically be loaded onto a variety of constructs that would allow for specific molecular targeting. Once specifically targeted, radiotracers have unmatched and outstanding sensitivity and specificity. However, several and diverse technical challenges will need to be overcome to make nuclear imaging more

Figure 3 Molecular and cellular targets for molecular imaging of atherosclerosis. Schematic of atherosclerosis pathogenesis ranging from endothelial dysfunction (left) through monocyte recruitment to the development of advanced plaque complicated that can be complicated by thrombosis (right). This schematic is quite simplified, however, it highlights processes and components such as cell adhesion molecules, macrophages, connective tissue elements, lipid core and fibrin, apoptosis, proteolysis, angiogenesis, and thrombosis in plaques that may prove useful for imaging. Abbreviations: ICAM, intercellular cell adhesion molecule; LDL, low-density lipoprotein; MMP, matrix metalloproteinase; NO, nitric oxide; VCAM, vascular cell adhesion molecule. Source: From Ref. 107.

Figure 3 Molecular and cellular targets for molecular imaging of atherosclerosis. Schematic of atherosclerosis pathogenesis ranging from endothelial dysfunction (left) through monocyte recruitment to the development of advanced plaque complicated that can be complicated by thrombosis (right). This schematic is quite simplified, however, it highlights processes and components such as cell adhesion molecules, macrophages, connective tissue elements, lipid core and fibrin, apoptosis, proteolysis, angiogenesis, and thrombosis in plaques that may prove useful for imaging. Abbreviations: ICAM, intercellular cell adhesion molecule; LDL, low-density lipoprotein; MMP, matrix metalloproteinase; NO, nitric oxide; VCAM, vascular cell adhesion molecule. Source: From Ref. 107.

practical. There is much room for improvement in terms of the resolution of current nuclear techniques when compared to other imaging modalities. There is also a lack of anatomic detail on many types of scans. However, the latter problem has been somewhat overcome with the help of combined anatomical and nuclear imaging methods such as PET/CT or the newer single photon emission CT (SPECT)/CT. Another challenge is related to scan acquisition times, which can be rather long. And finally, from a practical standpoint, synthesis of certain radionuclides requires the use of a cyclotron and in general, radiotracers/radionuclides can be a challenge to work with especially if they have short half-lives. However, all things considered nuclear imaging will certainly have a prominent role in nonin-vasive functional assessment of atherosclerotic disease pathology.

Currently the primary nuclear imaging modalities that have been used for imaging atherosclerosis are

SPECT and PET as well as combined PET/CT. SPECT uses y-emitting radionuclides/radiotracers and the imaging or detection of signal is setup thereof. In comparison, PET uses positron-emitting radoinuclides/ radiotracers and imaging is accomplished by detecting coincident 511 keV photons that arise from the decay of the positron-emitting isotope/radionuclide (118). Both SPECT and PET require acquisition of transmission maps to correct for attenuation as photons travel outside the body through different anatomical lengths and densities. With the use of PET/CT anatomical imaging is accomplished with CT while the PET scan takes place and then the two sets of scans can be viewed as an overlay or individually (119,120). Another advantage of PET/CT is that it is possible to obtain a transmission map for attenuation correction using CT X-ray photons instead of using 68Germanium (68Ge) segmented attenuation correction (118,121-123). At a resolution of roughly 5 mm PET is superior to SPECT, which has a resolution of approximately 15 mm. In addition, PET offers better sensitivity. Therefore, for imaging small pathological lesions, such as atherosclerotic plaques, PET is currently the more capable nuclear imaging modality.

Numerous molecular and cellular targets have been pursued with radiotracers for SPECT imaging including adhesion molecules, lipoproteins, SMCs, endothelial cells and macrophages (10,124). These studies have demonstrated feasibility, however, they have largely failed to yield strong target to background ratios. This was likely related to sluggish clearance of radiotracer from blood and nonspecific distribution in other tissues. There have been some attempts to overcome these challenges. In one study, investigators used SPECT imaging using a radionuclide-labeled antibody to the glycoprotein Ilb/IIIa (GPIIb/IIIa) platelet receptors. The idea behind this was to image platelet-rich thrombus often found on atheromatous plaques that have ruptured or are vulnerable to rupture. In the study, a canine coronary arterial thrombus model was used. The results were promising in terms of identification of thrombus (10). However, newer studies have not been performed.

Tsimikas et al. have performed several studies using radiotracer-labeled monoclonal antibodies to oxidized-low-density lipoprotein (ox-LDL). These studies have been performed in both mouse and rabbit models of atherosclerosis. The methods used for the detection were autoradiography, gamma-camera scin-tigraphy or both. In these studies, the investigators demonstrated that radiolabeled antibodies to ox-LDL could be used for detecting atherosclerosis (125). Furthermore, they also showed that it was potentially possible to estimate plaque volume as well as follow progression and regression of atheromatous plaques (126,127).

Apoptosis is believed to play a role in the formation of necrotic debris that constitutes necrotic cores often found in unstable vulnerable plaques (5). There is data to suggest that apoptosis of macrophages contributes to the size of a necrotic core (128). Furthermore, there is evidence that apoptosis of SMCs is associated with a thin fibrous cap (129). Recently, Narula et al. used radiolabeled annexin V to target apoptotic cells in a rabbit model of atherosclerosis using gamma camera methods. Annexin V has a high affinity for phosphatidylserine (PS), which becomes exposed on the surface of apoptotic cells. In this study, the investigators measured the in vivo aortic uptake of radiolabeled annexin V. They showed that there was an almost 10-fold higher uptake in the aorta of atherosclerotic rabbits compared to control rabbits (Fig. 4) (130). Given that apoptosis is a potential determinant of plaque instability, imaging atherosclerosis using annexin V may turn out to be useful in assessing plaque vulnerability. Quite interestingly, these methods are now being used in humans to study usefulness in assessment of carotid atherosclerosis (Fig. 5). Although preliminary, the results are suggesting that imaging carotid atherosclerosis with radiolabeled annexin V may discern carotid plaque features indicative of stability or rather lack thereof (131).

PET has shown interesting promise for imaging atherosclerosis. Thus far only 18-fluorodeoxyglucose (FDG) has been used in assessing atherosclerosis with PET. FDG is a fluorine-18 (18F)-labeled modified derivative of glucose. Lederman et al. first demonstrated marked increased FDG uptake in experimental atherosclerosis (132). Several studies in humans have examined FDG uptake in the region of the aorta (133-135). However, these studies yielded little information regarding frequency, location, and intensity of uptake. Although subsequently, one study found a correlation between certain risk factors for CAD, such as age and hypercholesterolemia, and the magnitude of FDG uptake in the abdominal aorta, iliac arteries and femoral arteries (136).

Rudd et al. used FDG to perform PET on patients with symptomatic carotid atherosclerotic disease (9). Their study found that FDG accumulated to a significantly greater degree in unstable plaques compared to the stable contralateral-sided plaques (9). Furthermore, ex vivo analysis of endarterectomy samples showed that the FDG accumulated mostly in macrophages found in plaque (9). Interestingly, this suggests that FDG may be suitable for assessing plaque vulnerability since a high and active macrophage content has been linked with instability (114).

Taking advantage of combined functional and anatomical imaging Tatsumi et al. used PET/CT to study aortic FDG-uptake in patients undergoing FDG-PET/CT scans for cancer staging (137). In that study, investigators could anatomically approximate the location of FDG uptake by using the CT imaging (Fig. 6). The results showed that FDG uptake was primarily in the thoracic aorta and that it was associated with age (137). Interestingly, areas of FDG uptake were mostly distinct and separate from areas of calcification in the aorta (137).

Recently, M. Ogawa et al. performed PET/CT study correlating atherosclerosis pathology to FDG uptake in the aorta of Watanabe heritable hyperlipid-emic (WHHL) rabbits. They found that there was a strong correlation between FDG uptake and the number of macrophages found in plaque (138). The findings of this study have been recently confirmed by A. Tawakol et al., who examined the relationship between FDG uptake and vascular inflammation in an induced atherosclerosis model using New Zealand white (NZW) rabbits. They also found a strong relationship between macrophage staining on immunohistopathologic slides

Figure 4 Gamma camera imaging of atherosclerosis using annexin V in rabbits. (A) Left lateral decubitus image injected with 99mTc-labeled annexin V showing blood pool activity immediately after administration. (B) Clear delineation of radiolabeled within the abdominal aorta at two hours. (C) Magnification of the abdominal aorta. Source: From Ref. 130.

Figure 4 Gamma camera imaging of atherosclerosis using annexin V in rabbits. (A) Left lateral decubitus image injected with 99mTc-labeled annexin V showing blood pool activity immediately after administration. (B) Clear delineation of radiolabeled within the abdominal aorta at two hours. (C) Magnification of the abdominal aorta. Source: From Ref. 130.

and the amount of FDG uptake in plaques (139). However, instead of using macrophage number they assessed inflammation via RAM-11 immuno-staining, which stains for macrophages found in plaque. Both of these studies demonstrated that FDG uptake in atherosclerosis is related to macrophage content, which in turn is thought to be a marker of instability.

PET using FDG has demonstrated good promise in terms of quantifying macrophage activity and possibly inflammation. Further study is necessary to examine whether FDG-uptake correlates with future risk of atherosclerosis-related clinical events or plaque rupture. After that, investigations must be done to assess true sensitivity and specificity. However, there still remain significant challenges to the use of FDG in assessing atherosclerosis. Unfortunately, FDG is taken up into any metabolically active tissue. In fact, myocar-dial uptake of FDG is among the highest of all tissues, which currently excludes FDG from use in imaging coronary atherosclerosis.

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