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Article: Editorial: Brain injury and neurodegenerative diseases: imaging and mechanisms.

Wang, Zhuonan / Zhou, Iris Yuwen / Gao, Lei / Chen, Li

2024 Volume 17, Page(s) 1372246

Language	English
Publishing date	2024-02-16
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2024.1372246
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Article ; Online: Effects of the New Thrombolytic Compound LT3001 on Acute Brain Tissue Damage After Focal Embolic Stroke in Rats.

Jiang, Yinghua / Ji, Yang / Zhou, Iris Yuwen / Liu, Ning / Sun, Phillip Zhe / Ning, Mingming / Dumont, Aaron S / Wang, Xiaoying

Translational stroke research

2022 Volume 15, Issue 1, Page(s) 30–40

Abstract: LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received ... ...

Abstract	LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10 mg/kg LT3001 or tPA at 1.5, 3, or 4.5 h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5 h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3 h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5 h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke.
MeSH term(s)	Rats ; Animals ; Tissue Plasminogen Activator ; Plasminogen Activator Inhibitor 1 ; Embolic Stroke ; Rats, Wistar ; Fibrinolytic Agents/therapeutic use ; Stroke/complications ; Stroke/drug therapy ; Stroke/pathology ; Brain Injuries/drug therapy ; Brain/pathology ; Disease Models, Animal ; Thrombolytic Therapy
Chemical Substances	Tissue Plasminogen Activator (EC 3.4.21.68) ; Plasminogen Activator Inhibitor 1 ; Fibrinolytic Agents
Language	English
Publishing date	2022-11-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2541897-X
ISSN	1868-601X ; 1868-4483
ISSN (online)	1868-601X
ISSN	1868-4483
DOI	10.1007/s12975-022-01107-3
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Article ; Online: Dual Hydrazine-Equipped Turn-On Manganese-Based Probes for Magnetic Resonance Imaging of Liver Fibrogenesis.

Ning, Yingying / Zhou, Iris Yuwen / Rotile, Nicholas J / Pantazopoulos, Pamela / Wang, Huan / Barrett, Stephen Cole / Sojoodi, Mozhdeh / Tanabe, Kenneth K / Caravan, Peter

Journal of the American Chemical Society

2022 Volume 144, Issue 36, Page(s) 16553–16558

Abstract: Liver fibrogenesis is accompanied by upregulation of lysyl oxidase enzymes, which catalyze oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing amino acid allysine ( ... ...

Abstract	Liver fibrogenesis is accompanied by upregulation of lysyl oxidase enzymes, which catalyze oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing amino acid allysine (Lys
MeSH term(s)	Animals ; Contrast Media/chemistry ; Hydrazines ; Liver/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Manganese/chemistry ; Mice
Chemical Substances	Contrast Media ; Hydrazines ; Manganese (42Z2K6ZL8P)
Language	English
Publishing date	2022-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c06231
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Article: Dual Hydrazine-Equipped Turn-On Manganese-Based Probes for Magnetic Resonance Imaging of Liver Fibrogenesis

Ning, Yingying / Zhou, Iris Yuwen / Rotile, Nicholas J. / Pantazopoulos, Pamela / Wang, Huan / Barrett, Stephen Cole / Sojoodi, Mozhdeh / Tanabe, Kenneth K. / Caravan, Peter

Journal of the American Chemical Society. 2022 Aug. 23, v. 144, no. 36

2022

Abstract	Liver fibrogenesis is accompanied by upregulation of lysyl oxidase enzymes, which catalyze oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing amino acid allysine (Lysᴬˡᵈ). Here, we describe the design and synthesis of novel manganese-based MRI probes with high signal amplification for imaging liver fibrogenesis. Rational design of a series of stable hydrazine-equipped manganese MRI probes gives Mn-2CHyd with the highest affinity and turn-on relaxivity (4-fold) upon reaction with Lysᴬˡᵈ. A dynamic PET-MRI study using [⁵²Mn]Mn-2CHyd showed low liver uptake of the probe in healthy mice. The ability of the probe to detect liver fibrogenesis was then demonstrated in vivo in CCl₄-injured mice. This study enables further development and application of manganese-based hydrazine-equipped probes for imaging liver fibrogenesis.
Keywords	aldehydes ; extracellular matrix ; liver ; lysine ; magnetism ; manganese ; oxidation ; protein-lysine 6-oxidase
Language	English
Dates of publication	2022-0823
Size	p. 16553-16558.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c06231
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Article ; Online: Optimization of an Allysine-Targeted PET Probe for Quantifying Fibrogenesis in a Mouse Model of Pulmonary Fibrosis.

Shuvaev, Sergey / Knipe, Rachel S / Drummond, Matt / Rotile, Nicholas J / Ay, Ilknur / Weigand-Whittier, Jonah P / Ma, Hua / Zhou, Iris Yuwen / Roberts, Jesse D / Black, Katherine / Hariri, Lida P / Ning, Yingying / Caravan, Peter

Molecular imaging and biology

2023 Volume 25, Issue 5, Page(s) 944–953

Abstract: Purpose: Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment ... ...

Abstract	Purpose: Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions. Methods: Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed. Results: In vivo screening of probes identified Conclusion: A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe,
Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2079160-4
ISSN	1860-2002 ; 1536-1632
ISSN (online)	1860-2002
ISSN	1536-1632
DOI	10.1007/s11307-023-01845-2
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Article ; Online: Positron Emission Tomography-Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A.

Zhou, Iris Yuwen / Ramsay, Ian A / Ay, Ilknur / Pantazopoulos, Pamela / Rotile, Nicholas J / Wong, Alison / Caravan, Peter / Gale, Eric M

Investigative radiology

2020 Volume 56, Issue 4, Page(s) 261–270

Abstract: Objectives: Mn-PyC3A is an experimental manganese (Mn)-based extracellular fluid magnetic resonance imaging (MRI) contrast agent that is being evaluated as a direct replacement for clinical gadolinium (Gd)-based contrast agents. The goals of this study ... ...

Abstract	Objectives: Mn-PyC3A is an experimental manganese (Mn)-based extracellular fluid magnetic resonance imaging (MRI) contrast agent that is being evaluated as a direct replacement for clinical gadolinium (Gd)-based contrast agents. The goals of this study were to use simultaneous positron emission tomography (PET)-MRI to (1) compare the whole-body pharmacokinetics, biodistribution, and elimination of Mn-PyC3A with the liver-specific contrast agent mangafodipir (Mn-DPDP), (2) determine the pharmacokinetics and fractional excretion of Mn-PyC3A in a rat model of renal impairment, and (3) compare whole-body elimination of Mn-PyC3A to gadoterate (Gd-DOTA) in a rat model of renal impairment. Methods: Mn-PyC3A and Mn-DPDP were radiolabeled with the positron emitting isotope Mn-52 via Mn2+ exchange with 52MnCl2. Dynamic simultaneous PET-MRI was used to measure whole-body pharmacokinetics and biodistribution of Mn-52 immediately and out to 7 days after an intravenous 0.2 mmol/kg dose of [52Mn]Mn-PyC3A to normal or to 5/6 nephrectomy rats or a 0.01 mmol/kg dose of [52Mn]Mn-DPDP to normal rats. The fractional excretion and 1- and 7-day biodistribution in rats after the injection of 2.0 mmol/kg [52Mn]Mn-PyC3A (n = 11 per time point) or 2.0 mmol/kg Gd-DOTA (n = 8 per time point) were quantified by gamma counting or Gd elemental analysis, respectively. Comparisons of Mn-PyC3A pharmacokinetics and in vivo biodistribution in normal and 5/6 nephrectomy rats and comparisons of ex vivo Mn versus Gd biodistribution data in 5/6 nephrectomy were made with an unpaired t test. Results: Dynamic PET-MRI data demonstrate that both [52Mn]Mn-PyC3A and [52Mn]Mn-DPDP were eliminated by mixed renal and hepatobiliary elimination but that a greater fraction of [52Mn]Mn-PyC3A was eliminated by renal filtration. Whole-body PET images show that Mn-52 from [52Mn]Mn-PyC3A was efficiently eliminated from the body, whereas Mn-52 from [52Mn]Mn-DPDP was retained throughout the body. The blood elimination half-life of [52Mn]Mn-PyC3A in normal and 5/6 nephrectomy rats was 13 ± 3.5 minutes and 23 ± 12 minutes, respectively (P = 0.083). Area under the curve between 0 and 60 minutes postinjection (AUC0-60) in the bladder of normal and 5/6 nephrectomy rats was 2600 ± 1700 %ID/ccmin and 750 ± 180 %ID/ccmin, respectively (P = 0.024), whereas AUC0-60 in the liver of normal and 5/6 nephrectomy rats was 33 ± 13 %ID/ccmin and 71 ± 16 %ID/ccmin, respectively (P = 0.011), indicating increased hepatobiliary elimination in 5/6 nephrectomy rats. The %IDs of Mn from [52Mn]Mn-PyC3A and Gd from Gd-DOTA recovered from 5/6 nephrectomy rats 1 day after injection were 2.0 ± 1.1 and 1.3 ± 0.34, respectively (P = 0.10) and 7 days after injection were 0.14 ± 0.11 and 0.41 ± 0.24, respectively (P = 0.0041). Conclusions: Mn-PyC3A has different pharmacokinetics and is more efficiently eliminated than Mn-DPDP in normal rats. Mn-PyC3A is efficiently eliminated from both normal and 5/6 nephrectomy rats, with increased fractional hepatobiliary excretion from 5/6 nephrectomy rats. Mn-PyC3A is more completely eliminated than Gd-DOTA from 5/6 nephrectomy rats after 7 days.
MeSH term(s)	Animals ; Contrast Media ; Diamines ; Magnetic Resonance Imaging ; Manganese ; Manganese Compounds ; Picolinic Acids ; Positron-Emission Tomography ; Radioisotopes ; Rats ; Tissue Distribution
Chemical Substances	Contrast Media ; Diamines ; Manganese Compounds ; Manganese-52 ; Mn-PyC3A ; Picolinic Acids ; Radioisotopes ; Manganese (42Z2K6ZL8P)
Language	English
Publishing date	2020-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80345-5
ISSN	1536-0210 ; 0020-9996
ISSN (online)	1536-0210
ISSN	0020-9996
DOI	10.1097/RLI.0000000000000736
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Article ; Online: Quantitative chemical exchange saturation transfer (CEST) MRI of glioma using Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting.

Zhou, Iris Yuwen / Wang, Enfeng / Cheung, Jerry S / Zhang, Xiaoan / Fulci, Giulia / Sun, Phillip Zhe

Scientific reports

2017 Volume 7, Issue 1, Page(s) 84

Abstract: Chemical Exchange Saturation Transfer (CEST) MRI is sensitive to dilute metabolites with exchangeable protons, allowing tissue characterization in diseases such as acute stroke and tumor. CEST quantification using multi-pool Lorentzian fitting is ... ...

Abstract	Chemical Exchange Saturation Transfer (CEST) MRI is sensitive to dilute metabolites with exchangeable protons, allowing tissue characterization in diseases such as acute stroke and tumor. CEST quantification using multi-pool Lorentzian fitting is challenging due to its strong dependence on image signal-to-noise ratio (SNR), initial values and boundaries. Herein we proposed an Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting algorithm that quantifies CEST images based on initial values from multi-pool Lorentzian fitting of iteratively less downsampled images until the original resolution. The IDEAL fitting in phantom data with superimposed noise provided smaller coefficient of variation and higher contrast-to-noise ratio at a faster fitting speed compared to conventional fitting. We further applied the IDEAL fitting to quantify CEST MRI in rat gliomas and confirmed its advantage for in vivo CEST quantification. In addition to significant changes in amide proton transfer and semisolid macromolecular magnetization transfer effects, the IDEAL fitting revealed pronounced negative contrasts of tumors in the fitted CEST maps at 2 ppm and -1.6 ppm, likely arising from changes in creatine level and nuclear overhauser effects, which were not found using conventional method. It is anticipated that the proposed method can be generalized to quantify MRI data where SNR is suboptimal.
MeSH term(s)	Algorithms ; Animals ; Brain Neoplasms/diagnostic imaging ; Cell Line, Tumor ; Glioma/diagnostic imaging ; Image Interpretation, Computer-Assisted/methods ; Least-Squares Analysis ; Magnetic Resonance Imaging/methods ; Male ; Neoplasm Transplantation ; Phantoms, Imaging ; Rats ; Signal-To-Noise Ratio
Language	English
Publishing date	2017-03-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-00167-y
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Article ; Online: A theoretical analysis of chemical exchange saturation transfer echo planar imaging (CEST-EPI) steady state solution and the CEST sensitivity efficiency-based optimization approach.

Jiang, Weiping / Zhou, Iris Yuwen / Wen, Lingyi / Zhou, Xin / Sun, Phillip Zhe

Contrast media & molecular imaging

2016 Volume 11, Issue 5, Page(s) 415–423

Abstract: Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironmental properties, augmenting routine relaxation-based MRI. Recent developments of quantitative CEST (qCEST) analysis such as omega plots and RF-power ... ...

Abstract	Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironmental properties, augmenting routine relaxation-based MRI. Recent developments of quantitative CEST (qCEST) analysis such as omega plots and RF-power based ratiometric calculation have extended our ability to elucidate the underlying CEST system beyond the simplistic apparent CEST measurement. CEST MRI strongly varies with experimental factors, including the RF irradiation level and duration as well as repetition time and flip angle. In addition, the CEST MRI effect is typically small, and experimental optimization strategies have to be carefully evaluated in order to enhance the CEST imaging sensitivity. Although routine CEST MRI has been optimized largely based on maximizing the magnitude of the CEST effect, the CEST signal-to-noise (SNR) efficiency provides a more suitable optimization index, particularly when the scan time is constrained. Herein, we derive an analytical solution of the CEST effect that takes into account key experimental parameters including repetition time, imaging flip angle and RF irradiation level, and solve its SNR efficiency. The solution expedites CEST imaging sensitivity calculation, substantially faster than the Bloch-McConnell equation-based numerical simulation approach. In addition, the analytical solution-based SNR formula enables the exhaustive optimization of CEST MRI, which simultaneously predicts multiple optimal parameters such as repetition time, flip angle and RF saturation level based on the chemical shift and exchange rate. The sensitivity efficiency-based optimization approach could simplify and guide imaging of CEST agents, including glycogen, glucose, creatine, gamma-aminobutyric acid and glutamate. Copyright © 2016 John Wiley & Sons, Ltd.
Language	English
Publishing date	2016-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2232678-9
ISSN	1555-4317 ; 1555-4309
ISSN (online)	1555-4317
ISSN	1555-4309
DOI	10.1002/cmmi.1699
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Article ; Online: A method for accurate pH mapping with chemical exchange saturation transfer (CEST) MRI.

Sun, Phillip Zhe / Xiao, Gang / Zhou, Iris Yuwen / Guo, Yingkun / Wu, Renhua

Contrast media & molecular imaging

2016 Volume 11, Issue 3, Page(s) 195–202

Abstract: Chemical exchange saturation transfer (CEST) MRI holds enormous promise for imaging pH. Whereas the routine CEST-weighted MRI contrast is complex and susceptible to confounding factors such as labile proton ratio, chemical shift, bulk water relaxation ... ...

Abstract	Chemical exchange saturation transfer (CEST) MRI holds enormous promise for imaging pH. Whereas the routine CEST-weighted MRI contrast is complex and susceptible to confounding factors such as labile proton ratio, chemical shift, bulk water relaxation and RF saturation, ratiometric CEST imaging simplifies pH determination. However, the conventional ratiometric CEST (RCEST) MRI approach is limited to CEST agents with multiple exchangeable groups. To address this limitation, RF power-based ratiometric CEST (PRCEST) imaging has been proposed that ratios CEST effects obtained under different RF power levels. Nevertheless, due to concomitant RF saturation (spillover) effect, the recently proposed PRCEST imaging is somewhat dependent on parameters including bulk water relaxation time and chemical shift. Herein we hypothesized that RF power-based ratiometric analysis of RF spillover effect-corrected inverse CEST asymmetry (PRICEST) provides enhanced pH measurement. The postulation was verified numerically, and validated experimentally using an in vitro phantom. Briefly, our study showed that the difference between MRI-determined pH (pHMRI ) and electrode-measured pH being 0.12 ± 0.13 and 0.04 ± 0.03 for PRCEST and PRICEST imaging, respectively, and the newly proposed PRICEST imaging provides significantly more accurate pH determination than PRCEST imaging (P < 0.01, Wilcoxon signed-rank test). Notably, the exchange rate shows dominantly base-catalysed relationship with pH, independent of creatine concentration (P > 0.10, Analysis of Covariance). In addition, the derived labile proton ratio linearly scales with creatine concentration (P < 0.01, Pearson Regression). To summarize, PRICEST MRI provides concentration-independent pH imaging, augmenting prior quantitative CEST methods for accurate pH mapping. Copyright © 2015 John Wiley & Sons, Ltd.
Language	English
Publishing date	2016-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2232678-9
ISSN	1555-4317 ; 1555-4309
ISSN (online)	1555-4317
ISSN	1555-4309
DOI	10.1002/cmmi.1680
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Article ; Online: In vivo microscopic diffusional kurtosis imaging with symmetrized double diffusion encoding EPI.

Ji, Yang / Paulsen, Jeffrey / Zhou, Iris Yuwen / Lu, Dongshuang / Machado, Patrick / Qiu, Bensheng / Song, Yi-Qiao / Sun, Phillip Zhe

Magnetic resonance in medicine

2018 Volume 81, Issue 1, Page(s) 533–541

Abstract: Purpose: Diffusional kurtosis imaging (DKI) measures the deviation of the displacement probability from a normal distribution, complementing the data commonly acquired by diffusion MRI. It is important to elucidate the sources of kurtosis contrast, ... ...

Abstract	Purpose: Diffusional kurtosis imaging (DKI) measures the deviation of the displacement probability from a normal distribution, complementing the data commonly acquired by diffusion MRI. It is important to elucidate the sources of kurtosis contrast, particularly in biological tissues where microscopic kurtosis (intrinsic kurtosis) and diffusional heterogeneity may co-exist. Methods: We have developed a technique for microscopic kurtosis MRI, dubbed microscopic diffusional kurtosis imaging (µDKI), using a symmetrized double diffusion encoding (s-DDE) EPI sequence. We compared this newly developed µDKI to conventional DKI methods in both a triple compartment phantom and in vivo. Results: Our results showed that whereas conventional DKI and µDKI provided similar measurements in a compartment of monosphere beads, kurtosis measured by µDKI was significantly less than that measured by conventional DKI in a compartment of mixed Gaussian pools. For in vivo brain imaging, µDKI showed small yet significantly lower kurtosis measurement in regions of the cortex, CSF, and internal capsule compared to the conventional DKI approach. Conclusions: Our study showed that µDKI is less susceptible than conventional DKI to sub-voxel diffusional heterogeneity. Our study also provided important preliminary demonstration of our technique in vivo, warranting future studies to investigate its diagnostic use in examining neurological disorders.
MeSH term(s)	Algorithms ; Animals ; Brain/diagnostic imaging ; Diffusion Tensor Imaging ; Echo-Planar Imaging ; Image Processing, Computer-Assisted/methods ; Intravital Microscopy ; Male ; Models, Statistical ; Normal Distribution ; Phantoms, Imaging ; Probability ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Signal-To-Noise Ratio
Language	English
Publishing date	2018-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.27419
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