Publications by authors named "James Ratnakar"

28 Publications

  • Page 1 of 1

Hyperpolarized C MR Spectroscopy Depicts in Vivo Effect of Exercise on Pyruvate Metabolism in Human Skeletal Muscle.

Radiology 2021 Jun 22:204500. Epub 2021 Jun 22.

From the Advanced Imaging Research Center (J.M.P., C.E.H., J.M., J.C., J.R., J.L., G.D.R., A.C., C.R.M.), Department of Radiology (J.M.P., A.C., C.R.M.), Department of Neurology and Neurotherapeutics (R.G.H.), and Department of Internal Medicine (C.R.M.), University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8568; Department of Electrical and Computer Engineering, University of Texas at Dallas, Dallas, Tex (J.M.P.); Department of Diagnostic Imaging and Radiology, Developing Brain Institute, Children's National Hospital, Washington, DC (Z.Z.); Department of Pediatrics and Radiology, George Washington University, Washington, DC (Z.Z.); GE Healthcare, Dallas, Tex (G.D.R.); Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, Calif (T.J.); and Veterans Affairs North Texas Healthcare System, Dallas, Tex (C.R.M.).

Background Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed. Purpose To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 (C) MRI with hyperpolarized (HP) [1-C]-pyruvate. Materials and Methods For this prospective study, sedentary adults in good general health (mean age, 42 years ± 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1-C]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired test was used for comparing C data among the states. Results At rest, HP [1-C]-lactate and [1-C]-alanine were detected in calf muscle, but [C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP C signals (tC) increased 2.8-fold because of increased muscle perfusion ( = .005), and HP [1-C]-lactate-to-tC ratio increased 1.7-fold ( = .04). HP [C]-bicarbonate-to-tC ratio increased 8.4-fold ( = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting ( = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {C}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1-C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021204500DOI Listing
June 2021

Cardiac measurement of hyperpolarized C metabolites using metabolite-selective multi-echo spiral imaging.

Magn Reson Med 2021 09 6;86(3):1494-1504. Epub 2021 Apr 6.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as s of the HP signals is critical. This study is to measure in vivo cardiac s of HP [1- C]pyruvate and the products in rodents and humans.

Methods: A dynamic C multi-echo spiral imaging sequence that acquires [ C]bicarbonate, [1- C]lactate, and [1- C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring using the sequence was first validated using a C phantom and then with rodents following a bolus injection of HP [1- C]pyruvate. In humans, of each metabolite was calculated for left ventricle, right ventricle, and myocardium.

Results: Cardiac s of HP [1- C]pyruvate, [1- C]lactate, and [ C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, of [1- C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. of [1- C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. of [ C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection.

Conclusion: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac s of HP [1- C]pyruvate and products.
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http://dx.doi.org/10.1002/mrm.28796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212421PMC
September 2021

Manganese(II)-Based Responsive Contrast Agent Detects Glucose-Stimulated Zinc Secretion from the Mouse Pancreas and Prostate by MRI.

Inorg Chem 2021 Feb 28;60(4):2168-2177. Epub 2021 Jan 28.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

A Mn(II)-based zinc-sensitive MRI contrast agent, MnPyC3A-BPEN, was prepared, characterized, and applied in imaging experiments to detect glucose-stimulated zinc secretion (GSZS) from the mouse pancreas and prostate . Thermodynamic and kinetic stability tests showed that MnPyC3A-BPEN has superior kinetic inertness compared to GdDTPA, is less susceptible to transmetalation in the presence of excess Zn ions, and less susceptible to transchelation by albumin. In comparison with other gadolinium-based zinc sensors bearing a single zinc binding moiety, MnPyC3A-BPEN appears to be a reliable alternative for imaging β-cell function in the pancreas and glucose-stimulated zinc secretion from the prostate.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112388PMC
February 2021

Hyperpolarized Y-EDTMP complex as a chemical shift-based NMR sensor for pH at the physiological range.

J Magn Reson 2020 11 29;320:106837. Epub 2020 Sep 29.

Department of Physics, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, USA. Electronic address:

Yttrium (III) complexes are interesting due to the similarity of their chemistry with gadolinium complexes that are used as contrast agents in nuclear magnetic resonance (NMR) spectroscopy or imaging (MRI). While most of the paramagnetic Gd-based MRI contrast agents are T or T relaxation-based sensors such as Gd-complexes for zinc or pH detection, a number of diamagnetic Y-complexes rely on changes in the chemical shift for potential quantitative MRI in biological milieu. Y, however, is a challenging nucleus to work with in conventional NMR or MRI due to its inherently low sensitivity and relatively long T relaxation time. This insensitivity problem in Y-based complexes can be circumvented with the use of dissolution dynamic nuclear polarization (DNP) which allows for several thousand-fold enhancement of the NMR or MRI signal relative to thermal equilibrium signal. Herein, we report on the feasibility of using hyperpolarized Y-complexes with phosphonated open-chain ligands, Y-EDTMP and Y-DTPMP, as potential chemical shift-based pH NMR sensors. Our DNP-NMR data show that hyperpolarized Y-DTPMP has an apparent pK ~ 7.01 with a 4 ppm-wide chemical shift dispersion with the signal disappearing at pH below 6.2. On the other hand, pH titration data on hyperpolarized Y-EDTMP show that it has an apparent pK of pH 6.7 and a 16-ppm wide chemical shift dispersion at pH 5-9 range. In comparison, the previously reported hyperpolarized pH NMR sensor Y-DOTP has a pK of 7.64 and ~ 10-ppm wide chemical shift dispersion at pH 4-9 range. Overall, our data suggest that hyperpolarized Y-EDTMP is better than hyperpolarized Y-DOTP in terms of pH sensing capability at the physiological range.
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http://dx.doi.org/10.1016/j.jmr.2020.106837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895333PMC
November 2020

A Frequency-Selective pH-Responsive paraCEST Agent.

Angew Chem Int Ed Engl 2020 11 6;59(48):21671-21676. Epub 2020 Oct 6.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based on an exchanging Ln -bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T exchange. We report herein a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound -OH group for CEST activation. The Yb complex, Yb(1), displayed a single, highly shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6 to 8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd(1) remains in the vascular system much longer than anticipated but is cleared slowly via renal filtration.
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http://dx.doi.org/10.1002/anie.202008888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719596PMC
November 2020

Crystallographic Characterization and Non-Innocent Redox Activity of the Glycine Modified DOTA Scaffold and Its Impact on Eu Electrochemistry.

Eur J Inorg Chem 2018 Apr 23;2018(14):1556-1562. Epub 2018 Mar 23.

Department of Chemistry and Biochemistry, Texas Christian University, 2950 W. Bowie, Fort Worth, TX, 76129, USA, http://chemistry.tcu.edu/staff/kayla-green/.

EuDOTA-glycine derivatives have been explored as alternatives to typical gadolinium-containing complexes for MRI agents used in diagnostic imaging. Different imaging modalities can be accessed ( or PARACEST) dependent on the oxidation state of the europium ion. Throughout the past 30 years, there have been significant manipulations and additions made to the DOTA scaffold; yet, characterizations related to electrochemistry and structure determined through XRD analysis have not been fully analyzed. In this work, electrochemical analysis using cyclic voltammetry was carried out on EuDOTA derivatives, including the free ligand DOTAGly () and the complexes. Effects of glycinate substitution on the DOTA scaffold, specifically, ligand interactions with the glassy carbon electrode were observed. A range of electrochemical investigations were carried out to show that increased glycinate substitution led to increased interaction with the electrode surface, thus implicating a new factor to consider when evaluating the electrochemistry of glycinate substituted ligands. In addition, the solid-state structure of EuDOTAGly () was determined by X-ray diffraction and a brief analysis is presented compared to known Ln structures found within literature. The complex crystalizes in a rare polymer type arrangement via bridging side-arms between adjacent complexes.
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http://dx.doi.org/10.1002/ejic.201701398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263031PMC
April 2018

Engineering a pH-Sensitive Liposomal MRI Agent by Modification of a Bacterial Channel.

Small 2018 05 11;14(19):e1704256. Epub 2018 Apr 11.

Department of Physiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.

MscL is a bacterial mechanosensitive channel that serves as a cellular emergency release valve, protecting the cell from lysis upon a drop in external osmolarity. The channel has an extremely large pore (30 Å) and can be purified and reconstituted into artificial membranes. Moreover, MscL is modified to open in response to alternative external stimuli including changes in pH. These properties suggest this channel's potential as a triggered "nanopore" for localized release of vesicular contents such as magnetic resonance imaging (MRI) contrast agents and drugs. Toward this end, several variants of pH-triggered MscL nanovalves are engineered. Stealth vesicles previously been shown to evade normal in vivo clearance and passively accumulate in inflamed and malignant tissues are reconstituted. These vesicles are loaded with 1,4,7,10-tetraazacyclododecane tetraacetic acid gadolinium complex (Gd-DOTA), an MRI contrast reagent, and the resulting nanodevices tested for their ability to release Gd-DOTA as evidenced by enhancement of the longitudinal relaxation rate (R ) of the bulk water proton spins. Nanovalves that are responsive to physiological pH changes are identified, but differ in sensitivity and efficacy, thus giving an array of nanovalves that could potentially be useful in different settings. These triggered nanodevices may be useful in delivering both diagnostic and therapeutic agents.
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http://dx.doi.org/10.1002/smll.201704256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140348PMC
May 2018

Electrochemical investigation of the Eu redox couple in complexes with variable numbers of glycinamide and acetate pendant arms.

Eur J Inorg Chem 2017 Nov 21;2017(43):5001-5005. Epub 2017 Nov 21.

Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas 75390.

The Eu redox couple provides a convenient design platform for responsive O sensors for magnetic resonance imaging (MRI). Specifically the Eu ion provides contrast enhancement under hypoxic conditions in tissues, whereas, under normoxia, the Eu ion can produce contrast from chemical exchange saturation transfer in MRI. The oxidative stability of the Eu redox couple for a series of tetraaza macrocyclic complexes was investigated in this work using cyclic voltammetry. A series of Eu-containing cyclen-based macrocyclic complexes revealed positive shifts in the Eu redox potentials with each replacement of a carboxylate coordinating arm of the ligand scaffold with glycinamide pendant arms. The data obtained reveal that the complex containing four glycinamide coordinating pendant arms has the highest oxidative stability of the series investigated.
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http://dx.doi.org/10.1002/ejic.201701070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795619PMC
November 2017

Elucidating the structural organization of a novel low-density lipoprotein nanoparticle reconstituted with docosahexaenoic acid.

Chem Phys Lipids 2017 04 22;204:65-75. Epub 2017 Mar 22.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address:

Low-density lipoprotein nanoparticles reconstituted with unesterified docosahexaenoic acid (LDL-DHA) is promising nanomedicine with enhanced physicochemical stability and selective anticancer cytotoxic activity. The unique functionality of LDL-DHA ultimately relates to the structure of this nanoparticle. To date, however, little is known about the structural organization of this nanoparticle. In this study chemical, spectroscopic and electron microscopy analyses were undertaken to elucidate the structural and molecular organization of LDL-DHA nanoparticles. Unesterified DHA preferentially incorporates into the outer surface layer of LDL, where in this orientation the anionic carboxyl end of DHA is exposed to the LDL surface and imparts an electronegative charge to the nanoparticles surface. This negative surface charge promotes the monodisperse and homogeneous distribution of LDL-DHA nanoparticles in solution. Further structural analyses with cryo-electron microscopy revealed that the LDL-DHA nanostructure consist of a phospholipid bilayer surrounding an aqueous core, which is distinctly different from the phospholipid monolayer/apolar core organization of plasma LDL. Lastly, apolipoprotein B-100 remains strongly associated with this complex and maintains a discrete size and shape of the LDL-DHA nanoparticles similar to plasma LDL. This preliminary structural assessment of LDL-DHA now affords the opportunity to understand the important structure-function relationships of this novel nanoparticle.
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http://dx.doi.org/10.1016/j.chemphyslip.2017.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477227PMC
April 2017

Hepatic gluconeogenesis influences (13)C enrichment in lactate in human brain tumors during metabolism of [1,2-(13)C]acetate.

Neurochem Int 2016 07 26;97:133-6. Epub 2016 Mar 26.

Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.

(13)C-enriched compounds are readily metabolized in human malignancies. Fragments of the tumor, acquired by biopsy or surgical resection, may be acid-extracted and (13)C NMR spectroscopy of metabolites such as glutamate, glutamine, 2-hydroxyglutarate, lactate and others provide a rich source of information about tumor metabolism in situ. Recently we observed (13)C-(13)C spin-spin coupling in (13)C NMR spectra of lactate in brain tumors removed from patients who were infused with [1,2-(13)C]acetate prior to the surgery. We found, in four patients, that infusion of (13)C-enriched acetate was associated with synthesis of (13)C-enriched glucose, detectable in plasma. (13)C labeled glucose derived from [1,2-(13)C]acetate metabolism in the liver and the brain pyruvate recycling in the tumor together lead to the production of the (13)C labeled lactate pool in the brain tumor. Their combined contribution to acetate metabolism in the brain tumors was less than 4.0%, significantly lower than the direct oxidation of acetate in the citric acid cycle in tumors.
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http://dx.doi.org/10.1016/j.neuint.2016.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951105PMC
July 2016

Oxidative Conversion of a Europium(II)-Based T1 Agent into a Europium(III)-Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging.

Angew Chem Int Ed Engl 2016 Apr 8;55(16):5024-7. Epub 2016 Mar 8.

Advanced Imaging Research Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.

The Eu(II) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tetra(glycinate) has a higher reduction potential than most Eu(II) chelates reported to date. The reduced Eu(II) form acts as an efficient water proton T1 relaxation reagent, while the Eu(III) form acts as a water-based chemical exchange saturation transfer (CEST) agent. The complex has extremely fast water exchange rate. Oxidation to the corresponding Eu(III) complex yields a well-defined signal from the paraCEST agent. The time course of oxidation was studied in vitro and in vivo by T1-weighted and CEST imaging.
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http://dx.doi.org/10.1002/anie.201511649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955383PMC
April 2016

Conditions for (13)C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas.

Anal Biochem 2015 Jul 20;481:4-6. Epub 2015 Apr 20.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

(13)C NMR (nuclear magnetic resonance) spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in isocitrate dehydrogenase (IDH)-mutant gliomas, (13)C labeling is obscured in oncometabolite 2-hydroxyglutaric acid (2 HG) by glutamate and glutamine, prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2 HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically cooled (13)C probe, but not J-resolved heteronuclear single quantum coherence spectroscopy, significantly improved detection of 2 HG. These methods enable the monitoring of (13)C-(13)C spin-spin couplings in 2 HG expressing IDH-mutant gliomas.
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http://dx.doi.org/10.1016/j.ab.2015.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458399PMC
July 2015

Redox- and hypoxia-responsive MRI contrast agents.

ChemMedChem 2014 Jun 13;9(6):1116-29. Epub 2014 May 13.

Department of Chemistry, The University of Texas at Dallas, 800 West Campbell, BE26, Richardson, TX 75080 (USA).

The development of responsive or "smart" magnetic resonance imaging (MRI) contrast agents that can report specific biomarker or biological events has been the focus of MRI contrast agent research over the past 20 years. Among various biological hallmarks of interest, tissue redox and hypoxia are particularly important owing to their roles in disease states and metabolic consequences. Herein we review the development of redox-/hypoxia-sensitive T1 shortening and paramagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agents. Traditionally, the relaxivity of redox-sensitive Gd(3+) -based complexes is modulated through changes in the ligand structure or molecular rotation, while PARACEST sensors exploit the sensitivity of the metal-bound water exchange rate to electronic effects of the ligand-pendant arms and alterations in the coordination geometry. Newer designs involve complexes of redox-active metal ions in which the oxidation states have different magnetic properties. The challenges of translating redox- and hypoxia-sensitive agents in vivo are also addressed.
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http://dx.doi.org/10.1002/cmdc.201402034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119595PMC
June 2014

Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

Magn Reson Med 2014 Mar;71(3):1179-85

Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Radiology, UT Southwestern Medical Center, Dallas, Texas, USA.

Purpose: The water molecule exchange rates in a series of DyDOTA-(amide)X chelates were fine-tuned to maximize the effects of T2-exchange line broadening and improve T2 contrast.

Methods: Four DyDOTA-(amide)X chelates having a variable number of glycinate side-arms were prepared and characterized as T2-exchange agents. The nonexchanging DyTETA chelate was also used to measure the bulk water T2 reduction due solely to T2*. The total transverse relaxivity (r2tot) at 22, 37, and 52°C for each chelate was measured in vitro at 9.4 Tesla (400 MHz) by fitting plots of total T2 (-1) versus concentration. The water molecule exchange rates for each complex were measured by fitting (17)O line-width versus temperature data taken at 9.4 Tesla (54.3 MHz).

Results: The measured transverse relaxivities due to water molecule exchange (r2ex) and bound water lifetimes (τM) were in excellent agreement with Swift-Connick theory, with DyDOTA-(gly)3 giving the largest r2ex = 11.8 s(-1) mM(-1) at 37°C.

Conclusion: By fine-tuning the water molecule exchange rate at 37°C, the transverse relaxivity has been increased by 2 to 30 times compared with previously studied Dy(3+)-based chelates. Polymerization or dendrimerization of the optimal chelate could yield a highly sensitive, molecule-sized T2 contrast agent for improved molecular imaging applications.
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http://dx.doi.org/10.1002/mrm.25091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219925PMC
March 2014

Modulation of CEST images in vivo by T1 relaxation: a new approach in the design of responsive PARACEST agents.

J Am Chem Soc 2013 Oct 25;135(40):14904-7. Epub 2013 Sep 25.

Advanced Imaging Research Center, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.

A novel approach for the design of responsive paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance imaging (MRI) agents has been developed where the signal is "turned on" by altering the longitudinal relaxation time (T1) of bulk water protons. To demonstrate this approach, a model Eu(DOTA-tetraamide) complex (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) containing two nitroxide free radical units was synthesized. The nitroxide groups substantially shortened the T1 of the bulk water protons which, in turn, resulted in quenching of the CEST signal. Reduction of paramagnetic nitroxide moieties to a diamagnetic species resulted in the appearance of CEST. The modulation of CEST by T1 relaxation provides a new platform for designing biologically responsive MRI agents.
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http://dx.doi.org/10.1021/ja406738yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858012PMC
October 2013

In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI.

Magn Reson Med 2014 Jan 6;71(1):286-93. Epub 2013 Mar 6.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1002/mrm.24603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681922PMC
January 2014

The efficiency of DPPH as a polarising agent for DNP-NMR spectroscopy.

RSC Adv 2012 Jan 25;2(33):12812-12817. Epub 2012 Oct 25.

Advanced Imaging Research Center, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 USA. ; Tel: +1-214-645-2750.

The free radical 2,2-diphenyl-1-pycrylhydrazyl (DPPH) was tested as a polarising agent for fast dissolution dynamic nuclear polarisation (DNP) NMR spectroscopy. DPPH was found to be reasonably soluble in sulfolane and the optimum concentration for DNP is 20-40 mM depending upon whether short polarisation times or the maximum signal intensity is needed. W-band ESR measurements revealed that the ESR linewidth D of DPPH is intermediate between that of BDPA and 4-oxo-TEMPO. Several thousand-fold NMR signal enhancements in the liquid-state were achieved for (13)C, (15)N, (89)Y, and (109)Ag compounds, demonstrating that DPPH can be added to the list of polarising agents for DNP-NMR spectroscopy. Furthermore, the hydrophobic DPPH free radical can be easily filtered out from the dissolution liquid when water is used as the dissolution solvent.
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http://dx.doi.org/10.1039/C2RA21853DDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507463PMC
January 2012

Europium(III) DOTA-tetraamide complexes as redox-active MRI sensors.

J Am Chem Soc 2012 Apr 23;134(13):5798-800. Epub 2012 Mar 23.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

PARACEST redox sensors containing the NAD(+)/NADH mimic N-methylquinolinium moiety as a redox-active functional group have been designed and synthesized. The Eu(3+) complex with two quinolinium moieties was nearly completely CEST-silent in the oxidized form but was "turned on" upon reduction with β-NADH. The CEST effect of the Eu(3+) complex containing only one quinolinium group was much less redox-responsive but showed an unexpected sensitivity to pH in the physiologically relevant pH range.
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http://dx.doi.org/10.1021/ja211601kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321733PMC
April 2012

Using frequency-labeled exchange transfer to separate out conventional magnetization transfer effects from exchange transfer effects when detecting ParaCEST agents.

Magn Reson Med 2012 Apr 27;67(4):906-11. Epub 2012 Jan 27.

University of Texas Southwestern Medical Center, Dallas, TX, USA.

Paramagnetic chemical exchange saturation transfer agents combine the benefits of a large chemical shift difference and a fast exchange rate for sensitive MRI detection. However, the in vivo detection of these agents is hampered by the need for high B(1) fields to allow sufficiently fast saturation before exchange occurs, thus causing interference of large magnetization transfer effects from semisolid macromolecules. A recently developed approach named frequency-labeled exchange transfer utilizes excitation pulses instead of saturation pulses for detecting the exchanging protons. Using solutions and gel phantoms containing the europium (III) complex of DOTA tetraglycinate (EuDOTA-(gly)(-) (4) ), it is shown that frequency-labeled exchange transfer allows the separation of chemical exchange effects and magnetization transfer (MT) effects in the time domain, therefore allowing the study of the individual resonance of rapidly exchanging water molecules (k(ex) >10(4) s(-1) ) without interference from conventional broad-band MT.
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http://dx.doi.org/10.1002/mrm.24161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306536PMC
April 2012

Production and NMR characterization of hyperpolarized (107,109)Ag complexes.

Angew Chem Int Ed Engl 2012 Jan 13;51(2):525-7. Epub 2011 Oct 13.

University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

Both isotopes of silver, (107)Ag and (109)Ag, were simultaneously polarized by dynamic nuclear polarization (DNP), thus allowing large signal enhancements and the NMR characterization of Ag complexes in the millimolar concentration range. Since both isotopes have long relaxation times T(1), the hyperpolarized NMR signal of one isotope could still be observed even after the magnetization of the other isotope had been destroyed by radio-frequency pulses.
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http://dx.doi.org/10.1002/anie.201106073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366488PMC
January 2012

BDPA: an efficient polarizing agent for fast dissolution dynamic nuclear polarization NMR spectroscopy.

Chemistry 2011 Sep 25;17(39):10825-7. Epub 2011 Aug 25.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, USA.

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http://dx.doi.org/10.1002/chem.201102037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366484PMC
September 2011

Activation of a PARACEST agent for MRI through selective outersphere interactions with phosphate diesters.

Inorg Chem 2010 Jul;49(13):5963-70

Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.

Ln(S-THP)(3+) complexes are paramagnetic chemical exchange saturation transfer (PARACEST) agents for magnetic resonance imaging (MRI; S-THP = (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane, Ln(III) = Ce(III), Eu(III), Yb(III)). CEST spectra at 11.7 T show that the PARACEST effect of these complexes is enhanced at neutral pH in buffered solutions containing 100 mM NaCl upon the addition of 1-2 equiv of diethylphosphate (DEP). CEST images of phantoms at 4.7 T confirm that DEP enhances the properties of Yb(S-THP)(3+) as a PARACEST MRI agent in buffered solutions at neutral pH and 100 mM NaCl. Studies using (1)H NMR, direct excitation Eu(III) luminescence spectroscopy, and UV-visible spectroscopy show that DEP is an outersphere ligand. Dissociation constants for [Ln(S-THP)(OH(2))](DEP) are 1.9 mM and 2.8 mM for Ln(III) = Yb(III) at pH 7.0 and Eu(III) at pH 7.4. Related ligands including phosphorothioic acid, O,O-diethylester, ethyl methylphosphonate, O-(4-nitrophenylphosphoryl)choline, and cyclic 3,5-adenosine monophosphate do not activate PARACEST. BNPP (bis(4-nitrophenyl phosphate) activates PARACEST of Ln(S-THP)(3+) (Ln(III) = Eu(III), Yb(III)), albeit less effectively than does DEP. These data show that binding through second coordination sphere interactions is selective for phosphate diesters with two terminal oxygens and two identical ester groups. A crystal structure of [Eu(S-THP)(OH(2))]((O(2)NPhO)(2)PO(2))(2)(CF(3)SO(3)) x 2 H(2)O x iPrOH has two outersphere BNPP anions that form hydrogen bonds to the alcohol groups of the macrocycle and the bound water ligand. This structure supports (1)H NMR spectroscopy studies showing that outersphere interactions of the phosphate diester with the alcohol protons modulate the rate of alcohol proton exchange to influence the PARACEST properties of the complex. Further, DEP interacts only with the nonionized form of the complex, Ln(S-THP)(OH(2))(3+) contributing to the pH dependence of the PARACEST effect.
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http://dx.doi.org/10.1021/ic1004616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893239PMC
July 2010

Alternatives to gadolinium-based metal chelates for magnetic resonance imaging.

Chem Rev 2010 May;110(5):2960-3018

Advanced Imaging Research Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

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http://dx.doi.org/10.1021/cr900284aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874212PMC
May 2010

A concentration-independent method to measure exchange rates in PARACEST agents.

Magn Reson Med 2010 Mar;63(3):625-32

GE Global Research, Niskayuna, New York, USA.

The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line-width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X-intercept of a plot of steady-state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/omega(1)(2), referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high-resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line-width methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown.
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http://dx.doi.org/10.1002/mrm.22242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925112PMC
March 2010

A multislice gradient echo pulse sequence for CEST imaging.

Magn Reson Med 2010 Jan;63(1):253-6

GE Global Research, Niskayuna, New York 12309, USA.

Chemical exchange-dependent saturation transfer and paramagnetic chemical exchange-dependent saturation transfer are agent-mediated contrast mechanisms that depend on saturating spins at the resonant frequency of the exchangeable protons on the agent, thereby indirectly saturating the bulk water. In general, longer saturating pulses produce stronger chemical and paramagnetic exchange-dependent saturation transfer effects, with returns diminishing for pulses longer than T1. This could make imaging slow, so one approach to chemical exchange-dependent saturation transfer imaging has been to follow a long, frequency-selective saturation period by a fast imaging method. A new approach is to insert a short frequency-selective saturation pulse before each spatially selective observation pulse in a standard, two-dimensional, gradient-echo pulse sequence. Being much less than T1 apart, the saturation pulses have a cumulative effect. Interleaved, multislice imaging is straightforward. Observation pulses directed at one slice did not produce observable, unintended chemical exchange-dependent saturation transfer effects in another slice. Pulse repetition time and signal-to noise ratio increase in the normal way as more slices are imaged simultaneously.
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http://dx.doi.org/10.1002/mrm.22193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925508PMC
January 2010

Multi-frequency PARACEST agents based on europium(III)-DOTA-tetraamide ligands.

Angew Chem Int Ed Engl 2009 ;48(49):9330-3

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

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http://dx.doi.org/10.1002/anie.200904649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873151PMC
February 2010

A new gadolinium-based MRI zinc sensor.

J Am Chem Soc 2009 Aug;131(32):11387-91

Departamento de Química, Universidad de Guanajuato, Cerro de la Venada s/n, Guanajuato, Gto., C.P. 36040, México.

The properties of a novel Gd(3+)-based MRI zinc sensor are reported. Unlike previously reported Gd(3+)-based MRI contrast agents, this agent (GdL) differs in that the agent alone binds only weakly with human serum albumin (HSA), while the 1:2 GdL:Zn(2+) ternary complex binds strongly to HSA resulting in a substantial, 3-fold increase in water proton relaxivity. The GdL complex is shown to have a relatively strong binding affinity for Zn(2+) (K(D) = 33.6 nM), similar to the affinity of the Zn(2+) ion with HSA alone. The agent detects as little as 30 microM Zn(2+) in the presence of HSA by MRI in vitro, a value slightly more than the total Zn(2+) concentration in blood (approximately 20 microM). This combination of binding affinity constants and the high relaxivity of the agent when bound to HSA suggests that this new agent may be useful for detection of free Zn(2+) ions in vivo without disrupting other important biological processes involving Zn(2+).
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http://dx.doi.org/10.1021/ja901875vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745615PMC
August 2009

Modulation of water exchange in europium(III) DOTA-tetraamide complexes via electronic substituent effects.

J Am Chem Soc 2008 Jan 8;130(1):6-7. Epub 2007 Dec 8.

Advanced Imaging Research Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

The chemical exchange saturation transfer (CEST) efficiency for a series Eu3+-based tetraamide complexes bearing p-substituents on a single coordinating pendant arm is highly sensitive to water exchange rates. The CEST effect increases in the order Me < MeO < F approximately CO2tBu < CN < H. These results show that CEST contrast can be modulated by changes in electron density at a single ligating atom, and this forms the basis of creating imaging agents that respond to chemical oxidation and reduction.
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http://dx.doi.org/10.1021/ja076325yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716115PMC
January 2008
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