PET/SPECT imaging of hindlimb ischemia: focusing on angiogenesis and blood flow

Abstract

Peripheral artery disease (PAD) is a result of the atherosclerotic narrowing of blood vessels to the extremities, and the subsequent tissue ischemia can lead to the up-regulation of angiogenic growth factors and formation of new vessels as a recovery mechanism. Such formation of new vessels can be evaluated with various non-invasive molecular imaging techniques, where serial images from the same subjects can be obtained to allow the documentation of disease progression and therapeutic response. The most commonly used animal model for preclinical studies of PAD is the murine hindlimb ischemia model, and a number of radiotracers have been investigated for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of PAD. In this review article, we summarize the PET/SPECT tracers that have been tested in the murine hindlimb ischemia model as well as those used clinically to assess the extremity blood flow.

Fig. 1

a Laser Doppler imaging of the ischemic foot of a patient with diabetes before and after infrainguinal revascularization. The areas with improved perfusion are shown in red and the areas with poor perfusion are shown in blue. b Serial laser Doppler imaging of ischemic hindlimb of a C57 mouse. Decreased perfusion soon after the surgery (dark blue) was observed in the ischemic limb, whereas high perfusion pattern (red to orange) was detected in the control hindlimb. The recovery of perfusion was clearly detectable on day 7. Adapted from [75, 76].

Fig. 2

a Noninvasive PET/CT images of angiogenesis in a murine hindlimb ischemia model. An integrin α_vβ₃-targeted dendritic nanoprobe had significantly higher uptake in the ischemic hindlimb than the control hindlimb. b Serial ¹³N-ammonia PET images of spontaneous perfusion recovery in a murine hindlimb ischemia model, at different time points after surgery. Adapted from [40, 47].

Fig. 3

In vivo planar pinhole images of ischemic hindlimb of a mouse at various time points after surgery, after intravenous injection of ^99mTc-NC100692. A significant increase in tracer uptake in the ischemic hindlimb was observed on days 3 and 7 after surgery (red circle). Adapted from [48].

Fig. 4

Serial PET imaging of CD105 expression in a murine hindlimb ischemia model at different days after surgery, acquired at 48 h post-injection of ⁶⁴Cu-NOTA-TRC105. The white arrowheads indicate increased uptake in the ischemic hindlimb, which returned to background level on day 25.