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Next Generation of MRI Agents

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Radiopharmaceutical Sciences".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 34200

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Special Issue Editors

Prof. Dr. Andre F. Martins

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Guest Editor

1. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
2. Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, 72076 Tübingen, Germany
3. German Cancer Consortium, DKFZ Partner Site Tübingen, 72076 Tübingen, Germany
Interests: multimodal imaging; metabolic imaging; hybrid PET-MRI imaging; metabolic sensors; metallomics
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Dr. Mark Pagel

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Guest Editor

MD Anderson Cancer Center, University of Texas, Houston, TX, USA
Interests: cancer imaging; tumor microenvironment; CEST MRI; PET/MRI; optoacoustic tomography

Special Issue Information

Dear Colleagues,

Contrast agents have served an essential role in the development and clinical translation of magnetic resonance imaging (MRI) during the last 40 years. The first agents developed in the 1980s were designed to change the MR image contrast to identify anatomical features, such as solid tumors that had enhanced the uptake of nonspecific tracers. These agents are still commonly used for qualitative assessments of many clinical pathologies. These nonspecific tracer agents began to be temporally monitored in the 1990s as an agent was intravenously injected, then flowed through the vasculature and eventually permeated into the tissue of interest, such as a kidney or tumor. Semiquantitative and quantitative evaluations of the pharmacokinetics of these agents provided functional information, especially for studies in cardiology and oncology. During the 2000s, MRI contrast agents were developed to interrogate molecular-level biomarkers, including protein and gene expressions, enzyme activity, metabolites, oxygen, ions, and pH. These MR molecular imaging agents represent the next generation of MRI agents, which can be designed to identify molecular-level information to improve the selection of the best pharmaceutical, or the molecular changes that occur in early response to pharmaceuticals. Therefore, this next generation of MR molecular imaging agents can provide strong support for the evaluation of many pharmaceuticals during preclinical and clinical testing, as well as clinical application.

Molecular imaging agents can employ a variety of MRI contrast mechanisms. T1- and T2-based contrast agents change the longitudinal and transverse relaxation rates of water in tissues, which changes the bright/dark contrast in the image. Interactions between relaxation-based MR agents and their intended molecular biomarker cause the bright/ark contrast to change, indicating that the molecular biomarker has been identified. Chemical exchange saturation transfer is a relatively new MR imaging mechanism that causes image contrast thorough the transfer of protons that were labeled through radiofrequency saturation from the agent to water, followed by the detection of an altered water MR signal. The chemical exchange of protons is a molecular-level process, which provides outstanding opportunities to interrogate molecular biomarkers. More recently, methods have been developed that hyperpolarize an MR agent, causing a tremendous boost of MR signal from the hyperpolarized agent, leading to outstanding sensitivity for detecting molecular-level activities such as cellular metabolism. This variety of techniques provides exceptional opportunities to creatively develop molecular imaging for detecting many types of biomarkers, fostering the next generation of molecular imaging diagnostic methods.

Dr. Andre F. Martins
Dr. Mark Pagel
Guest Editors

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Keywords

MRI contrast agents
relaxation-based agents
hyperpolarized agents
CEST agents
hybrid MR agents

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Published Papers (9 papers)

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Research

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18 pages, 3304 KiB

Open AccessArticle

pH Dependence of T₂ for Hyperpolarizable ¹³C-Labelled Small Molecules Enables Spatially Resolved pH Measurement by Magnetic Resonance Imaging

by Martin Grashei, Christian Hundshammer, Frits H. A. van Heijster, Geoffrey J. Topping and Franz Schilling

Pharmaceuticals 2021, 14(4), 327; https://doi.org/10.3390/ph14040327 - 2 Apr 2021

Cited by 7 | Viewed by 3171

Abstract

Hyperpolarized ¹³C magnetic resonance imaging often uses spin-echo-based pulse sequences that are sensitive to the transverse relaxation time T₂. In this context, local T₂-changes might introduce a quantification bias to imaging biomarkers. Here, we investigated the pH dependence of the apparent transverse relaxation time constant (denoted here as T₂) of six ¹³C-labelled molecules. We obtained minimum and maximum T₂ values within pH 1–13 at 14.1 T: [1-¹³C]acetate (T_2,min = 2.1 s; T_2,max = 27.7 s), [1-¹³C]alanine (T_2,min = 0.6 s; T_2,max = 10.6 s), [1,4-¹³C₂]fumarate (T_2,min = 3.0 s; T_2,max = 18.9 s), [1-¹³C]lactate (T_2,min = 0.7 s; T_2,max = 12.6 s), [1-¹³C]pyruvate (T_2,min = 0.1 s; T_2,max = 18.7 s) and ¹³C-urea (T_2,min = 0.1 s; T_2,max = 0.1 s). At 7 T, T₂-variation in the physiological pH range (pH 6.8–7.8) was highest for [1-¹³C]pyruvate (ΔT₂ = 0.95 s/0.1pH) and [1-¹³C]acetate (ΔT₂ = 0.44 s/0.1pH). Concentration, salt concentration, and temperature alterations caused T₂ variations of up to 45.4% for [1-¹³C]acetate and 23.6% for [1-¹³C]pyruvate. For [1-¹³C]acetate, spatially resolved pH measurements using T₂-mapping were demonstrated with 1.6 pH units accuracy in vitro. A strong proton exchange-based pH dependence of T₂ suggests that pH alterations potentially influence signal strength for hyperpolarized ¹³C-acquisitions. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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15 pages, 2734 KiB

Open AccessArticle

Mapping of Absolute Host Concentration and Exchange Kinetics of Xenon Hyper-CEST MRI Agents

by Martin Kunth, Christopher Witte and Leif Schröder

Pharmaceuticals 2021, 14(2), 79; https://doi.org/10.3390/ph14020079 - 21 Jan 2021

Cited by 7 | Viewed by 2470

Abstract

Xenon magnetic resonance imaging (MRI) provides excellent sensitivity through the combination of spin hyperpolarization and chemical exchange saturation transfer (CEST). To this end, molecular hosts such as cryptophane-A or cucurbit[n]urils provide unique opportunities to design switchable MRI reporters. The concentration determination of such xenon binding sites in samples of unknown dilution remains, however, challenging. Contrary to ¹H CEST agents, an internal reference of a certain host (in this case, cryptophane-A) at micromolar concentration is already sufficient to resolve the entire exchange kinetics information, including an unknown host concentration and the xenon spin exchange rate. Fast echo planar imaging (EPI)-based Hyper-CEST MRI in combination with Bloch–McConnell analysis thus allows quantitative insights to compare the performance of different emerging ultra-sensitive MRI reporters. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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17 pages, 3408 KiB

Open AccessArticle

New Class of Efficient T₂ Magnetic Resonance Imaging Contrast Agent: Carbon-Coated Paramagnetic Dysprosium Oxide Nanoparticles

by Huan Yue, Ji Ae Park, Son Long Ho, Mohammad Yaseen Ahmad, Hyunsil Cha, Shuwen Liu, Tirusew Tegafaw, Shanti Marasini, Adibehalsadat Ghazanfari, Soyeon Kim, Kwon Seok Chae, Yongmin Chang and Gang Ho Lee

Pharmaceuticals 2020, 13(10), 312; https://doi.org/10.3390/ph13100312 - 15 Oct 2020

Cited by 10 | Viewed by 4119

Abstract

Nanoparticles are considered potential candidates for a new class of magnetic resonance imaging (MRI) contrast agents. Negative MRI contrast agents require high magnetic moments. However, if nanoparticles can exclusively induce transverse water proton spin relaxation with negligible induction of longitudinal water proton spin relaxation, they may provide negative contrast MR images despite having low magnetic moments, thus acting as an efficient T₂ MRI contrast agent. In this study, carbon-coated paramagnetic dysprosium oxide (DYO@C) nanoparticles (core = DYO = Dy_xO_y; shell = carbon) were synthesized to explore their potential as an efficient T₂ MRI contrast agent at 3.0 T MR field. Since the core DYO nanoparticles have an appreciable (but not high) magnetic moment that arises from fast 4f-electrons of Dy(III) (⁶H_15/2), the DYO@C nanoparticles exhibited an appreciable transverse water proton spin relaxivity (r₂) with a negligible longitudinal water proton spin relaxivity (r₁). Consequently, they acted as a very efficient T₂ MRI contrast agent, as proven from negative contrast enhancements seen in the in vivo T₂ MR images. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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14 pages, 1531 KiB

Open AccessArticle

A Photocleavable Contrast Agent for Light-Responsive MRI

by Friederike Reeßing, Sèvrin E. M. Huijsse, Rudi A. J. O. Dierckx, Ben L. Feringa, Ronald J.H. Borra and Wiktor Szymański

Pharmaceuticals 2020, 13(10), 296; https://doi.org/10.3390/ph13100296 - 8 Oct 2020

Cited by 3 | Viewed by 3979

Abstract

Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the modulation of magnetic resonance imaging (MRI) contrast agents’ relaxivity with the aim to increase the sensitivity, selectivity and amount of functional information obtained from this outstanding whole-body medical imaging technique. This approach requires the development of molecular contrast agents that show high relaxivity and strongly pronounced photo-responsiveness. To this end, we report here the design and synthesis of a light-activated MRI contrast agent, together with its evaluation using UV–vis spectroscopy, Fast Field Cycling (FFC) relaxometry and relaxometric measurements on clinical MRI scanners. The high relaxivity of the reported agent changes substantially upon irradiation with light, showing a 17% decrease in relaxivity at 0.23T upon irradiation with λ = 400 nm (violet) light for 60 min. On clinical MRI scanners (1.5T and 3.0T), irradiation leads to a decrease in relaxivity of 9% and 19% after 3 and 60 min, respectively. The molecular design presents an important blueprint for the development of light-activatable MRI contrast agents. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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11 pages, 2370 KiB

Open AccessArticle

A Second Generation Mn-Porphyrin Dimer with a Twisted Linker as a Potential Blood Pool Agent for MRI: Tuning the Geometry and Binding with HSA

by Hanlin Liu, Weiran Cheng, Shili Dong, David Feng Xu, Keith Tang and Xiao-an Zhang

Pharmaceuticals 2020, 13(10), 282; https://doi.org/10.3390/ph13100282 - 29 Sep 2020

Cited by 8 | Viewed by 2857

Abstract

Blood-pool agents (BPAs) are MRI contrast agents (CAs) characterized by their long circulation in the vascular system to provide an extended time window for high-resolution MR angiography (MRA). Prolonged vascular retention, however, impedes the excretion of BPAs. Therefore, chemical strategy to regulate the balance between retention and clearance is important to reach optimal pharmacokinetics. We recently developed MnP2, the first Mn(III)-porphyrin (MnP) based BPA. MnP2 shows high T₁ relaxivity (r₁) and high affinity to human serum albumin (HSA) that leads to up to 48-h vascular retention in rats. However, upon albumin binding, the r₁ is decreased. To modulate vascular retention time and plasma r₁, a regioisomer of MnP2, m-MnP2, was synthesized. The free m-MnP2 exhibits lower r₁ than that of MnP2 at magnetic fields above 2 MHz, which agrees with their relative hydrodynamic sizes. The HSA binding of m-MnP2 was evaluated using UV-Vis spectroscopy and found to have tuned-down affinity in comparison with MnP2. Upon HSA binding, the protein complex of m-MnP2 exhibits an r₁ of 11.8 mM⁻¹ s⁻¹ at 3 T, which is higher than that of MnP2 bound to HSA. Taken together, this demonstrated the role of molecular geometry in optimizing the pharmacokinetics of albumin-targeting BPAs. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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17 pages, 1929 KiB

Open AccessReview

Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation

by Chukwuazam Nwasike, Erin Purr, Eunsoo Yoo, Jaspreet Singh Nagi and Amber L. Doiron

Pharmaceuticals 2021, 14(1), 69; https://doi.org/10.3390/ph14010069 - 16 Jan 2021

Cited by 2 | Viewed by 2924

Abstract

The emergence of activatable magnetic resonance (MR) contrast agents has prompted significant interest in the detection of functional markers of diseases, resulting in the creation of a plethora of nanoprobes capable of detecting these biomarkers. These markers are commonly dysregulated in several chronic diseases, specifically select cancers and inflammatory diseases. Recently, the development of redox-sensitive nanoparticle-based contrast agents has gained momentum given advances in medicine linking several inflammatory diseases to redox imbalance. Researchers have pinpointed redox dysregulation as an opportunity to use activatable MR contrast agents to detect and stage several diseases as well as monitor the treatment of inflammatory diseases or conditions. These new classes of agents represent an advancement in the field of MR imaging as they elicit a response to stimuli, creating contrast while providing evidence of biomarker changes and commensurate disease state. Most redox-sensitive nanoparticle-based contrast agents are sensitive to reductive glutathione or oxidative reactive oxygen species. In this review, we will explore recent investigations into redox-activatable, nanoparticle-based MR contrast agent candidates. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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23 pages, 4177 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Repurposing Clinical Agents for Chemical Exchange Saturation Transfer Magnetic Resonance Imaging: Current Status and Future Perspectives

by Zelong Chen, Zheng Han and Guanshu Liu

Pharmaceuticals 2021, 14(1), 11; https://doi.org/10.3390/ph14010011 - 24 Dec 2020

Cited by 17 | Viewed by 4658

Abstract

Molecular imaging is becoming an indispensable tool to pursue precision medicine. However, quickly translating newly developed magnetic resonance imaging (MRI) agents into clinical use remains a formidable challenge. Recently, Chemical Exchange Saturation Transfer (CEST) MRI is emerging as an attractive approach with the capability of directly using low concentration, exchangeable protons-containing agents for generating quantitative MRI contrast. The ability to utilize diamagnetic compounds has been extensively exploited to detect many clinical compounds, such as FDA approved drugs, X-ray/CT contrast agents, nutrients, supplements, and biopolymers. The ability to directly off-label use clinical compounds permits CEST MRI to be rapidly translated to clinical settings. In this review, the current status of CEST MRI based on clinically available compounds will be briefly introduced. The advancements and limitations of these studies are reviewed in the context of their pre-clinical or clinical applications. Finally, future directions will be briefly discussed. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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29 pages, 6766 KiB

Open AccessReview

From Zn(II) to Cu(II) Detection by MRI Using Metal-Based Probes: Current Progress and Challenges

by Kyangwi P. Malikidogo, Harlei Martin and Célia S. Bonnet

Pharmaceuticals 2020, 13(12), 436; https://doi.org/10.3390/ph13120436 - 30 Nov 2020

Cited by 9 | Viewed by 5218

Abstract

Zinc and copper are essential cations involved in numerous biological processes, and variations in their concentrations can cause diseases such as neurodegenerative diseases, diabetes and cancers. Hence, detection and quantification of these cations are of utmost importance for the early diagnosis of disease. Magnetic resonance imaging (MRI) responsive contrast agents (mainly Lanthanide(+III) complexes), relying on a change in the state of the MRI active part upon interaction with the cation of interest, e.g., switch ON/OFF or vice versa, have been successfully utilized to detect Zn²⁺ and are now being developed to detect Cu²⁺. These paramagnetic probes mainly exploit the relaxation-based properties (T₁-based contrast agents), but also the paramagnetic induced hyperfine shift properties (paraCEST and parashift probes) of the contrast agents. The challenges encountered going from Zn²⁺ to Cu²⁺ detection will be stressed and discussed herein, mainly involving the selectivity of the probes for the cation to detect and their responsivity at physiologically relevant concentrations. Depending on the response mechanism, the use of fast-field cycling MRI seems promising to increase the detection field while keeping a good response. In vivo applications of cation responsive MRI probes are only in their infancy and the recent developments will be described, along with the associated quantification problems. In the case of relaxation agents, the presence of another method of local quantification, e.g., synchrotron X-Ray fluorescence, single-photon emission computed tomography (SPECT) or positron emission tomography (PET) techniques, or ¹⁹F MRI is required, each of which has its own advantages and disadvantages. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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17 pages, 2287 KiB

Open AccessReview

Imaging Tissue Physiology In Vivo by Use of Metal Ion-Responsive MRI Contrast Agents

by Pooyan Khalighinejad, Daniel Parrott and A. Dean Sherry

Pharmaceuticals 2020, 13(10), 268; https://doi.org/10.3390/ph13100268 - 24 Sep 2020

Cited by 11 | Viewed by 3567

Abstract

Paramagnetic metal ion complexes, mostly based on gadolinium (Gd³⁺), have been used for over 30 years as magnetic resonance imaging (MRI) contrast agents. Gd³⁺-based contrast agents have a strong influence on T₁ relaxation times and are consequently the most commonly used agents in both the clinical and research environments. Zinc is an essential element involved with over 3000 different cellular proteins, and disturbances in tissue levels of zinc have been linked to a wide range of pathologies, including Alzheimer’s disease, prostate cancer, and diabetes mellitus. MR contrast agents that respond to the presence of Zn²⁺ in vivo offer the possibility of imaging changes in Zn²⁺ levels in real-time with the superior spatial resolution offered by MRI. Such responsive agents, often referred to as smart agents, are typically composed of a paramagnetic metal ion with a ligand encapsulating it and one or more chelating units that selectively bind with the analyte of interest. Translation of these agents into clinical radiology is the next goal. In this review, we discuss Gd³⁺-based MR contrast agents that respond to a change in local Zn²⁺ concentration. Full article

(This article belongs to the Special Issue Next Generation of MRI Agents)

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