Magnetic Resonance in MedicineVolume 87, Issue 6 p. 3025-3026 ERRATUM Erratum to: Dual-phase imaging of cardiac metabolism using hyperpolarized pyruvate (Magn Reson Med. 2022;87:302-311.) Junjie Ma, Junjie Ma orcid.org/0000-0001-5751-887X Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorCraig R. Malloy, Craig R. Malloy orcid.org/0000-0001-5077-0642 Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorSalvador Pena, Salvador Pena Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorCrystal E. Harrison, Crystal E. Harrison Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorJames Ratnakar, James Ratnakar Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorVlad G. Zaha, Vlad G. Zaha orcid.org/0000-0003-4878-891X Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorJae Mo Park, Corresponding Author Jae Mo Park jaemo.park@utsouthwestern.edu orcid.org/0000-0002-7404-6971 Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Electrical and Computer Engineering, The University of Texas at Dallas, Richardson, Texas, USA Correspondence Jae Mo Park, Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas TX 75019, USA. Email: jaemo.park@utsouthwestern.eduSearch for more papers by this author Junjie Ma, Junjie Ma orcid.org/0000-0001-5751-887X Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorCraig R. Malloy, Craig R. Malloy orcid.org/0000-0001-5077-0642 Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorSalvador Pena, Salvador Pena Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorCrystal E. Harrison, Crystal E. Harrison Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorJames Ratnakar, James Ratnakar Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorVlad G. Zaha, Vlad G. Zaha orcid.org/0000-0003-4878-891X Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USASearch for more papers by this authorJae Mo Park, Corresponding Author Jae Mo Park jaemo.park@utsouthwestern.edu orcid.org/0000-0002-7404-6971 Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA Electrical and Computer Engineering, The University of Texas at Dallas, Richardson, Texas, USA Correspondence Jae Mo Park, Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas TX 75019, USA. Email: jaemo.park@utsouthwestern.eduSearch for more papers by this author First published: 21 February 2022 https://doi.org/10.1002/mrm.29146Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume87, Issue6June 2022Pages 3025-3026 RelatedInformation

77Se is a spin ½, low sensitivity nucleus with a natural abundance of 7.6%. Although 77Se NMR is very useful in the characterization of selenium containing molecules including seleno-proteins, the detection of 77Se is challenging in biological samples without enrichment. Therefore, the goal of this work was to establish whether the 77Se signal could be enhanced in the liquid state by dissolution dynamic nuclear polarization (DNP) NMR without the need of enrichment. The dominant spin-lattice relaxation mechanism for 77Se is via chemical shift anisotropy, which is highly dependent on the molecular symmetry. Here we tested three selenium compounds (sodium selenate, sodium selenite and selenocystine) with different molecular symmetries in dissolution DNP experiments and demonstrated that 77Se DNP using commercially available hardware is feasible but the achieved NMR signal enhancements (1368-fold for selenate, 125-fold for selenite and no enhancement for selenocystine at 9.4 T) were strongly dependent on molecular symmetry.

Purpose Previous cardiac imaging studies using hyperpolarized (HP) [1-C-13]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED. Methods A dual-phase C-13 MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1-C-13]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP C-13 metabolites at each cardiac phase was correlated to multiphase H-1 MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane. Results In addition to mechanical changes, metabolic profiles of the heart detected by HP [1-C-13]pyruvate differed between ES and ED. The myocardial signal of [C-13]bicarbonate relative to [1-C-13]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism. Conclusion The study demonstrates that metabolic profiles of the heart, measured by HP [1-C-13]pyruvate, are affected by the cardiac cycle in which that the data are acquired.

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 T-2*s of the HP signals is critical. This study is to measure in vivo cardiac T-2*s of HP [1-C-13]pyruvate and the products in rodents and humans. Methods: A dynamic C-13 multi-echo spiral imaging sequence that acquires [C-13]bicarbonate, [1-C-13]lactate, and [1-C-13]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. T-2* 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 T-2* using the sequence was first validated using a C-13 phantom and then with rodents following a bolus injection of HP [1-C-13]pyruvate. In humans, T-2* of each metabolite was calculated for left ventricle, right ventricle, and myocardium. Results: Cardiac T-2* s of HP [1-C-13]pyruvate, [1-C-13]lactate, and [C-13]bicarbonate in rodents were measured as 24.9 +/- 5.0, 16.4 +/- 4.7, and 16.9 +/- 3.4 ms, respectively. In humans, T-2* of [1-C-13]pyruvate was 108.7 +/- 22.6 ms in left ventricle and 129.4 +/- 8.9 ms in right ventricle. T-2* of [1-C-13]lactate was 40.9 +/- 8.3, 44.2 +/- 5.5, and 43.7 +/- 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. T-2* of [C-13] 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 T-2* s of HP [1-C-13]pyruvate and products.

PurposeThis study is to investigate time‐resolved 13C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1‐13C]pyruvate in the human brain.MethodsTime‐resolved 13C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1‐13C]pyruvate. 13C MRS with low flip‐angle excitations and a multichannel 13C/1H dual‐frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice‐wise areas under the curve (AUCs) of 13C‐metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and . Linear regression analysis between brain volumes and HP signals was performed. Region‐focused pyruvate metabolism was estimated using coil‐wise 13C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45‐minutes interval.Results[1‐13C]Lactate relative to the total 13C signal (tC) was 0.21–0.24 in all slices. [13C]/tC was 0.065–0.091. Apparent conversion rate constants from pyruvate to lactate and were calculated as 0.014–0.018 s−1 and 0.0043–0.0056 s−1, respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1‐13C]pyruvate.ConclusionsDynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1‐13C]pyruvate.

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 (13C) MRI with hyperpolarized (HP) [1-13C]-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 [1-13C]-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 t test was used for comparing 13C data among the states. Results At rest, HP [1-13C]-lactate and [1-13C]-alanine were detected in calf muscle, but [13C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP 13C signals (tC) increased 2.8-fold because of increased muscle perfusion (P = .005), and HP [1-13C]-lactate-to-tC ratio increased 1.7-fold (P = .04). HP [13C]-bicarbonate-to-tC ratio increased 8.4-fold (P = .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 (P = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {13C}]-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 [1-13C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021 Online supplemental material is available for this article.

A Mn(II)-based zinc-sensitive MRI contrast agent, Mn(PyC3A)-BPEN, was prepared and characterized and the agent was used in imaging experiments to detect glucose-stimulated zinc secretion (GSZS) from the mouse pancreas and prostate in vivo. Thermodynamic and kinetic stability tests showed that Mn(PyC3A-BPEN) has superior kinetic inertness compared to Gd(DTPA), is less susceptible to transmetallation in the presence of excess Zn2+ ions, and less susceptible to transchelation by albumin. In comparison with other gadolinium-based zinc sensors bearing a single zinc binding moiety, Mn(PyC3A-BPEN) appears to be a reliable alternative for imaging b-cell function in the pancreas and glucose-stimulated zinc secretion from prostate cells.

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 Gd3+-based MRI contrast agents are T-1 or T-2 relaxation-based sensors such as Ge-complexes for zinc or pH detection, a number of diamagnetic Y3+-complexes rely on changes in the chemical shift for potential quantitative MRI in biological milieu. Y-89, however, is a challenging nucleus to work with in conventional NMR or MRI due to its inherently low sensitivity and relatively long T-1 relaxation time. This insensitivity problem in Y-89-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-89-complexes with phosphonated open-chain ligands, Y-89-EDTMP and Y-89-DTPMP, as potential chemical shift-based pH NMR sensors. Our DNP-NMR data show that hyperpolarized Y-89-DTPMP has an apparent pK(a) similar to 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-89-EDTMP show that it has an apparent pK(a) 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-89-DOTP has a pK(a) of 7.64 and similar to 10-ppm wide chemical shift dispersion at pH 4-9 range. Overall, our data suggest that hyperpolarized Y-89-EDTMP is better than hyperpolarized Y-89-DOTP in terms of pH sensing capability at the physiological range. (C) 2020 Elsevier Inc. All rights reserved.

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 Ln3+ -bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T2 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 Yb3+ 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.

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 (T 1 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 DOTAGly4 (4) 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 EuDOTAGly4 (Eu4) was determined by X-ray diffraction and a brief analysis is presented compared to known Ln3+ structures found within literature. The Eu4 complex crystalizes in a rare polymer type arrangement via bridging side-arms between adjacent complexes.

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 (R1 ) 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.

Contrast agents for magnetic resonance imaging (MRI) currently used and approved by the Food and Drug Administration (FDA) of the United States of America are GdIII-based. Yet, GdIII complexes are only one class of contrast agents for MRI. The fundamentals described in this chapter are intended to assist with the design of future imaging agents for MRI. Ligands affect not only relaxivity but also thermodynamic stability and kinetic inertness of GdIII complexes, which in turn affect the safety profiles of contrast agents. Divided into four sections, this chapter describes syntheses and characterization of ligands and metal complexes as well as the determination of the stability and lability of metal complexes.

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.

The Eu3+/2+ redox couple provides a convenient design platform for responsive pO2 sensors for magnetic resonance imaging (MRI). Specifically the Eu2+ ion provides T1w contrast enhancement under hypoxic conditions in tissues, whereas, under normoxia, the Eu3+ ion can produce contrast from chemical exchange saturation transfer in MRI. The oxidative stability of the Eu3+/2+ 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 Eu3+/2+ 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.

Contrast agents for magnetic resonance imaging (MRI) currently used and approved by the Food and Drug Administration (FDA) of the United States of America are GdIII-based. Yet, GdIII complexes are only one class of contrast agents for MRI. The fundamentals described in this chapter are intended to assist with the design of future imaging agents for MRI. Ligands affect not only relaxivity but also thermodynamic stability and kinetic inertness of GdIII complexes, which in turn affect the safety profiles of contrast agents. Divided into four sections, this chapter describes syntheses and characterization of ligands and metal complexes as well as the determination of the stability and lability of metal complexes.

(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.

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.

13C NMR (nuclear magnetic resonance) spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in isocitrate dehydrogenase (IDH)-mutant gliomas, 13C labeling is obscured in oncometabolite 2-hydroxyglutaric acid (2HG) by glutamate and glutamine, prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically cooled 13C probe, but not J-resolved heteronuclear single quantum coherence spectroscopy, significantly improved detection of 2HG. These methods enable the monitoring of 13C–13C spin–spin couplings in 2HG expressing IDH-mutant gliomas.