Mol Imaging Biol

2015

DOI: 10.1007/s11307-015-0873-1

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Comparison of Somatostatin Receptor 2-Targeting PET Tracers in the Detection of Mouse Atherosclerotic Plaques

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Abstract: Our results demonstrate superior applicability for [(68)Ga]DOTANOC and [(68)Ga]DOTATATE in the detection of atherosclerotic plaques compared to [(18)F]FDR-NOC.

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Rationale For Study Of 68 Ga-dotatate In Atherosclerosis1

Pet/spect Probes For Imaging Inflammatory Cells1

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Cited by 49 publications

(65 citation statements)

References 37 publications

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“…Two studies demonstrated autoradiographic 68 Ga-DOTATATE binding within macrophage-rich aortic atherosclerotic plaques in mice 6, 7. Five retrospective analyses of PET scans from patients who underwent imaging for oncological indications reported significant statistical relationships between vascular SST 2 signals and clinical CVD factors, including older age, male sex, hypercholesterolemia, presence of calcified coronary plaque, prior CVD events, and Framingham risk score calculated using BMI 8, 9, 10, 18, 19.…”

Section: Discussionmentioning

confidence: 99%

“…Pre-clinical 6, 7 and retrospective 8, 9, 10 studies suggest that gallium-68-labeled [1,4,7,10-tetraazacyclododecane- N , N ', N '', N '''-tetraacetic acid]- d -Phe 1 , Tyr 3 -octreotate (DOTATATE), a PET ligand with high-specificity binding affinity for SST 2 (11), may be superior to [ 18 F]FDG in marking macrophage activity, particularly in the coronary arteries. However, robust evaluation of 68 Ga-DOTATATE in atherosclerosis is lacking.…”

mentioning

confidence: 99%

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Detection of Atherosclerotic Inflammation by 68 Ga-DOTATATE PET Compared to [ 18 F]FDG PET Imaging

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et al. 2017

Journal of the American College of Cardiology

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BackgroundInflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover.ObjectivesThis study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation.MethodsWe confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis.ResultsTarget SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients.ConclusionsWe validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

“…Two studies demonstrated autoradiographic 68 Ga-DOTATATE binding within macrophage-rich aortic atherosclerotic plaques in mice 6, 7. Five retrospective analyses of PET scans from patients who underwent imaging for oncological indications reported significant statistical relationships between vascular SST 2 signals and clinical CVD factors, including older age, male sex, hypercholesterolemia, presence of calcified coronary plaque, prior CVD events, and Framingham risk score calculated using BMI 8, 9, 10, 18, 19.…”

Section: Discussionmentioning

confidence: 99%

“…Pre-clinical 6, 7 and retrospective 8, 9, 10 studies suggest that gallium-68-labeled [1,4,7,10-tetraazacyclododecane- N , N ', N '', N '''-tetraacetic acid]- d -Phe 1 , Tyr 3 -octreotate (DOTATATE), a PET ligand with high-specificity binding affinity for SST 2 (11), may be superior to [ 18 F]FDG in marking macrophage activity, particularly in the coronary arteries. However, robust evaluation of 68 Ga-DOTATATE in atherosclerosis is lacking.…”

mentioning

confidence: 99%

Detection of Atherosclerotic Inflammation by 68 Ga-DOTATATE PET Compared to [ 18 F]FDG PET Imaging

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,

²

,

³

et al. 2017

Journal of the American College of Cardiology

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BackgroundInflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover.ObjectivesThis study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation.MethodsWe confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis.ResultsTarget SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients.ConclusionsWe validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

“…68 Ga-DOTATATE, a specific sst2 receptor agonist, therefore was thought to have the potential to be a surrogate marker of inflammation to study plaque biology. This has been recently validated in 2 preclinical murine experiments (apolipoprotein 2/2 mice model) at a tissue level (24,25). Four recent studies examined the potential role of these in atherosclerosis, retrospectively in patients with neuroendocrine tumors.…”

Section: Rationale For Study Of 68 Ga-dotatate In Atherosclerosismentioning

confidence: 97%

“…It is also known that vessels can express somatostatin receptors under certain conditions (22,23). Recently, 2 preclinical murine studies have demonstrated the potential of somatostatin receptor PET in atherosclerosis imaging (24,25). Retrospective human studies with these tracers have also shown promise (26)(27)(28)(29).…”

mentioning

confidence: 99%

PET/CT Imaging of Unstable Carotid Plaque with ⁶⁸Ga-Labeled Somatostatin Receptor Ligand

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et al. 2016

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68 Ga-labeled somatostatin receptor ligand PET imaging has recently been shown in preclinical and early human studies to have a potential role in the evaluation of vulnerable arterial plaques. We prospectively evaluated carotid plaque 68 Ga-DOTATATE uptake in patients with recent carotid events, assessed inter-and intraobserver variability of such measurements, and explored the mechanism of any plaque DOTATATE activity with immunohistochemistry in resected specimens. Methods: Twenty consecutively consenting patients with recent symptomatic carotid events (transient ischemic attack, stroke, or amaurosis fugax), due for carotid endarterectomy, were prospectively recruited. 68 Ga-DOTATATE PET/CT of the neck was performed before surgery. 68 Ga-DOTATATE uptake was measured by drawing regions of interest along the carotid plaques and contralateral plaques/carotid arteries by an experienced radionuclide radiologist and radiographer. Two PET quantification methods with inter-and intraobserver variability were assessed. Resected carotid plaques were retrieved for somatostatin receptor subtype-2 (sst2) immunohistochemical staining. Results: The median time delay between research PET and surgery was 2 d. SUVs and target-to-background ratios for the symptomatic plaques and the asymptomatic contralateral carotid arteries/plaques showed no significant difference (n 5 19, P . 0.10), regardless of quantification method. The intraclass correlation coefficient was greater than 0.8 in all measures of carotid artery/plaque uptake (SUV) and greater than 0.6 in almost all measures of target-to-background ratio. None of the excised plaques was shown to contain cells (macrophages, lymphocytes, vessel-associated cells) expressing sst2 on their cell membrane. Conclusion: 68 Ga-DOTATATE activity on PET in recently symptomatic carotid plaques is not significantly different from contralateral carotids/plaques. Any activity seen on PET is not shown to be from specific sst2 receptor-mediated uptake in vitro. It is therefore unlikely that sst2 PET/CT imaging will have a role in the detection and characterization of symptomatic carotid plaques. At herosclerosis is a leading cause of mortality and morbidity.There is the concept that although atherosclerotic plaques may contribute to symptoms by luminal stenosis, it is the disruption of unstable plaques that leads to catastrophic events, including stroke and myocardial infarction. Termed vulnerable plaques, these unstable plaques are believed to have characteristic features such as inflammatory cell infiltration, lipid cores, and fibrous caps (1,2).Measuring the degree of luminal stenosis was the mainstay of assessment and directed management decisions until recently (3-5). Recognition of this method's limitation has driven the use of biomarkers, such as fractional flow reserve, in coronary disease and exploration of functional imaging to noninvasively identify vulnerable plaques (6,7).Radionuclide imaging has the advantageous capability of directly probing molecular mechanisms in vivo using radi...

“…Rinne et al [39] compared several PET probes targeting SSTR-2 in a mouse model and indicated the superior applicabilities of 68 Ga-DOTANOC and 68 Ga-DOTATATE in the detection of atherosclerotic plaques compared with 68 Ga-FDR-NOC. Several clinical studies have also indicated the potential roles of 68 Ga-DOTATATE and 64 Cu-DOTATATE in oncology patients and patients undergoing endarterectomy [6][7][8].…”

Section: Pet/spect Probes For Imaging Inflammatory Cellsmentioning

confidence: 99%

Recent Advances in the Development of PET/SPECT Probes for Atherosclerosis Imaging

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2016

Nucl Med Mol Imaging

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The rupture of vulnerable atherosclerotic plaques and subsequent thrombus formation are the major causes of myocardial and cerebral infarction. Accordingly, the detection of vulnerable plaques is important for risk stratification and to provide appropriate treatment. Inflammation imaging using 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 F-FDG) has been most extensively studied for detecting vulnerable atherosclerotic plaques. It is of great importance to develop PET/SPECT probes capable of specifically visualizing the biological molecules involved in atherosclerotic plaque formation and/or progression. In this article, we review recent advances in the development of PET/SPECT probes for visualizing atherosclerotic plaques and their application to therapy monitoring, mainly focusing on experimental studies.

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