Gadolinium-based contrast agents (CAs) are widely used to enhance the contrast of images in magnetic resonance imaging procedures. Two categories of gadolinium chelates exist: the macrocyclic molecules where Gd3+ is caged in the pre-organized cavity of the ligand and the linear molecules. Gadolinium chelates differ in their thermodynamic stability constants and in their kinetic stability. In general, macrocyclic chelates such as Gd-DOTA or Gd-HP-DO3A are more stable than linear molecules. Even among linear agents, differences can be found. There is increasing evidence that transmetallation can be found in vivo, in the case of certain CAs (especially linear chelates), with body cations such as zinc, calcium or iron. Furthermore, analytical interference with colorimetric determination of calcium has been clinically evidenced with two linear chelates. Gd-DTPA-BMA and Gd-DTPA-BMEA. Clinical cases of spurious hypocalcaemia have been reported with these molecules. Such interference with some colorimetric assays for calcium is clinically relevant in that it can lead to unnecessary and potentially harmful treatment for hypocalcaemia.

AbstractGadolinium‐based contrast agents (CAs) are widely used to enhance the contrast of images in magnetic resonance imaging procedures. Two categories of gadolinium chelates exist: the macrocyclic molecules where Gd3+ is caged in the pre‐organized cavity of the ligand and the linear molecules. Gadolinium chelates differ in their thermodynamic stability constants and in their kinetic stability. In general, macrocyclic chelates such as Gd‐DOTA or Gd‐HP‐DO3A are more stable than linear molecules. Even among linear agents, differences can be found. There is increasing evidence that transmetallation can be found in vivo, in the case of certain CAs (especially linear chelates), with body cations such as zinc, calcium or iron. Furthermore, analytical interference with colorimetric determination of calcium has been clinically evidenced with two linear chelates, Gd‐DTPA‐BMA and Gd‐DTPA‐BMEA. Clinical cases of spurious hypocalcaemia have been reported with these molecules. Such interference with some colorimetric assays for calcium is clinically relevant in that it can lead to unnecessary and potentially harmful treatment for hypocalcaemia.

The sections in this article are Introduction Physicochemical Characteristics Physicochemical Properties of the Crystal Hydrodynamic Particle Size and Charge Pharmacology and Metabolism Role of Physicochemical Parameters Mechanism and Consequences of Interaction with Macrophages Pharmacokinetics Nanoparticle Vectorization Current Clinical Uses and Future Developments Gastrointestinal Tract Imaging Liver and Spleen Diseases Lymph Node Metastases Blood Pool Characteristics Characterization of the Atheromatous Plaque Other Potential Uses Stroke Cerebral Tumor Characterization Multiple Sclerosis Arthritis Infection Kidney Imaging Acute Cardiac Transplant Rejection In Vivo Monitoring of Cell Therapy T-staging of Uterine Neoplasms MRI-detectable Embolotherapy Conclusion

An original gadolinium chelate, termed P760, which diffuses through the vascular endotheliun but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm(3)) than that of gadolinium (Gd)-DOTA (0.38 nm(3)). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM(-1).s(-1) compared with 3.4 mM(-1).s(-1) for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (ie, glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties. (C) 2000 Wiley-Liss, Inc.

RATIONALE AND OBJECTIVES:In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties.METHODS:The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging.RESULTS AND CONCLUSION:Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

Macromolecular conjugates of Gd3+-diethylenetriaminepentaacetic acid with dextran were synthesized from dextran 40 (about 40 kg/mol). Diethylenetriaminepentaacetic acid (DTPA) was coupled to aminated dextran by means of a watersoluble carbodiimide and macromolecular conjugates containing DTPA ratios as high as 1.25 mmol/g of polymer were obtained. First, it was found that the polymer had a favourable influence on relaxivity, as at 20 MHz, the r1 longitudinal relaxivity of the Gd3+-complexed macromolecular conjugates was 2 to 4 times as great as that of free GdDTPA2−, depending on the DTPA content. Second, r1 greatly increased with the increase in the conjugate DTPA content, from 7.4 to 15.9 mM−1s−1 for an increase in the DTPA content from 0.36 to 0.96 mmol/g. Further increase in the ligand content had no more effect on relaxivity.

Macromolecular conjugates of dextran 40 (Mn = 38 kg/mol, Mw = 43 kg/mol) and diethylenetriaminepentaacetic acid (DTPA), capable of complexing Gd3+, were synthesized in order to obtain contrast agents for nuclear magnetic resonance imaging, with long intravascular persistence. As already reported, relaxivity of these macromolecular complexes was greater than that of molecular complexes (2-2.5 times). On the other hand, as relaxivity of paramagnetic agents partially depends on their rotation speed, the influence of the length of the spacer arm inserted between DTPA and dextran was investigated. Various conjugates with spacer arms comprised of methylenic chains (-(CH2)n-) with varying lengths (2 < or = n < or = 6) were prepared. The result was that, whatever the distance between DTPA and dextran, all of the Gd(3+)-complexed polymeric conjugates with similar DTPA content (0.6-0.8 mmol/g) exhibited, at 20 MHz, about the same relaxivity values. On the other hand, in the same way, no significant effect of the molecular masses (Mn between 166 and 224 kg/mol and Mw between 332 and 865 kg/mol) of the polymeric conjugates on relaxivity were observed. Toxicity studies carried out on mice, showed very similar LD50 values whatever the spacer arm and molecular mass of the macromolecular conjugates. Finally the urinary excretion studied on rats (after 4 h) and on rabbits (after 24 h) was relatively low (15-20% of the administered dose), and, as expected, the lower values were obtained with the higher molecular mass conjugates.

Several studies were undertaken to compare four magnetic resonance imaging (MRI) contrast media (CM) as regards acute haemodynamic effects in rats and to investigate the mechanisms involved. (1) Normotensive rats received a rapid bolus intravenous injection of 0.5 mmol kg of each CM. The effects of Gd-DOTA, Gd-HP-DO3A, Gd-DTPA and Gd-DTPA-BMA on blood pressure (BP) were compared. (2) The haemo-dynamic effects of Gd-DTPA (0.5 mmol kg ) were compared to those of isovolumic and isoosmolar Zn-DTPA and glucose solutions. (3) The haemodynamic profiles of Gd-DTPA and Gd-DTPA-BMA were recorded with and without addition of ionized calcium. (4) The mechanism of Gd-HP-DO3A-induced tran-sient rise in BP was investigated by evaluating the effects of phentolamine or diltiazem pretreatment. For (1) the greatest drop in BP occurred following Gd-DTPA (a linear chelate) injection (–18 ± 2% vs base-line, P < 0.01). Gd-DTPA-BMA, another lineate chelate, also induced a slight but significant reduction in BP (–8 ± 2% at 45 s, P < 0.05). Gd-DOTA, a macrocyclic CM, had virtually no haemodynamic effects. For (2) the Gd-DTPA-induced drop in BP was greater than that of the osmolality-matched glucose control and lower than that of osmolality-matched Zn-DTPA. For (3) a transmetallation phenomenon versus free ionized calcium is possible in the case of both linear CM (Gd-DTPA and Gd-DTPA-BMA) since Ca significantly reduced the CM-induced decrease in BP. For (4) a transient rise in BP was observed following Gd-HP-DO3A, another macrocyclic chelate, associated with a concomitant increase in stroke volume. This effect was antagonized neither by phentolamine nor by diltiazem. The decrease in BP following injection of Gd-DTPA or Gd-DTPA-BMA may not only be osmolality-related since (a) Gd-DOTA solution, whose osmo-lality is greater than that of Gd-DTPA-BMA, had a lesser effect, and (b) this hypotensive effect was corrected by addition of ionized calcium. The transient Gd-HP-DO3A-induced rise in BP is probably the consequence of a positive inotropic effect. © Rapid Science 1998

Macromolecular conjugates of dextran and diethylenetriaminepentaacetic acid (DTPA), aimed to complex gadolinium, were synthesized to obtain contrast agents for nuclear magnetic resonance imaging with good paramagnetic properties and long intravascular persistence. These conjugates were prepared from dextran 40 (Mn = 38 kg/mol and Mw = 43 kg/mol), which was first carboxymethylated. Then amines were introduced by reacting ethylenediamine with dextran carboxylic acid groups in the presence of 2-ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline. DTPA was then covalently linked to aminated dextran by using three different coupling procedures (DTPA bisanhydride, dicyclohexylcarbodiimide/N-hydroxysuccinimide, and isobutyl chloroformate). The different final products were compared in terms of DTPA contents, molecular masses, and sizes, and it was proved that the last synthesis step led to a small fraction of cross-linked chains as Mn was between 128 and 166 kg/mol and Mw between 332 and 371 kg/mol. In spite of this partial cross-linking which theoretically decreases the complexation capacity of the dextran-linked DTPA molecules, the Gd(3+)-complexed conjugates exhibited relaxivities at 20 MHz/mol of gadolinium-2.5 times as great as that of free GdDTPA2-.

PURPOSE:We investigated the synthesis and physical, chemical and biological characterisation of a carboxymethyl-dextran polymer substituted with the paramagnetic macrocyclic complex Gd-DOTA using an amino spacer.MATERIAL AND METHODS:The product was synthesised in 4 steps. Using rigorous purification conditions in each step, a polymer was obtained, i.e. CMD-A2-Gd-DOTA, whose polydispersity profile was comparable to the initial dextran (I = 1.66-Mw = 50.5 kDa). Approximately 22% of the glucose groups were replaced by Gd-DOTA and 39% were replaced by carboxyl groups. The paramagnetic efficacy of the polymer was 3 times higher than Gd-DOTA alone, which suggests that the injected doses of Gd(III) can be reduced. The vascular residence time of the polymer was measured in rats and rabbits, showing that the pharmacokinetics of the product is similar whatever the dose. Forty-five percent of the product was excreted in urine after 24 h and 1.64% was found in the liver. No acute toxicity was observed at the maximum dose injected (> 5 mmol Gd/kg) and the general biocompatibility of the product tested in vitro was comparable to that of Gd-DOTA.RESULTS AND CONCLUSION:These results show the advantages of using paramagnetic macrocyclic complexes in the synthesis of macromolecules to preserve biological stability, in contrast with linear chelates. Additional studies will be carried out to demonstrate the benefits of this type of product, particularly in functional imaging.

Meyer D, Schaefer M, Chambon C, Beaute S. Paramagnetic Dextrans as magnetic resonance blood pool tracers. Invest Radio] 1994;29:S90–S92.