A new polysaccharide macromolecular contrast agent for MR imaging: biodistribution and imaging characteristics.

The aims of this study were to characterize certain physicochemical, pharmacokinetic, and enhancement properties of a new macromolecular contrast agent, carboxymethyl hydroxyethyl starch-(Gd-DO3A)(35) [CMHES-(Gd-DO3A)(35)], consisting of a polysaccharide backbone covalently derivatized with multiple macrocyclic chelating groups for gadolinium. CMHES-(Gd-DO3A)(35) has an average molecular weight of 72 kD and a plasma half-time of 8.4 hours. T1 and T2 relaxivities are 14.1 +/- 0.1 L mmol(-1) * sec(-1) and 17.8 +/- 0.9 L mmol(-1) * sec(-1), respectively, for each gadolinium ion measured at 39 degrees C and 20 Mhz; this T1 relaxivity is more than 4 times that of gadopentetate. Seven days after intravenous administration only relatively small amounts of gadolinium could be detected in blood or other tissues of rats. The compound was well tolerated in diagnostic dosages by all experimental animals. Magnetic resonance angiography performed within 1 hour of CMHES-(Gd-DO3A)(35) administration showed a near-constant and strong enhancement of blood in arteries and veins. Analysis of dynamic enhancement patterns of experimental tumors (MAT-LyLu prostate cancer implanted in rats) following intravenous CMHES-(Gd-DO3A)(35) administration yielded quantitative estimates of tumor plasma volume and microvessel permeability; the demonstrated hyperpermeability of tumor microvessels was easily distinguished from the absence of measurable microvascular permeability in non-neoplastic soft tissues.

Gadofluorine 8: initial experience with a new contrast medium for interstitial MR lymphography.

RATIONALE AND OBJECTIVES: Differential diagnosis of malignant and beign lymph nodes is still a problem in lymphographic imaging modalities. Plain magnetic resonance imaging (MRI) and computed tomography (CT) are inadequate for detecting metastases in normal-sized lymph nodes and for differentiating enlarged nodes. Therefore it is important to have a contrast agent that accumulates in healthy lymphatic tissue but does not accumulate in metastatic deposits. METHODS: The lymphographic contrast agent Gadofluorine 8 (Schering AG, Berlin, Germany) is a lipophilic but water-soluble gadolinium complex. Lymphographic effects were investigated in guinea pigs, dogs, and tumor-bearing rabbits after interstitial (subcutaneous or intracutaneous) injection. MR imaging was performed using T1-weighted gradient-echo sequences until 120 min after administration. RESULTS: After interstitial injection Gadofluorine 8 accumulates in regional lymph nodes, resulting in a pronounced increase in signal intensity in the lymph nodes. Differentiation between normal and metastatic lymph nodes was achieved. CONCLUSIONS: Gadofluorine 8 is an innovative contrast agent that can distinguish between normal and tumorous lymph nodes in interstitial MR lymphography.

Synthesis and Physicochemical Characterization of a New Gadolinium Chelate: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA.

A convenient synthesis of disodium S-[4-(4-ethoxybenzyl)-3,6,9-tris[(carboxy-kappaO)methyl]-3,6,9-triazaundecandioato)(5-)-kappa(3)N(3)(),N(6)(),N(9)(),kappa(2)O(1)(),O(11)()]gadolinate(2-) (Gd-EOB-DTPA), 1, is reported. This water-soluble complex is presently undergoing phase III clinical trials as a liver-specific contrast agent for magnetic resonance imaging (MRI). The thermodynamic complex stability constant of 1 and the acid dissociation constants of the ligand have been determined as well as the stability constant of the calcium complex Ca-EOB-DTPA (2), which is used as an additive in the pharmaceutical formulation of the contrast agent. The solid-state structure of the ligand S-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid (H(5)EOB-DTPA), 3, has been elucidated in a single crystal X-ray diffraction study. Additionally, HPLC evidence is given that the enantiomerically pure ligand forms two diastereomeric gadolinium complexes in a 65:35 ratio. The kinetics of isomerization of the isolated diastereomers-as dependent on pH and temperature-has been investigated, and thus, the activation energy for the interconversion of these isomers has been estimated to be 75.3 kJ mol(-1). Finally, the structures of the two components of 1 are discussed in terms of four possible diastereomers.

Synthesis and Structure of a New Macrocyclic Polyhydroxylated Gadolinium Chelate Used as a Contrast Agent for Magnetic Resonance Imaging.

Three approaches to the synthesis of a new ligand 1,4,7-tris(carboxymethyl)-10-(1-(hydroxymethyl)-2,3-dihydroxypropyl)-1,4,7,10-tetraazacyclododecane (6) are described. This ligand forms the both thermodynamically and kinetically very stable gadolinium chelate Gadobutrol (1), which is a neutral and highly hydrophilic compound that is used for magnetic resonance imaging in the clinic. According to the crystal structure the Gd(III) ion in 1 is nine coordinated. The ligand provides eight coordination sites whereas the ninth coordination partner surprisingly is a carboxylate oxygen of a neighboring centrosymmetrically-related complex molecule. Ligand 6 was also utilized to prepare the calcium complex 12 which is used as an additive in the pharmaceutical formulation of 1. For the calcium complex 12, two complex molecules adopting almost identical conformations are present in the crystal.

Noninvasive temperature measurement in vivo using a temperature-sensitive lanthanide complex and 1H magnetic resonance spectroscopy.

A new lanthanide complex, praseodymium-2-methoxyethyl-DO3A, was tested as a temperature indicator for 1H magnetic resonance spectroscopy under in vivo conditions, using a 2-T imaging system. The chemical shift of the methoxy group of the compound is strongly temperature dependent. In vitro, a shift change of -0.131 ppm/degree C was found. The signal was shifted by about -24 ppm relative to the water signal, allowing easy water suppression and signal identification in vivo. The body temperatures of eight anesthetized rats were measured in the liver after intravenous administration of 1 mmol/kg of the praseodymium complex under different heating conditions of the animal. The temperatures calculated from the spectra were in good agreement (deviation < +/- 1 degree C) with values obtained simultaneously with a thermocouple placed in the rectum of the animals.

Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging.

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.

Characterization of a gadolinium-labeled cholesterol derivative as an organ-specific contrast agent for adrenal MR imaging.

The purpose of the study was to determine if derivatization of cholesterol with a paramagnetic label could result in an organ-specific contrast agent for magnetic resonance imaging of the adrenal glands. Gadolinium-DO3A-labeled cholesterol was synthesized and the relaxivities in water and blood plasma determined at 0.47 T and 40 degrees C. Organ distribution was measured at 2 (n = 2) and 24 (n = 2) hours after intravenous injection of a 50 mumol/kg dose of Gd-DO3A-cholesterol in rats weighing 220-240 g. T1-weighted spin-echo images were acquired at 2 T before and after injection of 50 mumol/kg Gd-DO3A-cholesterol (n = 2) and Gd-DTPA (diethylenetriaminepentaacetic acid)-albumin (n = 2). More than 99% of the Gd-DO3A-cholesterol was found to be protein bound in bovine serum. High T1 and T2 relaxivities were found in water and plasma. High tissue concentrations of Gd-DO3A-cholesterol were found only in adrenal glands and liver. At 24 hours, adrenal gadolinium concentrations were about 10 times higher than in blood. At 2 hours after injection of Gd-DO3A-cholesterol, enhancement was 162% in adrenal glands and 146% in liver. With Gd-DTPA-albumin, enhancement values were 57% and 56%, respectively.

Stable 9 beta- or 11 alpha-halogen-15-cyclohexyl-prostaglandins with high affinity to the PGD2-receptor.

Various chemically stable prostaglandin analogues were studied for their affinity towards the PGD2-receptor in human platelet membranes in order to define the requirements for specific ligand binding to this receptor. On replacing the 11- or 9-hydroxyl groups of PGF2 alpha by an 11 alpha- or 9 beta-chloro- or fluoro atom, stable prostaglandin analogues were obtained, which showed high affinity towards the PGD2-receptor. The lower side chain consisted of a 15-cyclohexyl group or of the natural 15-n-pentyl group, other substitutents decreased the affinity substantially. The highest PGD2-mimetic activity with a relative affinity of 0.5 to the PGD2-receptor was found in 9-deoxy-9 beta-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-PGF2 alpha (ZK 110 841, compound 16 in Table 1). ZK 110 841 is a chemically stable crystalline substance, which is orally active and which might thus turn out to be an interesting tool for the study of PGD2-receptor interactions. Some other prostaglandin as well as prostacyclin analogues with a 15-cyclohexyl or 15-n-pentyl group exhibited in addition to their known high affinity to the PGE2-receptor of human uterine membranes or the PGI2-receptor of human platelets also affinities to the PGD2-receptor. Generally, the receptor affinities correlate with the activities as stimulators of adenylate cyclase and inhibitors of thrombin induced elevation of cytoplasmic free calcium as well as their ability to inhibit ADP-induced platelet aggregation. The PGI2-character regarding the effector systems prevails in compounds with affinity to both the PGI2- and PGD2-receptor. Compounds which bind to the PGE2- and PGD2-receptor show a flat dose response curve regarding platelet activation suggesting a mixture of pro- and antiaggregatory properties within these molecules.

15,15-Ketals of natural prostaglandins and prostaglandin analogues. Synthesis and biological activities.

The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues. Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetranorprostaglandin F2alpha is a very active inducer of luteolysis in laboratory animals and cattle.