Systematically Evaluating DOTATATE and FDG as PET Immuno-Imaging Tracers of Cardiovascular Inflammation

Abstract

The somatostatin receptor 2-binding PET tracer DOTATATE is emerging as an alternative to 18F-FDG to assess cardiovascular inflammation. The strengths and weaknesses of each tracer and their different specificity for inflammatory cells still need to be fully elucidated. In this manuscript, we employed mouse and rabbit animal models of inflammation. In mice, 64Cu-DOTATATE’s pharmacokinetics and timed biodistribution were determined in control (C57BL/6) and atherosclerotic (Apoe−/−) mice by ex vivo gamma counting. In vivo PET/CT, combined with ex vivo flow cytometry and gamma counting, was used to evaluate the quantification of cardiovascular inflammation by 64Cu-DOTATATE and 18F-FDG and the tracers’ cellular specificity in control versus infarcted and atherosclerotic mice. In a translational PET/MRI rabbit study, we then compared DOTATATE labeled with short-lived radioisotope 68Ga and 18F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. In infarcted mice, in vivo 64Cu-DOTATATE PET showed higher differential uptake than 18F-FDG between infarcted and remote myocardium (p=0.0286), and with respect to controls (p=0.0286; n=4-6). In atherosclerotic mice, 64Cu-DOTATATE PET aortic signal, but not 18F-FDG, was higher compared to controls (p=0.0286; n=4). In both models, 64Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while 18F-FDG uptake was less cell-specific. The translational rabbit PET/MRI study showed significantly higher aortic accumulation of both 68Ga-DOTATATE and 18F-FDG in atherosclerotic compared to control animals (p=0.0002 and p=0.0159, respectively; n=10-32). In conclusion, we introduce a workflow integrating in vivo PET and ex vivo immunological and radioactivity counting assays to characterize DOTATATE and 18F-FDG as inflammation tracers in small animal models of cardiovascular disease. Our results support the use of DOTATATE to assess cardiovascular inflammation, as alternative and complement to 18F-FDG. In addition, our study establishes a comprehensive and robust framework for the thorough assessment and comparison of novel and validated PET immuno-tracers in the cardiovascular arena.

Novel Approach for Assessing Postinfarct Myocardial Injury and Inflammation Using Hybrid Somatostatin Receptor Positron Emission Tomography/Magnetic Resonance Imaging

“…2 The mechanism of 64 Cu-DOTATATE binding to SST 2 receptors expressed by inflammatory macrophages within recently infarcted myocardial tissue has been shown in a mouse model, using a combination of in vivo PET/CT imaging and ex vivo radiometric and immunologic assays. 4 In that study, 64 Cu-DOTATATE uptake within cell-sorted macrophages from infarcted mouse myocardium was 3-fold higher than 18 F-FDG.…”

Imaging of Atherosclerosis with [64Cu]Cu-DOTA-TATE: a Translational Head-to-Head Comparison Study with 2-[18F]FDG, and Na[18F]F in Rabbits

“…2-[18F]FDG is useful to both quantify and track in ammation in atherosclerosis [7][8][9][10][11]. Unfortunately, the physiological uptake of 2-[ 18 F]FDG by cardiomyocytes challenges the visualization of in ammation in the coronary arteries [12]. These limitations can be eliminated using other PET tracers that more speci cally target in ammatory cells.…”