Imaging of VEGF Receptor in a Rat Myocardial Infarction Model Using PET

Rodriguez-Porcel, Martin; Cai, Weibo; Gheysens, Olivier; Willmann, Jürgen K.; Chen, Kai; Wang, Hui; Chen, Ian Y.; He, Lina; Wu, Joseph C.; Li, Zibo; Mohamedali, Khalid A.; Kim, Se-Hoon; Rosenblum, Michael G.; Chen, Xiaoyuan; Gambhir, Sanjiv S.

doi:10.2967/jnumed.107.040576

Cited by 93 publications

(57 citation statements)

References 33 publications

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“…For example, extracellular VEGF imaging was accomplished by coupling anti-VEGF monoclonal antibodies (bevacizumab, HuMV833) with 89 Zr (21,22), 111 In (23), and 124 I (24). Recombinant VEGF 165 was efficiently labeled with 123 I and VEGF 121 with both 99m Tc and 64 Cu for VEGF imaging in preclinical models (25)(26)(27)(28). In the reported studies, successful visualization of VEGFR expression was demonstrated; however, low to moderate tumor-to-background ratios were obtained despite the high receptor affinity of these probes.…”

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confidence: 96%

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

Jiang

et al. 2014

J Nucl Med

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Tyrosine kinase receptors including vascular endothelial growth factor receptor (VEGFR) have gained significant attention as pharmacologic targets. However, clinical evaluation of small-molecule drugs or biologics that target these pathways has so far yielded mixed results in a variety of solid tumors. The reasons for response variability remain unknown, including the temporal and spatial patterns of receptor tyrosine kinase expression. Methods to detect and quantify the presence of such cellular receptors would greatly facilitate drug development and therapy response assessment. We aimed to generate specific imaging agents as potential companion diagnostics that could also be used for targeted radionuclide therapy. Here, we report on the synthesis and initial preclinical performance of 64 Cu-labeled probes that were based on the kinase inhibitor already in clinical use, vandetanib (ZD6474), as a VEGFR-selective theranostic radiopharmaceutical. Methods: A monomeric (ZD-G1) and a dimeric (ZD-G2) derivative of ZD6474 were synthesized and conjugated with DOTA for chelation with 64 Cu to produce the probes 64 Cu-DOTA-ZD-G1 and 64 Cu-DOTA-ZD-G2. The binding affinity and specificity to VEGFR were measured using U-87 MG cells known to overexpress VEGFR. Small-animal PET and biodistribution studies were performed with 64 Cu-labeled probes (3-4 MBq) intravenously administered in U-87 MG tumor-bearing mice with or without coinjection of unlabeled ZD-G2 for up to 24 h after injection. Results: Receptor-binding assays yielded a mean equilibrium dissociation constant of 44.7 and 0.45 nM for monomeric and dimeric forms, respectively, indicating a synergistic effect in VEGFR affinity by multivalency. Small-animal PET/CT imaging showed rapid tumor accumulation of 64 Cu-DOTA-ZD-G2, with excellent tumor-to-normal tissue contrast by 24 h. Coinjection of the 64 Cu-DOTA-ZD-G2 with 50 nmol (60 μg) of nonradioactive ZD-G2 effectively blocked tumor uptake. Conclusion: A 64 Cu-labeled probe derived from an approved oncologic drug selective for VEGFR demonstrates excellent tumor targeting, particularly for the dimeric form. The multivalent probe yielded a 100-fold improvement in receptor affinity while maintaining pharmacokinetic and biodistribution properties well suited for PET imaging in our preclinical model. These results indicate that a clinically relevant theranostic platform can be rapidly developed from known small molecules that target key cellular receptors.

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confidence: 96%

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

Jiang

et al. 2014

J Nucl Med

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“…16,21 64 CuCl 2 (10 mCi) was diluted in 300 L of 0.1 mol/L sodium acetate buffer (pHϭ6.5) and added to 100 g DOTA-VEGF 121 or DOTA-VEGF mutant . 16,22 The reaction mixture was incubated for 1 hour at 40°C with constant shaking. 64 Cu-DOTA-VEGF 121 and 64 Cu-DOTA-VEGF DEE were then purified by size exclusion chromatography using phosphate-buffered saline as the mobile phase.…”

Section: Micropet Studiesmentioning

confidence: 99%

Positron Emission Tomography Imaging of Poststroke Angiogenesis

Cai

Guzman

Hsu

et al. 2009

Stroke

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Background and Purpose— Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis. Methods— Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, 18 F-FDG PET, and 64 Cu-DOTA-VEGF 121 PET scans. Several control experiments were performed to confirm the VEGFR specificity of 64 Cu-DOTA-VEGF 121 uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and 125 I-VEGF 165 autoradiography on stroke brain tissue slices were performed to validate the in vivo findings. Results— T2-weighed MRI correlated with the “cold spot” on 18 F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The 64 Cu-DOTA-VEGF 121 uptake in the stroke border zone peaked at ≈10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of 64 Cu-DOTA-VEGF 121 uptake was confirmed by significantly lower uptake of 64 Cu-DOTA-VEGF mutant in vivo and intense 125 I-VEGF 165 uptake ex vivo in the stroke border zone. No appreciable uptake of 64 Cu-DOTA-VEGF 121 was observed in the brain of sham-operated rats. Conclusions— For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.

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“…37 Studies also reported that RGD (Arg-Gly-Asp)-based integrin PET probes, such as 18 F-AlF-NOTA-PRGD2, can noninvasively image ischemia/reperfusion-induced myocardial angiogenesis with favorable pharmacokinetics. 38 Another clinical trial study with this PET probe demonstrated that 18 F-AlF-NOTA-PRGD2 PET/CT enabled the noninvasive visualization of glioblastoma multiforme lesions and the prediction of sensitivity to concurrent chemoradiotherapy as early as 3 weeks after treatment initiation.…”

Section: Pet Imaging Targeting Angiogenesismentioning

confidence: 99%

Pet Imaging and its Application in Cardiovascular Diseases

Li¹,

Gupte²,

Zhang³

et al. 2017

Methodist DeBakey Cardiovascular Journal

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Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a great challenge for modern research and medicine. Despite advances in preventing and treating CVD over the decades, there remains an urgent need to develop sensitive and safe methods for early detection and personalized treatment. With refinements of molecular imaging technologies such as positron emission tomography (PET), noninvasive imaging of CVDs is experiencing impressive progress in both preclinical and clinical settings. In this review, we summarize advances in cardiovascular PET imaging, highlight the latest development of CVD imaging probes, and illustrate the potential for individualized therapy based on metabolic phenotype.

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Imaging of VEGF Receptor in a Rat Myocardial Infarction Model Using PET

Cited by 93 publications

References 33 publications

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

Positron Emission Tomography Imaging of Poststroke Angiogenesis

Pet Imaging and its Application in Cardiovascular Diseases

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