Michel Schaefer

Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review

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.

Physical, chemical, and biological evaluations of P760: a new gadolinium complex characterized by a low rate of interstitial diffusion.

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium 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 nm3) than that of gadolinium (Gd)‐DOTA (0.38 nm3). 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°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. J. Magn. Reson. Imaging 2000;11:182–191.

P760 and P775: MRI contrast agents characterized by new pharmacokinetic properties.

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.

Gd-DOTA, a potential MRI contrast agent. Current status of physicochemical knowledge.

Meyer D, Schaefer M, Bonnemain B. Gd‐DOTA, a potential MRI contrast agent: current status of physicochemical knowledge. Invest Radiol 1988;23(Suppl 1):S232‐S235. The complex (Gd‐DOTA) meglumine has recently been used as an MRI contrast agent in humans. Due to its particularly interesting physicochemical properties, the risk of in vivo dissociation of the complex is reduced. Indeed, as a result of the macrocyclic nature of the DOTA ligand, Gd‐DOTA appears very stable, demonstrating a calculated conditional stability constant of 1022.19 at pH = 7. Other characteristics making Gd‐DOTA a positively attractive compound include slow dissociation kinetics inherent in the rigidity of the macrocycle and marked specific affinity of DOTA for gadolinium in comparison with other endogenous ions. Finally, although the relaxivity R1 of Gd‐DOTA at 20 MHz appears similar to that of Gd‐DTPA, Gd‐DOTA demonstrates higher paramagnetic efficacy at low field strength due to greater symmetry of the complex. Such promising properties open up wide prospects for the use of Gd‐DOTA in MRI.

Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation

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.

Macromolecular contrast agents for magnetic resonance imaging: Influence of polymer content in ligand on the paramagnetic properties

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.