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1.
Proc Natl Acad Sci U S A ; 117(6): 3144-3149, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32001509

RESUMO

Glycogen plays a central role in glucose homeostasis and is abundant in several types of tissue. We report an MRI method for imaging glycogen noninvasively with enhanced detection sensitivity and high specificity, using the magnetic coupling between glycogen and water protons through the nuclear Overhauser enhancement (NOE). We show in vitro that the glycogen NOE (glycoNOE) signal is correlated linearly with glycogen concentration, while pH and temperature have little effect on its intensity. For validation, we imaged glycoNOE signal changes in mouse liver, both before and after fasting and during glucagon infusion. The glycoNOE signal was reduced by 88 ± 16% (n = 5) after 24 h of fasting and by 76 ± 22% (n = 5) at 1 h after intraperitoneal (i.p.) injection of glucagon, which is known to rapidly deplete hepatic glycogen. The ability to noninvasively image glycogen should allow assessment of diseases in which glucose metabolism or storage is altered, for instance, diabetes, cardiac disease, muscular disorders, cancer, and glycogen storage diseases.

2.
NMR Biomed ; 33(1): e4188, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31793114

RESUMO

Amide-, amine-, and hydroxyl-water proton exchange can generate MRI contrast through chemical exchange saturation transfer (CEST). In this study, we show that thiol-water proton exchange can also generate quantifiable CEST effects under near-physiological conditions (pH = 7.2 and 37°C) through the characterization of the pH dependence of thiol proton exchange in phosphate-buffered solutions of glutathione, cysteine, and N-acetylcysteine. The spontaneous, base-catalyzed, and buffer-catalyzed exchange contributions to the thiol exchange were analyzed. The thiol-water proton exchange of glutathione and cysteine was found to be too fast to generate a CEST effect around neutral pH due to significant base catalysis. The thiol-water proton exchange of N-acetylcysteine was found to be much slower, yet still in the fast-exchange regime with significant base and buffer catalysis, resulting in a 9.5% attenuation of the water signal at pH 7.2 in a slice-selective CEST NMR experiment. Furthermore, the N-acetylcysteine thiol CEST was also detectable in human serum albumin and agarose phantoms.

3.
Magn Reson Med ; 84(1): 247-262, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31872916

RESUMO

PURPOSE: Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood-brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with translating d-glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T. METHODS: Exchange rates of the different hydroxyl proton pools and the field-dependent T2 relaxivity of water in d-glucose solution were used to simulate the water saturation spectra (Z-spectra) and DGE signal differences as a function of static field strength B0 , radiofrequency field strength B1 , and saturation time tsat . Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients. RESULTS: Simulations showed that DGE signal decreases with B0 , because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z-spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B1 of 1.6 µT and a tsat of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably. CONCLUSION: Multislice glucoCEST-based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths.

4.
Magn Reson Med ; 82(4): 1471-1479, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31106918

RESUMO

PURPOSE: Vascular disrupting therapy of cancer has become a promising approach not only to regress tumor growth directly but also to boost the delivery of chemotherapeutics in the tumor. An imaging approach to monitor the changes in tumor vascular permeability, therefore, has important applications for monitoring of vascular disrupting therapies. METHODS: Mice bearing CT26 subcutaneous colon tumors were injected intravenously with 150 kD dextran (Dex150, diameter, d~ 20 nm, 375 mg/kg), tumor necrosis factor-alpha (TNF-α; 1 µg per mouse), or both (n = 3 in each group). The Z-spectra were acquired before and 2 h after the injection, and the chemical exchange saturation transfer (CEST) signals in the tumors as quantified by asymmetric magnetization transfer ratio (MTRasym ) at 1 ppm were compared. RESULTS: The results showed a significantly stronger CEST contrast enhancement at 1 ppm (∆MTRasym = 0.042 ± 0.002) in the TNF-α-treated tumors than those by Dex150 alone (∆MTRasym = 0.000 ± 0.005, P = 0.0229) or TNF-α alone (∆MTRasym = 0.002 ± 0.004, P = 0.0264), indicating that the TNF-α treatment strongly augmented the tumor uptake of 150 kD dextran. The MRI findings were verified by fluorescence imaging and immunofluorescence microscopy. CONCLUSIONS: High molecular weight dextrans can be used as safe and sensitive CEST MRI contrast agents for monitoring tumor response to vascular disrupting therapy and, potentially, for developing dextran-based theranostic drug delivery systems.

5.
Magn Reson Med ; 81(3): 1993-2000, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30206994

RESUMO

PURPOSE: 3-O-Methyl-D-glucose (3-OMG) is a nonmetabolizable structural analog of glucose that offers potential to be used as a CEST-contrast agent for tumor detection. Here, we explore it for CEST-detection of malignant brain tumors and compare it with D-glucose. METHODS: Glioma xenografts of a U87-MG cell line were implanted in five mice. Dynamic 3-OMG weighted images were collected using CEST-MRI at 11.7 T at a single offset of 1.2 ppm, showing the effect of accumulation of the contrast agent in the tumor, following an intravenous injection of 3-OMG (3 g/kg). RESULTS: Tumor regions showed higher enhancement as compared to contralateral brain. The CEST contrast enhancement in the tumor region ranged from 2.5-5.0%, while it was 1.5-3.5% in contralateral brain. Previous D-glucose studies of the same tumor model showed an enhancement of 1.5-3.0% and 0.5-1.5% in tumor and contralateral brain, respectively. The signal gradually stabilized to a value that persisted for the length of the scan. CONCLUSIONS: 3-OMG shows a CEST contrast enhancement that is approximately twice as much as that of D-glucose for a similar tumor line. In view of its suggested low toxicity and transport properties across the BBB, 3-OMG provides an option to be used as a nonmetallic contrast agent for evaluating brain tumors.

6.
Magn Reson Med ; 79(2): 1010-1019, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28480589

RESUMO

PURPOSE: Genetically encoded reporters can assist in visualizing biological processes in live organisms and have been proposed for longitudinal and noninvasive tracking of therapeutic cells in deep tissue. Cells can be labeled in situ or ex vivo and followed in live subjects over time. Nevertheless, a major challenge for reporter systems is to identify the cell population that actually expresses an active reporter. METHODS: We have used a nucleoside analog, pyrrolo-2'-deoxycytidine, as an imaging probe for the putative reporter gene, Drosophila melanogaster 2'-deoxynucleoside kinase. Bioengineered cells were imaged in vivo in animal models of brain tumor and immunotherapy using chemical exchange saturation transfer MRI. The number of transduced cells was quantified by flow cytometry based on the optical properties of the probe. RESULTS: We performed a comparative analysis of six different cell lines and demonstrate utility in a mouse model of immunotherapy. The proposed technology can be used to quantify the number of labeled cells in a given region, and moreover is sensitive enough to detect less than 10,000 cells. CONCLUSION: This unique technology that enables efficient selection of labeled cells followed by in vivo monitoring with both optical and MRI. Magn Reson Med 79:1010-1019, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Assuntos
Rastreamento de Células/métodos , Células Dendríticas/química , Genes Reporter/genética , Engenharia Genética/métodos , Imunoterapia/métodos , Imagem por Ressonância Magnética/métodos , Animais , Pesquisa Biomédica/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/análise , Desoxicitidina/química , Desoxicitidina/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Citometria de Fluxo , Genes de Insetos/genética , Células HEK293 , Humanos , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/terapia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirróis/análise , Pirróis/química , Pirróis/metabolismo
7.
Chemistry ; 24(6): 1259-1263, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29266443

RESUMO

Although T2 -exchange (T2ex ) NMR phenomena have been known for decades, there has been a resurgence of interest to develop T2ex MRI contrast agents. One indispensable advantage of T2ex MR agents is the possibility of using non-toxic and/or bio-compatible diamagnetic compounds with intermediate exchangeable protons. Herein a library of phenol-based compounds is screened and their T2ex contrast (exchange relaxivity, r2ex ) at 9.4 T determined. The T2ex contrast of phenol protons allows direct detection by MRI at a millimolar concentration level. The effect of chemical modification of the phenol on the T2ex MRI contrast through modulation of exchange rate and chemical shift was also studied and provides a guideline for use of endogenous and exogenous phenols for T2ex MRI contrast. As a proof-of-principle application, phenol T2ex contrast can be used to detect enzyme activity in a tyrosinase-catalyzed catechol oxidation reaction.

8.
Sci Rep ; 7(1): 10138, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860625

RESUMO

Magnetic Resonance Imaging (MRI) is rarely used for molecular binding studies and never without synthetic metallic labels. We designed an MRI approach that can specifically detect the binding of natural substrates (i.e. no chemical labels). To accomplish such detection of substrate-target interaction only, we exploit (i) the narrow resonance of aliphatic protons in free substrate for selective radio-frequency (RF) labeling and, (ii) the process of immobilisation upon binding to a solid-like target for fast magnetic transfer of this label over protons in the target backbone. This cascade of events is ultimately detected with MRI using magnetic interaction between target and water protons. We prove this principle using caffeine as a substrate in vitro and then apply it in vivo in the mouse brain. The combined effects of continuous labeling (label pumping), dynamic reversible binding, and water detection was found to enhance the detection sensitivity by about two to three orders of magnitude.


Assuntos
Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Animais , Encéfalo/metabolismo , Cafeína/farmacocinética , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Prótons
9.
NMR Biomed ; 30(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28961344

RESUMO

The current study aims to assign and estimate the total creatine (tCr) signal contribution to the Z-spectrum in mouse brain at 11.7 T. Creatine (Cr), phosphocreatine (PCr) and protein phantoms were used to confirm the presence of a guanidinium resonance at this field strength. Wild-type (WT) and knockout mice with guanidinoacetate N-methyltransferase deficiency (GAMT-/-), which have low Cr and PCr concentrations in the brain, were used to assign the tCr contribution to the Z-spectrum. To estimate the total guanidinium concentrations, two pools for the Z-spectrum around 2 ppm were assumed: (i) a Lorentzian function representing the guanidinium chemical exchange saturation transfer (CEST) at 1.95 ppm in the 11.7-T Z-spectrum; and (ii) a background signal that can be fitted by a polynomial function. Comparison between the WT and GAMT-/- mice provided strong evidence for three types of contribution to the peak in the Z-spectrum at 1.95 ppm, namely proteins, Cr and PCr, the latter fitted as tCr. A ratio of 20 ± 7% (protein) and 80 ± 7% tCr was found in brain at 2 µT and 2 s saturation. Based on phantom experiments, the tCr peak was estimated to consist of about 83 ± 5% Cr and 17 ± 5% PCr. Maps for tCr of mouse brain were generated based on the peak at 1.95 ppm after concentration calibration with in vivo magnetic resonance spectroscopy.


Assuntos
Encéfalo/metabolismo , Creatina/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fosfocreatina/metabolismo
10.
Kidney Int ; 92(3): 757-764, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709641

RESUMO

Acute cellular renal allograft rejection (AR) frequently occurs after kidney transplantations. It is a sterile T-cell mediated inflammation leading to increased local glucose metabolism. Here we demonstrate in an allogeneic model of Brown Norway rat kidneys transplanted into uninephrectomized Lewis rats the successful implementation of the recently developed glucose chemical exchange saturation transfer (glucoCEST) magnetic resonance imaging. This technique is a novel method to assess and differentiate AR. Renal allografts undergoing AR showed significantly increased glucoCEST contrast ratios of cortex to medulla of 1.61 compared to healthy controls (1.02), syngeneic Lewis kidney to Lewis rat transplants without rejection (0.92), kidneys with ischemia reperfusion injury (0.99) and kidneys affected by cyclosporine A toxicity (1.10). Receiver operating characteristic curve analysis showed an area under the curve value of 0.92, and the glucoCEST contrast ratio predicted AR with a sensitivity of 100% and a specificity of 69% at a threshold level over 1.08. In defined animal models of kidney injuries, the glucoCEST contrast ratios of cortex to medulla correlated positively with mRNA expression levels of T-cell markers (CD3, CD4, CD8a/b), but did not correlate to impaired renal perfusion. Thus, the glucoCEST parameter may be valuable for the assessment and follow up treatment of AR.


Assuntos
Aloenxertos/diagnóstico por imagem , Rejeição de Enxerto/diagnóstico por imagem , Transplante de Rim/efeitos adversos , Rim/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Traumatismo por Reperfusão/diagnóstico por imagem , Aloenxertos/imunologia , Aloenxertos/patologia , Animais , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8 , Meios de Contraste , Ciclosporina/toxicidade , Modelos Animais de Doenças , Glucose/administração & dosagem , Glucose/metabolismo , Rejeição de Enxerto/induzido quimicamente , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Rim/imunologia , Rim/patologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo/efeitos adversos
11.
J Am Chem Soc ; 138(35): 11136-9, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27548755

RESUMO

A two-step heteronuclear enhancement approach was combined with chemical exchange saturation transfer (CEST) to magnify (15)N MRI signal of molecules through indirect detection via water protons. Previous CEST studies have been limited to radiofrequency (rf) saturation transfer or excitation transfer employing protons. Here, the signal of (15)N is detected indirectly through the water signal by first inverting selectively protons that are scalar-coupled to (15)N in the urea molecule, followed by chemical exchange of the amide proton to bulk water. In addition to providing a small sensitivity enhancement, this approach can be used to monitor the exchange rates and thus the pH sensitivity of the participating (15)N-bound protons.


Assuntos
Imagem por Ressonância Magnética/métodos , Isótopos de Nitrogênio/química , Prótons , Água/química
12.
J Magn Reson ; 265: 224-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26969814

RESUMO

A chemical exchange saturation transfer (CEST) experiment can be performed in an ultrafast fashion if a gradient field is applied simultaneously with the saturation pulse. This approach has been demonstrated for studying dia- and para-magnetic CEST agents, hyperpolarized Xe gas and in vivo spectroscopy. In this study we present a simple method for the simultaneous screening of multiple samples. Furthermore, by interleaving a number of saturation and readout periods within the TR, a series of images with different saturation times can be acquired, allowing for the quantification of exchange rates using the variable saturation time (QUEST) approach in a much accelerated fashion, thus enabling high throughput screening of CEST contrast agents.


Assuntos
Meios de Contraste/química , Ensaios de Triagem em Larga Escala/métodos , Imagem por Ressonância Magnética/métodos , Algoritmos , Processamento de Imagem Assistida por Computador , Imagens de Fantasmas , Ondas de Rádio , Reprodutibilidade dos Testes , Xenônio
13.
Oncotarget ; 7(6): 6369-78, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26837220

RESUMO

Image-guided drug delivery is of great clinical interest. Here, we explored a direct way, namely CEST theranostics, to detect diamagnetic anticancer drugs simply through their inherent Chemical Exchange Saturation Transfer (CEST) MRI signal, and demonstrated its application in image-guided drug delivery of nanoparticulate chemotherapeutics. We first screened 22 chemotherapeutic agents and characterized the CEST properties of representative agents and natural analogs in three major categories, i.e., pyrimidine analogs, purine analogs, and antifolates, with respect to chemical structures. Utilizing the inherent CEST MRI signal of gemcitabine, a widely used anticancer drug, the tumor uptake of the i.v.-injected, drug-loaded liposomes was successfully detected in CT26 mouse tumors. Such label-free CEST MRI theranostics provides a new imaging means, potentially with an immediate clinical impact, to monitor the drug delivery in cancer.


Assuntos
Adenocarcinoma/patologia , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Desoxicitidina/análogos & derivados , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Nanomedicina Teranóstica , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Meios de Contraste , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Sistemas de Liberação de Medicamentos , Feminino , Fluorescência , Humanos , Técnicas Imunoenzimáticas , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Magn Reson Med ; 75(1): 88-96, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26445350

RESUMO

PURPOSE: To use the variable delay multipulse (VDMP) chemical exchange saturation transfer (CEST) approach to obtain clean amide proton transfer (APT) and relayed Nuclear Overhauser enhancement (rNOE) CEST images in the human brain by suppressing the conventional magnetization transfer contrast (MTC) and reducing the direct water saturation contribution. METHODS: The VDMP CEST scheme consists of a train of RF pulses with a specific mixing time. The CEST signal with respect to the mixing time shows distinguishable characteristics for protons with different exchange rates. Exchange rate filtered CEST images are generated by subtracting images acquired at two mixing times at which the MTC signals are equal, while the APT and rNOE-CEST signals differ. Because the subtraction is performed at the same frequency offset for each voxel and the CEST signals are broad, no B0 correction is needed. RESULTS: MTC-suppressed APT and rNOE-CEST images of human brain were obtained using the VDMP method. The APT-CEST data show hyperintensity in gray matter versus white matter, whereas the rNOE-CEST images show negligible contrast between gray and white matter. CONCLUSION: The VDMP approach provides a simple and rapid way of recording MTC-suppressed APT-CEST and rNOE-CEST images without the need for B0 field correction.


Assuntos
Algoritmos , Amidas/metabolismo , Encéfalo/metabolismo , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Proteínas/metabolismo , Humanos , Prótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Magn Reson Med ; 73(2): 488-96, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25516490

RESUMO

PURPOSE: The aim of this study was to develop a technique for rapid collection of chemical exchange saturation transfer images with the saturation varied to modulate signal loss transfer and enhance contrast. METHODS: Multi-echo Length and Offset VARied Saturation (MeLOVARS) divides the saturation pulse of length Tsat into N = 3-8 submodules, each consisting of a saturation pulse with length of Tsat /N (∼0.3-1 s), one or more low flip-angle gradient-echo readout(s) and a flip back pulse. This results in N readouts with increasing saturation time from Tsat /N to Tsat without extra scan time. RESULTS: For phantoms, eight images with Tsat incremented every 0.5 s from 0.5-4 s were collected simultaneously using MeLOVARS, which allows rapid determination of exchange rates for agent protons. For live mice bearing glioblastomas, the Z-spectra for five different Tsat values from 0.5 to 2.5 s were acquired in a time normally used for one Tsat . With the additional Tsat -dependence information, LOVARS phase maps were produced with a more clearly defined tumor boundary and an estimated 4.3-fold enhanced contrast-to-noise ratio (CNR). We also show that enhancing CNR is achievable by simply averaging the collected images or transforming them using the principal component analysis. CONCLUSIONS: MeLOVARS enables collection of multiple saturation-time-weighted images without extra time, producing a LOVARS phase map with increased CNR.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Imagem por Ressonância Magnética/métodos , Proteínas de Neoplasias/metabolismo , Algoritmos , Animais , Linhagem Celular Tumoral , Humanos , Aumento da Imagem/métodos , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Camundongos SCID , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador
16.
Tomography ; 1(2): 105-114, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26779568

RESUMO

Recent animal studies have shown that D-glucose is a potential biodegradable MRI contrast agent for imaging glucose uptake in tumors. Here, we show the first translation of that use of D-glucose to human studies. Chemical exchange saturation transfer (CEST) MRI at a single frequency offset optimized for detection of hydroxyl protons in D-glucose (glucoCEST) was used to image dynamic signal changes in the human brain at 7T during and after infusion of D-glucose. Dynamic glucose-enhanced (DGE) image data from four normal volunteers and three glioma patients showed strong signal enhancement in blood vessels, while the enhancement varied spatially over the tumor. Areas of enhancement differed spatially between DGE and conventional Gd-enhanced imaging, suggesting complementary image information content for these two types of agents. In addition, different tumor areas enhanced with D-glucose at different times post-infusion, suggesting a sensitivity to perfusion-related properties such as substrate delivery and blood-brain barrier (BBB) permeability. These preliminary results suggest that DGE MRI is feasible to study glucose uptake in humans, providing a time-dependent set of data that contains information regarding arterial input function (AIF), tissue perfusion, glucose transport across the BBB and cell membrane, and glucose metabolism.

17.
J Am Chem Soc ; 137(1): 78-81, 2015 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-25523816

RESUMO

The local presence and concentration of metal ions in biological systems has been extensively studied ex vivo using fluorescent dyes. However, the detection of multiple metal ions in vivo remains a major challenge. We present a magnetic resonance imaging (MRI)-based method for noninvasive detection of specific ions that may be coexisting, using the tetrafluorinated derivative of the BAPTA (TF-BAPTA) chelate as a (19)F chelate analogue of existing optical dyes. Taking advantage of the difference in the ion-specific (19)F nuclear magnetic resonance (NMR) chemical shift offset (Δω) values between the ion-bound and free TF-BAPTA, we exploited the dynamic exchange between ion-bound and free TF-BAPTA to obtain MRI contrast with multi-ion chemical exchange saturation transfer (miCEST). We demonstrate that TF-BAPTA as a prototype single (19)F probe can be used to separately visualize mixed Zn(2+) and Fe(2+) ions in a specific and simultaneous fashion, without interference from potential competitive ions.


Assuntos
Compostos Ferrosos/análise , Corantes Fluorescentes/química , Imagem por Ressonância Magnética de Flúor-19 , Zinco/análise
18.
Chemistry ; 20(48): 15824-32, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25302635

RESUMO

The optimal exchange properties for chemical exchange saturation transfer (CEST) contrast agents on 3 T clinical scanners were characterized using continuous wave saturation transfer, and it was demonstrated that the exchangeable protons in phenols can be tuned to reach these criteria through proper ring substitution. Systematic modification allows the chemical shift of the exchangeable protons to be positioned between 4.8 to 12 ppm from water and enables adjustment of the proton exchange rate to maximize CEST contrast at these shifts. In particular, 44 hydrogen-bonded phenols are investigated for their potential as CEST MRI contrast agents and the stereoelectronic effects on their CEST properties are summarized. Furthermore, a pair of compounds, 2,5-dihydroxyterephthalic acid and 4,6-dihydroxyisophthalic acid, were identified which produce the highest sensitivity through incorporating two exchangeable protons per ring.


Assuntos
Hidrogênio/química , Fenóis/química , Ácidos Ftálicos/química , Meios de Contraste/química , Ligações de Hidrogênio , Imagem por Ressonância Magnética
19.
Magn Reson Med ; 72(3): 823-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24975029

RESUMO

PURPOSE: Demonstrate applicability of natural D-glucose as a T2 MRI contrast agent. METHODS: D-glucose solutions were prepared at multiple concentrations and variable pH. The relaxation rate (R2 = 1/T2 ) was measured at 3, 7, and 11.7 T. Additional experiments were performed on blood at 11.7 T. Also, a mouse was infused with D-glucose (3.0 mmol/kg) and dynamic T2 weighted images of the abdomen acquired. RESULTS: The transverse relaxation rate depended strongly on glucose concentration and solution pH. A maximum change in R2 was observed around physiological pH (pH 6.8-7.8). The transverse relaxivities at 22°C (pH 7.3) were 0.021, 0.060, and 0.077 s(-1) mM(-1) at 3.0, 7.0, and 11.7 T, respectively. These values showed good agreement with expected values from the Swift-Connick equation. There was no significant dependence on glucose concentration or pH for T1 and the diffusion coefficient for these solutions. The transverse relaxivity in blood at 11.7 T was 0.09 s(-1) mM(-1) . The dynamic in vivo experiment showed a 10% drop in signal intensity after glucose infusion followed by recovery of the signal intensity after about 50-100 s. CONCLUSION: Glucose can be used as a T2 contrast agent for MRI at concentrations that are already approved for human use.


Assuntos
Meios de Contraste , Desoxiglucose , Imagem por Ressonância Magnética/métodos , Abdome , Animais , Bovinos , Meios de Contraste/química , Desoxiglucose/química , Eritrócitos/metabolismo , Concentração de Íons de Hidrogênio , Aumento da Imagem/métodos , Camundongos , Camundongos Endogâmicos BALB C , Imagens de Fantasmas
20.
Magn Reson Med ; 71(1): 286-93, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23468384

RESUMO

PURPOSE: A main obstacle to in vivo applications of paramagnetic chemical exchange saturation transfer (paraCEST) is interference from endogenous tissue magnetization transfer contrast (MTC). The suitability of excitation-based frequency labeled exchange transfer (FLEX) to separate out such MTC effects in vivo was tested. METHODS: The FLEX sequence measures modulation of the water signal based on the chemical shift evolution of solute proton magnetization as a function of evolution time. Time-domain analysis of this water signal allows identification of different solute components and provides a mechanism to separate out the rapidly decaying MTC components with short effective transverse relaxation time ( T2*) values. RESULTS: FLEX imaging of paraCEST agents was possible in vitro in phantoms and in vivo in mouse kidneys and bladder. The results demonstrated that FLEX is capable of separating out the MTC signal from tissues in vivo while providing a quantitative exchange rate for the rapidly exchanging paraCEST water protons by fitting the FLEX time-domain signal to FLEX theory. CONCLUSIONS: The first in vivo FLEX images of a paraCEST agent were acquired, which allowed separation of the tissue MTC components. These results show that FLEX imaging has potential for imaging the distribution of functional paraCEST agents in biological tissues.


Assuntos
Água Corporal/metabolismo , Complexos de Coordenação/farmacocinética , Rim/metabolismo , Imagem por Ressonância Magnética/métodos , Imagem Molecular/métodos , Bexiga Urinária/metabolismo , Animais , Meios de Contraste , Interpretação de Imagem Assistida por Computador/métodos , Elementos da Série dos Lantanídeos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Coloração e Rotulagem
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