Abstract | UNLABELLED: METHODS:
Atherosclerotic plaques in BALB/C mice, maintained on a high-fat diet, were induced with streptozotocin injection and carotid artery ligation and verified by MR imaging. Knottin 3-4A was synthesized by solid-phase peptide synthesis chemistry and coupled to 1,4,7-triazacyclononane-1,4,7-triacetic acid ( NOTA) before radiolabeling with (64)Cu. PET probe stability in mouse serum was evaluated. Mice with carotid atherosclerotic plaques were injected via the tail vein with (64)Cu-NOTA-3-4A or (18)F-FDG, followed by small-animal PET/CT imaging at different time points. Receptor targeting specificity of the probe was verified by coinjection of c(RGDyK) administered in molar excess. Subsequently, carotid artery dissection and immunofluorescence staining were performed to evaluate target expression. RESULTS: (64)Cu-NOTA-3-4A was synthesized in high radiochemical purity and yield and demonstrated molecular stability in both phosphate-buffered saline and mouse serum at 4 h. Small-animal PET/CT showed that (64)Cu-NOTA-3-4A accumulated at significantly higher levels in the neovasculature of carotid atherosclerotic plaques (7.41 ± 1.44 vs. 0.67 ± 0.23 percentage injected dose/gram, P < 0.05) than healthy or normal vessels at 1 h after injection. (18)F-FDG also accumulated in atherosclerotic lesions at 0.5 and 1 h after injection but at lower plaque-to-normal tissue ratios than (64)Cu-NOTA-3-4A. For example, plaque-to-normal carotid artery ratios for (18)F-FDG and (64)Cu-NOTA-3-4A at 1 h after injection were 3.75 and 14.71 (P < 0.05), respectively. Furthermore, uptake of (64)Cu-NOTA-3-4A in atherosclerotic plaques was effectively blocked (∼90% at 1 h after injection) by coinjection of c(RGDyK). Immunostaining confirmed integrin αvβ3 expression in both the infiltrating macrophages and the neovasculature of atherosclerotic plaques. CONCLUSION: (64)Cu-NOTA-3-4A demonstrates specific accumulation in carotid atherosclerotic plaques in which macrophage infiltration and angiogenesis are responsible for elevated integrin αvβ3 levels. Therefore, (64)Cu-NOTA-3-4A may demonstrate clinical utility as a PET probe for atherosclerosis imaging or for the evaluation of therapies used to treat atherosclerosis.
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Authors | Lei Jiang, Yingfeng Tu, Richard H Kimura, Frezghi Habte, Hao Chen, Kai Cheng, Hongcheng Shi, Sanjiv Sam Gambhir, Zhen Cheng |
Journal | Journal of nuclear medicine : official publication, Society of Nuclear Medicine
(J Nucl Med)
Vol. 56
Issue 6
Pg. 939-44
(Jun 2015)
ISSN: 1535-5667 [Electronic] United States |
PMID | 25908832
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc. |
Chemical References |
- 64Cu-NOTA-3-4A
- Coordination Complexes
- Heterocyclic Compounds
- Heterocyclic Compounds, 1-Ring
- Integrin alphaVbeta3
- Peptides
- 1,4,7-triazacyclononane-N,N',N''-triacetic acid
- Cysteine
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Topics |
- Amino Acid Sequence
- Animals
- Carotid Arteries
(diagnostic imaging, pathology)
- Carotid Artery Diseases
(diagnostic imaging)
- Coordination Complexes
(chemistry)
- Cysteine
(chemistry)
- Heterocyclic Compounds
(chemistry)
- Heterocyclic Compounds, 1-Ring
- Inflammation
- Integrin alphaVbeta3
(metabolism)
- Macrophages
(metabolism)
- Magnetic Resonance Imaging
- Male
- Mice
- Mice, Inbred BALB C
- Microscopy, Fluorescence
- Molecular Sequence Data
- Peptides
(chemistry)
- Plaque, Atherosclerotic
(diagnostic imaging)
- Positron-Emission Tomography
- Rupture
- Tomography, X-Ray Computed
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