Activation and Retention: A Magnetic Resonance Probe for the Detection of Acute Thrombosis

Loving, Galen S.; Caravan, Peter

doi:10.1002/ange.201308607

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…Particularly, fibrin is an ideal target for molecular imaging of thrombosis because its high specificity (present at high concentration in all clots but not in circulating blood) and high sensitivity (present in all thrombi whether arterial or venous, fresh or aged) of detection (4, 5). We previously reported feasibility of gadolinium-based fibrin-binding probes for thrombus imaging in both preclinical research (6-9) and clinical trials (10). Based on these results, we evaluated different peptides labeled with 64 Cu-DOTA as potential PET probes for thrombus imaging in animal models of thrombosis (11, 12).…”

Section: Introductionmentioning

confidence: 99%

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

et al. 2015

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We recently showed the high target specificity and favorable imaging properties of 64Cu and Al18F positron emission tomography (PET) probes for non-invasive imaging of thrombosis. Here, our aim was to evaluate new derivatives labeled with either with 68Ga, 111In, or 99mTc as thrombus imaging agents for PET and single-photon emission computed tomography (SPECT). In this study, the feasibility and potential of these probes for thrombus imaging was assessed in detail in two animal models of arterial thrombosis. The specificity of the probes was further evaluated using a triple-isotope approach with multimodal SPECT/PET/CT imaging. Methods Radiotracers were synthesized using a known fibrin-binding peptide conjugated to NODAGA, DOTA-MA, or a diethylenetriamine ligand (DETA-PA), followed by labeling with 68Ga (FBP14, 68Ga-NODAGA), 111In (FBP15, 111In-DOTA-MA) or 99mTc (FBP16, 99mTc(CO)3-DETA-PA), respectively. PET or SPECT imaging, biodistribution, pharmacokinetics and metabolic stability were evaluated in rat models of mural and occlusive carotid artery thrombosis. In vivo target specificity was evaluated by comparing the distribution of the SPECT and PET probes with preformed 125I-labeled thrombi and with a non-binding control probe using SPECT/PET/CT imaging. Results All three radiotracers showed similar affinity to soluble fibrin fragment DD(E) (Ki = 0.53–0.83 μM). After the kidneys, the highest uptake of 68Ga-FBP14 and 111In-FBP15 was in the thrombus (1.0 ± 0.2% ID/g) with low off-target accumulation. Both radiotracers underwent fast systemic elimination (t1/2 = 8-15 min) through the kidneys, which led to highly conspicuous thrombi on PET and SPECT images. 99mTc-FBP16 displayed low target uptake and distribution consistent with aggregation and/or degradation. Triple isotope imaging experiments showed that both 68Ga-FBP14 and 111In-FBP15, but not the nonbinding derivative 64Cu-D-Cys-FBP8, detected the location of the 125I-labeled thrombus, confirming high target specificity. Conclusion 68Ga-FBP14 and 111In-FBP15 have high fibrin affinity and thrombus specificity, and represent useful PET and SPECT probes for thrombus detection.

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Section: Introductionmentioning

confidence: 99%

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

et al. 2015

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“…Encouraged by this, the strategy of enzyme-mediated polymerization of Gd monomers into oligomers was extended by Liang and co-workers [45] to design an activatable MRI probe for highresolution visualization of furin levels in a human breast MDA-MB-468 tumor xenograft mouse model. Additionally, recent efforts have been made to develop new activatable MRI probes to detect other classes of enzymes, such as protein disulfide isomerase, which will allow for the detection of acute thrombosis [46].…”

Section: Activatable Mri Probesmentioning

confidence: 99%

“…The design of new activatable imaging probes for the detection of other classes of enzymes remains a challenge. However, the continuously emerging strategies (e.g., RIME) will pave the way to design activatable probes for in vivo imaging of protein disulfide isomerase [46] and oxidoreductase [57,58].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Molecular imaging of enzyme activity in vivo using activatable probes

Yan

2016

Science Bulletin

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“…Therefore this type of imaging probe cannot be adapted to detect a wide range of other targets. Recently, another MRI activatable probe was developed that upon activation binds efficiently to fibrin in fresh thrombi . The probe is based on a low‐affinity fibrin‐binding linear peptide that becomes cyclic by the activity of protein disulfide isomerase.…”

Section: Bioresponsive Probes Facilitating Site‐specific Retention Ofmentioning

confidence: 99%

Bioresponsive probes for molecular imaging: concepts and in vivo applications

Duijnhoven

Robillard

Langereis

et al. 2015

Contrast Media & Molecular

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Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo. In most molecular imaging approaches, probes are used to bind to disease-specific biomarkers highlighting disease target sites. In recent years, a new subset of molecular imaging probes, known as bioresponsive molecular probes, has been developed. These probes generally benefit from signal enhancement at the site of interaction with its target. There are mainly two classes of bioresponsive imaging probes. The first class consists of probes that show direct activation of the imaging label (from "off" to "on" state) and have been applied in optical imaging and magnetic resonance imaging (MRI). The other class consists of probes that show specific retention of the imaging label at the site of target interaction and these probes have found application in all different imaging modalities, including photoacoustic imaging and nuclear imaging. In this review, we present a comprehensive overview of bioresponsive imaging probes in order to discuss the various molecular imaging strategies. The focus of the present article is the rationale behind the design of bioresponsive molecular imaging probes and their potential in vivo application for the detection of endogenous molecular targets in pathologies such as cancer and cardiovascular disease.

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Activation and Retention: A Magnetic Resonance Probe for the Detection of Acute Thrombosis

Cited by 5 publications

References 20 publications

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

Molecular imaging of enzyme activity in vivo using activatable probes

Bioresponsive probes for molecular imaging: concepts and in vivo applications

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Activation and Retention: A Magnetic Resonance Probe for the Detection of Acute Thrombosis

Cited by 5 publications

References 20 publications

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of 111In- and 68Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of 111In- and 68Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

Molecular imaging of enzyme activity in vivo using activatable probes

Bioresponsive probes for molecular imaging: concepts and in vivo applications

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Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of ¹¹¹In- and ⁶⁸Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats