Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview

Abstract

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.

Fig 1

Non-invasive in vivo planar imaging of lectin-like oxLDL receptor-1 (LOX-1) with [^99mTc]-LOX-1-mAb. Non-invasive imaging of abdominal region with [^99mTc]-LOX-1-mAb (A, B, D, and E) and [^99mTc]-IgG2a (C and F). Planar images for WHHLMI (B, C, E, and F) and control (A and D) rabbits at 10 min (A–C) and 24 hours (D–F) after injection are shown. Field of view = 170 × 120 mm. Arrows = aorta; K = kidney; L = liver; S = spleen. Reproduced from [61] with permission from the Society of Nuclear Medicine.

Fig 2

Non-invasive in vivo planar imaging of macrophage CCR-2 receptors with [^99mTc]-MCP-1. Images were obtained in both New Zealand White (NZW) rabbits submited to deendothelialization of the abdominal aorta and fed a high-cholesterol diet (atherosclerotic, [A–C]) and control, unmanipulated, NZW animals fed normal rabbit chow (non-atherosclerotic, [D–F]) rabbits. (A–C) Planar γ-images of atherosclerotic rabbit. (A) Image obtained immediately after intravenous [^99mTc]-MCP-1 administration outlines aortic blood-pool activity (arrows). (B) At 3 hours after radiotracer administration, significant radiotracer accumulation is evident in abdominal aorta (arrows). (C) Ex vivo image of explanted aorta confirms in vivo evidence of [^99mTc]-MCP-1 uptake (arrows). (D–F) Planar γ-images of control rabbit. (D) Aortic blood pool is seen at time of intravenous [^99mTc]-MCP-1 injection (arrows). (E) Image shows lack of [^99mTc]-MCP-1 uptake in region of abdominal aorta, as denoted by arrows in normal rabbit with no atherosclerotic lesions. (F) Ex vivo aortic image of control animal demonstrates absence of [^99mTc]-MCP-1 uptake (arrows). L = liver; S = spleen; K = kidney. (G) Bar graphs show quantitative [^99mTc]-MCP-1 uptake within abdominal aortas of atherosclerotic and control animals represented as mean %ID/g ± SD. [^99mTc]-MCP-1 uptake (%ID/g) was significantly higher in atherosclerotic animals (P<0.0001) compared with that of control animals. Reproduced from [65] with permission from the Society of Nuclear Medicine.

Fig 3

Non-invasive in vivo PET imaging of macrophage metabolism using [¹⁸F]-FDG. PET images (A and D), CT images (B and E), and superimposed PET/CT images (C and F) in the sagittal (I) and coronal (II) planes for WHHL (A, B, and C) and control (D, E, and F) rabbits. Orange arrows, orange arrowheads, and white arrowheads indicate aortas, kidneys, and livers, respectively. Reproduced from [62] with permission from the Society of Nuclear Medicine.

Fig 4

Non-invasive in vivo PET imaging of macrophages with a ⁶⁴Cu-labeled trireporter nanoparticle [⁶⁴Cu]-TNP. [⁶⁴Cu]-TNP facilitates PET-CT imaging of inflammatory atherosclerosis in apoE^−/− mice. Fused PET-CT images of the aortic root (A), arch (B), and carotid artery (C) of aged apoE^−/− mice show strong PET signal in these vascular territories with high plaque burden, whereas no activity is observed in the same vasculature of wildtype mice (D through F). G and H, Hematoxylin and eosin histology of respective vascular regions, which carry a high plaque burden in apoE^−/− but not in wild-type mice (I through K) (magnification: x 400 for G and I, x200 for H and K; bar=0.4 mm). The 3-dimensional maximum intensity reconstruction of the fused data set (L) demonstrates focal PET signal (red) in the proximal thoracic aorta (blue) of an apoE^−/− mouse but not in a wild-type mouse (M). Reproduced from [88] with pending permission from the American Heart Association.

Fig 5

Non-invasive in vivo SPECT imaging of apoptosis using [^99mTc]-annexin A5. In vivo and ex vivo images of control mice (A) and apoE^−/− mice without cholesterol diet (B) and with cholesterol diet (C). For all images, left panel represents transverse images, middle panel represents sagittal images, and right panel represents ex vivo images (A–C). Top panel shows micro-CT, middle panel shows micro-SPECT, and bottom panel shows fusion images. (A) No obvious [^99mTc]-annexin A5 uptake was seen on either in vivo or ex vivo images of control animals. (B) Distinct uptake was observed in the arch on in vivo images and in the arch and abdominal aorta on ex vivo image. (C) Distinct uptake and calcification were observed in the arch on the in vivo images; [^99mTc]-annexin A5 uptake was seen in whole aorta on the ex vivo image. (D) Quantitative uptake was highest in cholesterol-fed apoE^−/− mice, followed by chow-fed apoE^−/− and control mice in lesions at arch, thoracic, or abdominal level. Ch = cholesterol fed. Reproduced from [103] with permission the Society of Nuclear Medicine.