Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation

Abstract

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [18F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [64Cu]Cu to enable studying the tracer’s mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [68Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE’s pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [64Cu]Cu-DOTATATE and [18F]F-FDG. To evaluate differences in the tracers’ cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [64Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUVmax 1.3, IQR, 1.2–1.4, N = 4) and remote myocardium (SUVmax 0.7, IQR, 0.5–0.8, N = 4, p = 0.0286), and with respect to controls (SUVmax 0.6, IQR, 0.5–0.7, N = 4, p = 0.0286), than [18F]F-FDG PET. In atherosclerotic mice, [64Cu]Cu-DOTATATE PET aortic signal, but not [18F]F-FDG PET, was higher compared to controls (SUVmax 1.1, IQR, 0.9–1.3 and 0.5, IQR, 0.5–0.6, respectively, N = 4, p = 0.0286). In both models, [64Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [18F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [68Ga]Ga-DOTATATE and [18F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [68Ga]Ga-DOTATATE and [18F]F-FDG in atherosclerotic (SUVmax 0.415, IQR, 0.338–0.499, N = 32 and 0.446, IQR, 0.387–0.536, N = 27, respectively) compared to control animals (SUVmax 0.253, IQR, 0.197–0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299–0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [18F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [18F]F-FDG.

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.…”

Myeloperoxidase activity predicts atherosclerotic plaque disruption and atherothrombosis

“…68 Ga-DOTATATE targets more specifically the somatostatin receptor subtype-2 but is limited by its inability to distinguish beneficial from harmful inflammation. 49,50 Alternatively, ultra-small superparamagnetic iron oxide (USPIO), a clinically approved MRI contrast agent, can track and characterize macrophage-infiltration. 51,52 However, unlike Gd-based MRI agents that can be imaged within 1 h of administration, the typically 12-24 h time gap between pre-and postcontrast injection MRI acquisitions required for USPIO is impractical clinically and may preclude the possibility of short-term follow-up with other diagnostic MRI sequences.…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…Additionally, a retrospective study has found a strong correlation between CFs activation volume with cardiac function and peak creatine kinase via 68Ga-FAP-α inhibitor positron-emission tomography (PET) ( Kessler et al, 2021 ), while PET and single-photon emission computed tomography (SPECT) indirectly assessed cardiac fibrosis via myocardial perfusion imaging ( Gupta et al, 2021 ). PET immunoimaging DOTATATE tracers can find high expression of somatostatin receptor two in M1 inflammatory macrophages ( Toner et al, 2022 ). Multiparametric imaging characterizes the immune response transforming to tissue repair after MI ( Hess et al, 2022 ).…”