Specific somatostatin receptor II expression in arterial plaque: 68Ga-DOTATATE autoradiographic, immunohistochemical and flow cytometric studies in apoE-deficient mice

Li, Xiang; Bauer, Wolfgang R.; Kreißl, Michael C.; Weirather, Johannes; Bauer, Elisabeth; Israel, Ina; Richter, Dominik; Riehl, Gabriele; Buck, Andreas K.; Samnick, Samuel

doi:10.1016/j.atherosclerosis.2013.06.018

Cited by 72 publications

(52 citation statements)

References 31 publications

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“…Various processes and cellular targets involved with the presence of this cell type have been investigated and identified as targets for PET, with expression of the somatostatin receptor, a G-protein-coupled 7-transmembrane protein, being one of them. Five human somatostatin receptors have been identified, and in atherosclerotic plaques the somatostatin receptor 2 is the most frequent (4)(5)(6). The somatostatin analogs DOTATOC and DOTATATE bind to somatostatin receptors, with highest affinity for the somatostatin receptor 2.…”

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confidence: 99%

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

et al. 2015

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The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers 68 Ga-DOTATOC and 64 Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. Methods: Sixty consecutive patients with neuroendocrine tumors underwent both 68 Ga-DOTATOC and 64 Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool-corrected target-to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. Results: We found detectable uptake of both tracers in all arterial segments studied. Uptake of 64 Cu-DOTATATE was significantly higher than 68 Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of 64 Cu-DOTATATE using SUV (r 5 0.4; P 5 0.004) as well as target-to-background ratio (r 5 0.3; P 5 0.04), whereas no association was found with 68 Ga-DOTATOC. The association of risk factors and maximum SUV of 64 Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P , 0.001, P 5 0.01, P 5 0.005, and P 5 0.03, respectively). Conclusion: In a series of oncologic patients, vascular uptake of 68 Ga-DOTATOC and 64 Cu-DOTATATE was found, with highest uptake of the latter. Uptake of 64 Cu-DOTATATE, but not of 68 Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for 64 Cu-DOTATATE in the assessment of atherosclerosis.

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confidence: 99%

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

et al. 2015

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“…Preclinical124 and retrospective125, 126 studies suggest that gallium‐68‐labeled [1,4,7,10‐tetraazacy‐clododecane‐ N , N ′, N ″, N ‴‐tetraacetic acid]‐ d ‐Phe1, Tyr3‐octreotate (DOTATATE), a somatostatin receptor subtype‐2‐binding PET tracer, may be superior to 18 F‐FDG for imaging atherosclerotic inflammation. Tarkin et al127 validated 68 Ga‐DOTATATE PET as a novel marker of atherosclerotic inflammation and showed that 68 Ga‐DOTATATE PET offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high‐risk versus low‐risk coronary lesions than 18 F‐FDG.…”

Section: Alternative Pet Imaging Tracersmentioning

confidence: 99%

Imaging Cardiovascular Calcification

Wang

Osborne

Tung

et al. 2018

JAHA

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“…32 In a previous study using the somatostatin receptor-avid tracer 68 Ga-DOTATATE to image macrophages, the aorta uptake of 68 Ga-DOTATATE likely shows greater specificity to the vascular inflammation related to 18 F-FDG. 12,32 Because P-selectin expression is closely associated with increased macrophage infiltration into plaques, further correlation between 68 Ga-DOTATATE-PET, 18 F-FDG-PET, and 68 Ga-Fucoidan-PET would be of great interest. In addition, matrix-digesting enzymes (MMPs 2, 3, 9, etc) in the fibrous cap also play a vital role in the rupture of plaque; MMPs secreted by macrophages are specific indicators of the macrophage activity rather than only macrophage density.…”

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confidence: 99%

“…10 Furthermore, the somatostatin receptoravid radiotracer 68 Ga- [1,4,7,10-tetraazacyclododecane-N,N′,N″, N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) detected macrophages in atherosclerotic plaque both in human and animal studies. 11,12 In clinical and preclinical studies, 18F-fluorodeoxyglucose ( 18 F-FDG) is the most commonly used tracer to assess inflamed plaques by evaluating the glucose metabolism of activated macrophage. 13 P-selectin is an adhesion molecule, which is highly expressed on the surface of active endothelium and platelets.…”

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confidence: 99%

Targeting P-Selectin by Gallium-68–Labeled Fucoidan Positron Emission Tomography for Noninvasive Characterization of Vulnerable Plaques

Bauer

Israel

et al. 2014

ATVB

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Objective-Nuclear imaging of active plaques still remains challenging. Advanced atherosclerotic plaques have a strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques, but not on the endothelium overlying inactive fibrous plaques. We proposed a new approach for noninvasive in vivo characterization of P-selectin on active plaques based on 68 Ga-Fucoidan, which is a polysaccharidic ligand of P-selectin with a nanomolar affinity. Approach and Results-68 Ga-Fucoidan was tested for its potential to discriminate vulnerable plaques on apolipoprotein E-deficient mice receiving a high cholesterol diet by positron emission tomography and in correlation with 17.6T MRI. Furthermore, 68 Ga-Fucoidan was evaluated on endothelial cells in vitro and ex vivo on active plaques using autoradiography. The cellular uptake rate was increased ≈2-fold by lipopolysaccharide induction. Interestingly, on autoradiography, more intensive tracer accumulation at active plaques with thin fibrous caps and high-density foam cells were observed in comparison with a weaker focal uptake in inactive fibrous plaque segments (R=1.7±0.3; P<0.05) and fatty streaks (R=2.4±0.4; P<0.01). Strong uptake of radiotracer colocalized with increased P-selectin expression and high-density macrophage. Focal vascular uptake (mean of target to background ratio=5.1±0.8) of 68 Ga-Fucoidan was detected in all apolipoprotein E-deficient mice. Anatomic structures of plaque were confirmed by 17.6T MRI. The autoradiography showed a good agreement of 68 Ga-Fucoidan uptake with positron emission tomography. Conclusions-Our data suggest that 68 Ga-Fucoidan represents a versatile imaging biomarker for P-selectin with the potential to specifically detect P-selectin expression using positron emission tomography and to discriminate vulnerable plaques in vivo. pivotal role in recruiting leukocytes to the sites of injury. 14-16This interaction is mediated by P-selectin glycoprotein ligand 1, expressed by monocytes, neutrophils, and platelets. 17,18 Most active atherosclerotic lesions remain undetected until plaque rupture and thrombosis occur. A previous study found that inflamed atherosclerotic plaques have a strong expression of P-selectin on the overlying endothelium, but much less in normal arterial endothelium or in endothelium overlying inactive fibrous plaques.19 Consequently, P-selectin is thought to be an effective biomarker for assessing the bioactivity of active plaques.Fucoidan is a synthetic sialyl-lewis X mimic, which is the natural ligand of P-selectin and is found on leukocytes. 20,21 It is mainly derived from brown seaweed with an efficient binding of P-selectin as well. 22 In previous studies, a high specific affinity of fucoidan for P-selectin was confirmed. 22We developed a novel PET tracer by an efficient introduction of the positron emitter 68 Ga into the Fucoidan moiety. The 68 Ga-Fucoidan obtained this way was used to validate the P-selectin expression in vivo on an established apolipoprotein E-deficient (apoE −/− ) m...

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Specific somatostatin receptor II expression in arterial plaque: 68Ga-DOTATATE autoradiographic, immunohistochemical and flow cytometric studies in apoE-deficient mice

Cited by 72 publications

References 31 publications

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

Imaging Cardiovascular Calcification

Targeting P-Selectin by Gallium-68–Labeled Fucoidan Positron Emission Tomography for Noninvasive Characterization of Vulnerable Plaques

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Specific somatostatin receptor II expression in arterial plaque: 68Ga-DOTATATE autoradiographic, immunohistochemical and flow cytometric studies in apoE-deficient mice

Cited by 72 publications

References 31 publications

64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients

64Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with 68Ga-DOTATOC in 60 Patients

Imaging Cardiovascular Calcification

Targeting P-Selectin by Gallium-68–Labeled Fucoidan Positron Emission Tomography for Noninvasive Characterization of Vulnerable Plaques

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⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients

⁶⁴Cu-DOTATATE for Noninvasive Assessment of Atherosclerosis in Large Arteries and Its Correlation with Risk Factors: Head-to-Head Comparison with ⁶⁸Ga-DOTATOC in 60 Patients