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

We have developed a new class of magnetic resonance imaging contrast agents with large proton relaxation enhancements and high molecular relaxivities. The reagents are built from the polyamidoamine form of Starburst dendrimers in which free amines have been conjugated to the chelator 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid. The dendrimer gadolinium poly-chelates have enhancement factors, i.e., the ratio of the relaxivity per Gd(III) ion to that of Gd(III)-diethylenetriaminepentaacetic acid, of up to 6. These factors are more than twice those observed for analogous metal-chelate conjugates formed with serum albumins, polylysine, or dextran. One of the dendrimer-metal chelate conjugates has 170 gadolinium ions bound, which greatly exceeds the number bound to other macromolecular agents reported in the literature, and has a molecular relaxivity of 5,800 (mM.s)-1, at 25 MHz, 20 degrees C, and pH of 7.4. We observed that these dendrimer-based agents enhance conventional MR images and 3D time of flight MR angiograms, and that those with molecular weights of 8,508 and 139,000 g/mole have enhancement half lives of 40 +/- 10 and 200 +/- 100 min, much longer than the 24 +/- 4 min measured for Gd(III)-diethylenetriaminepentaacetic acid. Our results suggest that this new and powerful class of contrast agents have the potential for diverse and extensive application in MR imaging.

Dendrimer‐based metal chelates: A new class of magnetic resonance imaging contrast agents

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

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.

Classification and basic properties of contrast agents for magnetic resonance imaging

Lanthanide induced shifts and relaxation rate enhancements

Preparation and characterization of paramagnetic polychelates and their protein conjugates.

There are provided polychelants and their metal chelates which are useful in diagnostic imaging and in radiotherapy and which comprise a plurality of macrocyclic chelant moieties, e.g, DOTA residues, conjugated to a polyamine backbone molecule, e.g, polylysine. To produce a site-specific polychelate, one or more of the macrocyclic chelant carrying backbone molecules may be conjugated to a site-directed macromolecule, e.g. a protein.

Polychelants containing macrocyclic chelant moieties

There are provided polychelants and their metal chelates which are useful in diagnostic imaging and in radiotherapy and which comprise a plurality of macrocyclic chelant moieties, e.g. DOTA residues, conjugated to a polyamine backbone molecule, e.g. polylysine. To produce a site-specific polychelate, one or more of the macrocyclic chelant carrying backbone molecules may be conjugated to a site-directed macromolecule, e.g. a protein. For example, adducts of a macrocyclic chelant can be formed by the process of (a) dispersing a carboxylic macrocyclic chelant in a polar, anhydrous solvent, (b) adding a base with a pKa sufficient to remove all carboxyl protons to create an amine salt of the chelant soluble in the solvent, (c) chilling the reaction mixture to between about 5° C. and 55° C. above the freezing point of the solvent, and (d) adding substantial equimolar amount of chilled alkylhaloformate under anhydrous conditions so as to form a slurry containing the mixture carboxycarbonic anhydride of the chelant.

Adducts of macrocyclic chelants

An experimental rationale is provided to differentiate between the terms ionic and nonionic for magnetic resonance (MR) imaging contrast media such as gadodiamide and gadopentetate dimeglumine. Four independent types of physical measurements (electric conductivity, osmolality, electrophoresis, and ion exchange) were performed on a range of test compounds, including D-glucose, iohexol, gadopentetate dimeglumine, and gadodiamide. Iohexol, D-glucose, and gadodiamide are shown to be nonionic species at physiologic pH (7.4), not measurably dissociating in solution. A range of gadopentetate salts behave as electrolytes, dissociating into constituent charged ions in aqueous media. Operational definitions for the terms ionic and nonionic are provided, and the terms neutral and net zero charge are compared with nonionic for accuracy. The nomenclature nonionic and ionic is deemed appropriate for differentiating MR imaging contrast media.

Paul F. Sieving

Papers

Preparation and characterization of paramagnetic polychelates and their protein conjugates.

Polychelants containing macrocyclic chelant moieties

Adducts of macrocyclic chelants

Ionic versus nonionic MR imaging contrast media: operational definitions.