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.
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.
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