Bernd Radüchel

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.

Physicochemical Characterization of MS-325, a New Gadolinium Complex, by Multinuclear Relaxometry

The physicochemical characterization of MS-325 [trisodium {4-(R)-[(4,4-diphenylcyclohexyl)phosphanooxymethyl]-3,6,9-triaza-3,6,9-tris(methoxycarbonyl)undecanedioato}gadolinium(III)], a new derivative of Gd-DTPA {Magnevist®: dimeglumin [{3,6,9-triaza3,6,9-tris(methoxycarbonyl)undecanedioato}gadolinium(III)], presented as a potentially useful angiographic contrast agent, was carried out in various media. Water solution, protein-containing solution, phosphorylated metabolites solution, and Zn2+-containing solution were investigated using different NMR techniques such as water 1H nuclear magnetic relaxation rates, water 17O transverse relaxation rates, and 31P longitudinal relaxation rates of phosphorylated metabolites. The proton relaxivity of MS-325 in water was found to be higher than that of the parent compound Gd-DTPA; this can be attributed to the longer rotational correlation time (τR) of the hydrated complex, and possibly to an apparently shorter mean distance (r) between the protons of the coordinated water molecule and the gadolinium ion. The kinetic and thermodynamic stability of MS-325 in solutions containing phosphorylated metabolites (ATP, phosphocreatine and inorganic phosphate) were measured by 31P relaxation rate analysis and found to be higher than for Gd-DTPA. Similarly, the Zn2+ transmetallation process studied by proton relaxometry is slower than for the same reference compound. Finally, an analysis of the noncovalent binding of MS-325 to serum proteins by proton relaxometry showed that MS-325 interacts with human serum albumin (HSA) and that the association constant of this interaction is equal to 6100 ± 2130 M−1. A peak relaxivity of approx. 50 s−1mM−1 was determined at 25 MHz for the protein-bound paramagnetic complex. This value is lower than the maximal relaxivity predicted for a paramagnetic center totally immobilized at the surface of the protein.

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

Rationale and objectives: Differential diagnosis of malignant and benign 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 constrast 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.

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°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. J. Magn. Reson. Imaging 2000;11:694–701.

Stable 9ß- or 11α-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.

Chemistry of Stable Prostacyclin Analogues: Synthesis of Iloprost

The discovery of prostacyclin (PGI2) and its potent inhibitory action on platelet aggregation in 1976 by S. Moncada, R. Gryglewski, S. Bunting and J.R. Vane [1], has not only revolutionized concepts in cardiovascular research but has also made this important molecule a target for intensive biological and chemical research.

Comparative studies on the efficacy of MRI contrast agents in MRA

Values for the signal intensity (SI) of plasma samples spiked with different concentrations (0.005–25 mmol/L) of various paramagnetic agents (gadopentetate dimeglumine [Magnevist; Schering AG, Berlin, Germany]; gadoxetic acid [Eovist; Schering AG]; Gadomer-17 [Schering AG]; gadobenate dimeglumine [MultiHance; Bracco, Milan, Italy]; MS-325 [EPIX Medical, Cambridge, Mass); and the ultrasmall superparamagnetic iron oxide [USPIO], SH U 555C [Schering AG]) were measured at 1.5 T (Allegra; Siemens AG, Erlangen, Germany). A three-dimensional (3D) MRA sequence (4.7/1.89 [repetition time msec/echo time msec], 25° flip angle) was used. The SI values of the maximum intensity projections (MIP) were measured, and the apparent T1 and T2* relaxivities were calculated from the SI-versus-concentration curves using the known dependence of the SI from sequence parameters and relaxation times (1). MRA studies using a superconducting MR imager (Allegra; Siemens AG) were performed in rabbits after intravenous injection of two dose regimens. The contrast agents were injected after starting the imaging sequence to achieve optimum bolus concentrations during the k space of the sequence. Additional images were taken at 3, 10, and 30 minutes after dosing. A dose of 0.2 mmol/kg was used for all agents to allow a comparison of the various agents with the currently performed practice with extracellular gadolinium chelates (eg, Magnevist). A second dose was adjusted to the calculated T1 relaxivity of Magnevist in plasma.

Synthesis of prostacyclin analogs stabilized by acceptor substituents at the 5-position

The chemically labile natural prostacyclin (PGI2) 1 can be stabilized by introduction of an electron withdrawing 5-substituent like cyano, formyl, carboxy or alkoxycarbonyl resulting e.g. in 5-cyano-16-methyl-prostacyclin (nileprost) 6, a potent ulcer healing agent.

An approach to the synthesis of 5-azaprostacyclin

Abstract The synthesis of a biologically active 5-azaprostacyclin as well as some of its chemical properties are described.

A METHOD FOR THE INVERSION OF CONFIGURATION OF ALCOHOLS

SUMMARY 1 The displacement of sulfonate esters with nitrite ion is a useful and preparatively simple method for the inversion of hydroxy functions. 2 The method has turned out to be useful for the inversion of 9- and 11-hydroxy groups in the prostaglandin field. 3 Esters and acid sensitive protecting groups like tetrahydropyranyl ethers survive the reaction conditions.