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

https://mriquestions.com/uploads/3/4/5/7/34572113/lauffer_1999_review.pdf

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

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.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

Impact of albumin on drug delivery--new applications on the horizon.

Magnetism in medicine has had a long and interesting history In the 10 th century AD, Egyptian physician and philosopher Avicenna prescribed a grain of magnetite dissolved in milk for the accidental swallowing of rust reasoning that magnetite would render the poisonous iron inert by attracting it and accelerating its excretion through the intestine1 A thousand years later on July 3, 1977, “Indomitable”, the little machine that could, labored for five hours to produce one image, an event that used magnetism to change the landscape of modern medicine 2 Looking at the homemade superconducting magnet constructed from 30 miles of niobiumtitanium wire that now resides in its rightful place at the Smithsonian Institution, it is incredible to comprehend how in a mere 30 years magnetic resonance imaging (MRI) has gone from its crude, almost ugly, human scan to where physicians can now regularly order MRIs off their menu of diagnostic tools because of its exquisite anatomical resolution, routinely down to 05 to 1 mm When the field was first reviewed in this journal in 1987, 3 only 39 papers were found in Medline with keywords “gado-“ and “MRI” 4 Today, this same search on PubMed pulls out over 250,000 records, of which a significant component has been development of MR contrast agents The human body is essentially a super-sized water bottle, with about two-thirds of its weight consisting of water Water's hydrogen atoms are able to act as microscopic compass needles that stand “at attention” when placed in a strong magnetic field When submitted to pulses of radio waves, their magnetic alignment is disrupted and the differences in how they relax to the previous state are used to generate images Contrast agents can act to catalyze the process of the return to the ground relaxed state Now commonplace in the clinic, paramagnetic or superparamagnetic metal ions are administered in 40–50% of the 7–10 million MR examinations per year 5 These image-enhancing contrast agents add significant morphological and functional information to unenhanced MR images, allowing for enhanced tissue contrast, characterization of lesions, and evaluation of perfusion and flow-related abnormalities In this review, we will introduce small molecule agents, but focus primarily on macromolecular MR contrast agents, particularly those containing gadolinium (Gd 3+ ) that are assembled or based in part on these same small molecules A brief discussion on iron oxide and manganese (Mn 2+ ) agents is also provided

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Macromolecules, Dendrimers, and Nanomaterials in Magnetic Resonance Imaging: The Interplay between Size, Function, and Pharmacokinetics

Background Molecular imaging of thrombus within fissures of vulnerable atherosclerotic plaques requires sensitive detection of a robust thrombus-specific contrast agent. In this study, we report the development and characterization of a novel ligand-targeted paramagnetic molecular imaging agent with high avidity for fibrin and the potential to sensitively detect active vulnerable plaques. Methods and Results The nanoparticles were formulated with 2.5 to 50 mol% Gd-DTPA-BOA, which corresponds to >50 000 Gd3+ atoms/particle. Paramagnetic nanoparticles were characterized in vitro and evaluated in vivo. In contradistinction to traditional blood-pool agents, T1 relaxation rate as a function of paramagnetic nanoparticle number was increased monotonically with Gd-DTPA concentration from 0.18 mL · s−1 · pmol−1 (10% Gd-DTPA nanoparticles) to 0.54 mL · s−1 · pmol−1 for the 40 mol% Gd-DTPA formulations. Fibrin clots targeted in vitro with paramagnetic nanoparticles presented a highly detectable, homogeneous T1-weigh...

Novel MRI Contrast Agent for Molecular Imaging of Fibrin Implications for Detecting Vulnerable Plaques

PURPOSE: To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents. MATERIALS AND METHODS: Protein binding in human plasma was measured by means of ultrafiltration. T1 relaxation times (20 MHz) were measured in human plasma or ex vivo samples from rabbits and monkeys injected with 0.1 mmol of MS-325 per kilogram of body weight. Imaging (three-dimensional fast imaging with steady-state precession, or FISP) was performed at 1.0 T in phantoms, which contained varying concentrations of different agents, or rabbits after injection of 0.015-0.100 mmol/kg MS-325. RESULTS: MS-325 is 80%-96% bound in human plasma and exhibits a relaxivity approximately six to 10 times that of gadolinium diethylenetriaminepentaacetic acid (DTPA). Images of phantoms containing MS-325 were significantly brighter than those conta...

MS-325: albumin-targeted contrast agent for MR angiography.

PURPOSE: To evaluate the imaging performance and patient tolerance of a blood-pool contrast agent (MS-325) for magnetic resonance (MR) angiography. MATERIALS AND METHODS: Imaging of peripheral and carotid vessels was performed in seven healthy volunteers in a phase I clinical trial of the gadolinium chelate MS-325. Each volunteer received an intravenous injection of 0.05 mmol/kg MS-325 over 30 seconds. Dynamic (arterial phase) and steady-state (arterial-venous phase) three-dimensional gradient-echo MR angiograms were acquired during, immediately after, and approximately 50 minutes after injection. Images were ranked (1 [poor] to 5 [excellent]) for overall image quality, and signal-to-noise ratio (S/N) and contrast-to-noise ratio (C/N) were measured by using standard techniques. RESULTS: All volunteers tolerated the procedure well. The MS-325-enhanced studies demonstrated intense vascular signal. Mean peripheral arterial C/N was 12.9 +/- 4.8 (standard deviation), 78.8 +/- 29.4, 46.1 +/- 10.9, and 41.9 +/- ...

R C Walovitch

Papers

MS-325: albumin-targeted contrast agent for MR angiography.

Steady-state and dynamic MR angiography with MS-325: initial experience in humans.