The Feasibility of 18F-FDG Labeled RBC and PET/CT Imaging Blood Perfusion and Vascular Dysfunction Measurements in Pre-clinical Research

Heart disease, dementia, and stroke are significant public health issues and leading causes of mortality and morbidity worldwide. Abnormalities in blood perfusion and vascular structures are seen in varieties of pathologies, including cerebrovascular diseases like stroke and dementia, hypertension, cardiovascular disease like atherosclerosis, diabetes, peripheral artery disease, and vasculitis, and tumor angiogenesis. Imaging perfusion/vascular abnormalities in these patients often plays a vital role in clinical diagnosis and treatment decisions. Vascular diseases typically present as macrovascular or microvascular diseases. Microvascular disease (MVD) refers to vascular disease primarily affecting the arterioles, venules, and capillaries in various organs. Furthermore, MVD is widely found in vital organs like the brain, heart, and kidney. The assessment of MVD plays an important role in clinical diagnosis and treatment intervention. While some imaging modalities such as echocardiography, CT, SPECT are widely used to visualize vascular abnormalities, the ability to visualize the microvasculature is often limited or cumbersome. Compared with those imaging techniques, molecular imaging has advantages in visualizing pathology processes at the molecular level to provide early diagnosis like positron emission tomography (PET). Nuclear blood pool imaging is widely used in the clinical setting for the evaluation of various medical conditions, including impaired cardiac contractility, gastrointestinal hemorrhage, and altered cerebrovascular blood flow by using radiolabeled red blood cells. Nuclear blood perfusion imaging is commonly performed using Technetium-99m-labeled (99mTc) human erythrocytes (i.e., the “tagged RBC” scan) and gamma camera-based planar scintigraphic imaging. However, positron emission tomography (PET) provides superior image quality and sensitivity compared to typical clinical planar scintigraphy and single-photon emission computed tomographic (SPECT) imaging platforms. Several PET-based radionuclide agents have been proposed for blood pool imaging, but none have yet to be used widely in the clinical setting. In this body of work, I describe a fast and straightforward procedure for imaging the vasculature of the rat through a combination of a small animal positron emission tomography/computed tomography (PET/CT) scanner and red blood cells (RBC) labeled with widely available and inexpensive PET radiopharmaceutical tracer 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG). This imaging approach is expected to have significant advantages over traditional 99mTc -labeled erythrocyte scintigraphic nuclear imaging for a few reasons, including superior spatial resolution and sensitivity. We first demonstrate proof of concept that the entire vascular of an immunodeficient mouse could be visualized using FDG-labeled human red blood cells (RBC). We showed that FDG-labeled RBC is capable of visual discrimination of the major vessels in the mouse, such as the aorta, vena cava, and jugular veins. In addition, the microvascularity of other organs such as the liver, lungs, and bone marrow could be visualized as well. In this research, we also investigate the feasibility of this method to semiquantitatively characterize differences in the normal rat myocardial microvasculature between physiologic rest and pharmacologic vasodilatory stress conditions. We also demonstrate the ability of FDG-labeled RBC PET imaging to image the infarcted myocardium in a surgical myocardial infarction rat heart model by using FDG label rat RBC and microPET/CT. Furthermore, we show that FDG-labeled RBC can be used to image the myocardium in a streptozotocin (STZ) induced diabetes rat model under both rest and pharmacologic stress conditions. Compared with normal age-matched control rats, significant decreases in pharmacologic induced vasodilatory response in the myocardium of the diabetic rats could be detected. The results provide evidence that this method can be used to visualize differences in myocardial microvascular response to pharmacologic stress conditions in healthy rat diabetic rat myocardium in vivo. This work presents evidence that the 18F-FDG labeling RBC PET image technique may have valuable application for non-invasive PET imaging of various perfusion and vascular disease processes