First in vivo MRI assessment of a self‐assembled metallostar compound endowed with a remarkable high field relaxivity
TL;DR: These studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions.
Abstract: {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd3+ centers confined into a small mol. space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r1 = 15.8 mM-1 s-1 at 200 MHz, 37°C, in H2O). Here we report the first in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution expts. using the 153Sm-enriched compd. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small mol. wt. contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H2O)]- = GdDOTA). The metallostar was well tolerated by the animals at the concns. of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg-1 body wt.; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg-1 BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T1), as calcd. from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approx. four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate mol. wt., the metallostar does not function as a blood pool agent. The dynamic g scintigraphic studies performed in Wistar rats with the metallostar compd. having 153Sm enrichment also proved the renal elimination pathway. The biodistribution expts. are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.
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TL;DR: Two classes of lanthanide probes are focused on that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides.
Abstract: The chemistry of the less familiar elements is a fascinating topic especially for the inorganic minded. The lanthanides, or rare earths, comprise the 5d block of the periodic table and represent a huge array of applications from catalysis to lasers, and of course, imaging agents.1
Recent advances in luminescence and magnetic resonance microscopy have, in part, been stimulated by extraordinary success in the development of new lanthanide probes. The unique properties of the lanthanides provide for a deep tool chest for the chemist, biologist and the imaging scientist to exploit, and that exploitation is in full swing.
In this review we focus on two classes of lanthanide probes that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides. In Section 2 we discuss the general design and photophysical properties of lanthanides and how these parameters are tuned to develop bioresponsive probes for optical imaging. In Section 3 we provide a brief description of how MR images are acquired and the how MRI contrast agents are engineered to respond to biological events of interest. These guiding principles have driven research that has produced a truly diverse number of new agents that are target specific and bioresponsive (or bioactivatable). While other imaging modalities utilize lanthanide-based probes, these topics are beyond the scope of this review. We direct the reader to explore some excellent reviews in the important areas of radiometals and multimodal imaging.2–5
901 citations
TL;DR: This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety and efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives.
Abstract: Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.
817 citations
TL;DR: Challenges for CEST Agents and Hyperpolarized Probes: Use of Gd Contrast Agents with HyperPolarized Substances 3038.
Abstract: 3.3. Magnetic Particle Imaging 3029 4. Challenges for CEST Agents 3029 4.1. Technical Issues 3029 4.2. Chemical Issues 3031 4.3. Biological Issues 3032 5. Challenges for Heteronuclear MR Imaging 3033 5.1. F-Based Probes 3033 6. Challenges for Hyperpolarized Probes 3034 6.1. Brute Force 3034 6.2. Optical Pumping and Spin Exchange 3035 6.3. Dynamic Nuclear Polarization (DNP) 3035 6.4. para-Hydrogen Induced Polarization (PHIP) 3037 6.5. Use of Gd Contrast Agents with Hyperpolarized Substances 3038
714 citations
TL;DR: Classification includes composition, magnetic properties, biodistribution and imaging applications, which covers all types of MRI contrast agents including, among others, extracellular, blood pool, polymeric, particulate, responsive, oral, and organ specific.
Abstract: A comprehensive classification of contrast agents currently used or under development for magnetic resonance imaging (MRI) is presented. Agents based on small chelates, macromolecular systems, iron oxides and other nanosystems, as well as responsive, chemical exchange saturation transfer (CEST) and hyperpolarization agents are covered in order to discuss the various possibilities of using MRI as a molecular imaging technique. The classification includes composition, magnetic properties, biodistribution and imaging applications. Chemical compositions of various classes of MRI contrast agents are tabulated, and their magnetic status including diamagnetic, paramagnetic and superparamagnetic are outlined. Classification according to biodistribution covers all types of MRI contrast agents including, among others, extracellular, blood pool, polymeric, particulate, responsive, oral, and organ specific (hepatobiliary, RES, lymph nodes, bone marrow and brain). Various targeting strategies of molecular, macromolecular and particulate carriers are also illustrated.
506 citations
TL;DR: Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r(1) and transverse) relaxivity as a function of applied field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally.
Abstract: Simulations were performed to understand the relative contributions of molecular parameters to longitudinal (r(1)) and transverse (r(2)) relaxivity as a function of applied field, and to obtain theoretical relaxivity maxima over a range of fields to appreciate what relaxivities can be achieved experimentally. The field-dependent relaxivities of a panel of gadolinium and manganese complexes with different molecular parameters, water exchange rates, rotational correlation times, hydration state, etc. were measured to confirm that measured relaxivities were consistent with theory. The design tenets previously stressed for optimizing r(1) at low fields (very slow rotational motion; chelate immobilized by protein binding; optimized water exchange rate) do not apply at higher fields. At 1.5 T and higher fields, an intermediate rotational correlation time is desired (0.5-4 ns), while water exchange rate is not as critical to achieving a high r(1). For targeted applications it is recommended to tether a multimer of metal chelates to a protein-targeting group via a long flexible linker to decouple the slow motion of the protein from the water(s) bound to the metal ions. Per ion relaxivities of 80, 45, and 18 mM(-1) s(-1) at 1.5, 3 and 9.4 T, respectively, are feasible for Gd(3+) and Mn(2+) complexes.
455 citations
References
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TL;DR: A. Relaxivity 2331 E. Outerand Second-Sphere relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336.
Abstract: A. Water Exchange 2326 B. Proton Exchange 2327 C. Electronic Relaxation 2327 D. Relaxivity 2331 E. Outerand Second-Sphere Relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336 A. Introduction 2336 B. General Conjugation Methods 2336 C. Synthetic Linear Polymers 2336 D. Synthetic Dendrimer-Based Agents 2338 E. Naturally Occurring Polymers (Proteins, Polysaccharides, and Nucleic Acids) 2339
4,125 citations
"First in vivo MRI assessment of a s..." refers background or methods in this paper
...(1) A series of IR FLASH images (7) was acquired using the following parameters: flip angle a1⁄4 128, TE1⁄4 3....
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...Therefore, the experiments were also performed with the IR TrueFISP method which is in this respect superior to the IR FLASHmethod: (1) T2 effects are taken into account because the method also yields T2; (2) it has a higher accuracy for T1 determination than the IR FLASH method since 16 inversion delays are included instead of just one....
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...history of MRI, which was awarded the 2003 Nobel Prize for Physiology andMedicine, has been largely assisted by the concomitant development of MRI contrast agents (CA) (1)....
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TL;DR: It is shown that the ratio T1/T2 can be directly extracted from the inversion factor INV, which describes the relation of the signal value extrapolated to t = 0 and the steady‐state signal.
Abstract: A novel procedure is proposed to extract T1, T2, and relative spin density from the signal time course sampled with a series of TrueFISP images after spin inversion. Generally, the recovery of the magnetization during continuous TrueFISP imaging can be described in good approximation by a three parameter monoexponential function S(t) Sstst(1-INV exp(-t/T*). This apparent relaxation time T* ≤ T1 depends on the flip angle as well as on both T1 and T2. Here, it is shown that the ratio T1/T2 can be directly extracted from the inversion factor INV, which describes the relation of the signal value extrapolated to t 0 and the steady-state signal. Analytical expressions are given for the derivation of T1, T2, and relative spin density directly from the fit parameters. Phantom results show excellent agreement with single point reference measurements. In human volunteers T1, T2, and spin density maps in agreement with literature values were obtained. Magn Reson Med 51:661– 667, 2004.
256 citations
TL;DR: T1 values derived from inversion recovery TrueFISP were in excellent agreement with the single‐point method even for flip angles up to 50°, and the proposed method seems to be superior to the conventional inversion Recovery snapshot FLASH technique in terms of T1 accuracy and SNR.
Abstract: A snapshot FLASH sequence can be used to acquire the time course of longitudinal magnetization during its recovery after a single inversion pulse. However, excitation pulses disturb the exponential recovery of longitudinal magnetization and may produce systematic errors in T1 estimations. In this context the possibility of using the TrueFISP sequence to detect the recovery of longitudinal magnetization for quantitative T1 measurements was examined. Experiments were performed on different Gd-doped water phantoms and on humans. T1 values derived from inversion recovery TrueFISP were in excellent agreement with the single-point method even for flip angles up to 50°. In terms of T1 accuracy and SNR, the proposed method seems to be superior to the conventional inversion recovery snapshot FLASH technique. Magn Reson Med 45:720–723, 2001. © 2001 Wiley-Liss, Inc.
192 citations
"First in vivo MRI assessment of a s..." refers methods in this paper
...(2) A series of IR TrueFISP images (8) was acquired using following parameters: flip angle a1⁄4 308, TE1⁄4 1....
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TL;DR: The metallostar complex [Fe{Gd2L(H2O)4}3]4− displays exceptionally high proton relaxivity, which is explained in terms of a rigid supramolecular structure, two inner-sphere water molecules with a near-optimal exchange rate, and six efficiently relaxing GdIII centers confined to a small molecular space.
Abstract: Good things come in small packages: For its moderate molecular weight, the metallostar complex [Fe{Gd2L(H2O)4}3]4− (see picture; L is a bipyridine–poly(aminocarboxylate) derivative) displays exceptionally high proton relaxivity, which is explained in terms of a rigid supramolecular structure, two inner-sphere water molecules with a near-optimal exchange rate, and six efficiently relaxing GdIII centers confined to a small molecular space.
160 citations
"First in vivo MRI assessment of a s..." refers background in this paper
...The synthesis of the ligand H8bpy(DTTA)2 has been described in a previous communication (4)....
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...We have reported the synthesis (4) and physicochemical characterization (5) of a heterotritopic, bipyridine derivative poly(amino carboxylate) ligand which is capable of self-assembling with Gd and Fe into a rigid metallostar structure {Fe[Gd2bpy(DTTA)2(H2O)4]3} 4 (Fig....
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...Indeed, this compound represents the most concentrated paramagnetic relaxation effect among all Gd-based potential contrast agents ever reported (4)....
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TL;DR: This work describes snapshot FLASH MR using a single 180 degrees pulse prior to the acquisition of a series of FLASH images, which creates continuous dynamic inversion recovery (IR) T1 contrast in successive images.
Abstract: Snapshot fast low angle shot (FLASH) magnetic resonance (MR) imaging techniques have been developed to enable real time imaging of MR parameters. The method is based on a 64 x 128 FLASH tomogram acquired within less than 200 ms. This work describes snapshot FLASH MR using a single 180 degrees pulse prior to the acquisition of a series of FLASH images. The experiment creates continuous dynamic inversion recovery (IR) T1 contrast in successive images. The total acquisition time of 16 images displaying the IR behavior is less than 4 s. Representative snapshot FLASH IR MR images of the abdomen of healthy rats and of an implanted hepatic tumor are illustrated.
156 citations
"First in vivo MRI assessment of a s..." refers methods in this paper
...(1) A series of IR FLASH images (7) was acquired using the following parameters: flip angle a1⁄4 128, TE1⁄4 3....
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