Thomas Frenzel

Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent

Rationale and objectives: Gadomer-17 is a new magnetic resonance (MR) contrast medium presently in clinical development. It is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions. This study investigated the pharmacokinetic behavior of this contrast medium. Methods: The pharmacokinetics of Gadomer-17 were investigated in different species (rat, rabbit, dog, monkey) for up to 7 days after intravenous (i.v.) injection of 25–100 μmol/kg body weight. In addition, elimination and biodistribution were evaluated after single i.v. injection of Gadomer-17 in rats. Results: After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. The volume of distribution (Vc) in the initial or α-phase ranged from 0.04 1/kg (rats, rabbits) to 0.06 1 kg (monkeys) and 0.07 1/kg (dogs), which reflects mainly the plasma volume. The blood/plasma concentration profile was found to be biphasic. The volume of distribution at a steady state is clearly smaller than that of other contrast media, which distribute to the extracellular space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body, mainly via glomerular filtration. No long-term accumulation or retention of the nonmetabolized agent was detectable in organs or tissues. Conclusions: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.

Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting. Pre-clinical profile of SH U555A.

Rationale and objectives: To evaluate the physical and pharmacological profiles of SH U555A, a suspension of magnetic iron oxide particles that is designed to enhance the visualization of liver tumors and metastases. Material and Methods: Chemical and physical methods were used to characterize the size and structure of these magnetic iron oxide particles in aqueous solution. The biodistribution and pharmacokinetics of the particles were studied in mice, rats and dogs. The imaging efficacy of the particles was demonstrated by MR imaging in rat liver tumors Results: The SH U555A particles consist of low-molecular-weight carboxydextran-coated iron oxides predominantly of the γ-Fe2O3 form with a hydrodynamic diameter ranging from 57-59 nm and strong T2 relaxivity of 164 liters * mmol−1 * S−1 (water, 0.47 T). In rats the particles exhibited a dose-dependent half-life of between 2 and 3 days in the liver at a dose of 20 μmol Fe/kg and a shorter half-life at lower doses. No major side effects were found. In a rat tumor model the tumor-to-liver contrast was markedly improved after i.v. administration of SH U555A. At a dose of 14 μmol Fe/kg the half-maximal contrast-effect was obtained even in nonoptimized T1-weighted spin-echo images. Conclusion: SH U555A is a superparamagnetic MR contrast agent for i.v. administration and has substantial potential for the demarcation of liver tumors.

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.

Molecular imaging of tumor angiogenesis.

Abstract: Advances in imaging provide new insights into the pathophysiol‐ogy of many diseases. Established imaging technologies such as MRI, CT, PET, and ultrasound are routinely applied to determine features of tumor blood vessels that distinguish them from normal blood vessels. These techniques yield information on blood flow, blood volume, and vessel permeability. Often, an intravenously injected imaging contrast agent without affinity to a specific target structure is applied to enable detection of malignant lesions. One of the emerging innovations in diagnostic imaging is the evolution of molecular imaging techniques. Molecular imaging is a noninvasive approach to determine the expression of indicative marker molecules of the tumor angiogenesis process. Meanwhile, this approach has been established for all imaging modalities and may further improve sensitivity of diagnostic tumor imaging. Another goal is to provide information with respect to drug treatment monitoring and therapeutic vascular targeting strategies.

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.

Is absolute noninvasive temperature measurement by the Pr[MOE-DO3A] complex feasible

Recently, the feasibility of the praseodymium complex of 10-(2-methoxyethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetate (Pr[MOE-DO3A]) for non-invasive temperature measurement via1H spectroscopy has been demonstrated. Particularly the suitability of the complex for non-invasive temperature measurements including in vivo spectroscopy without spatial resolution as well as first spectroscopic imaging measurements at low temporal resolution (≥4 min) and high temporal resolution (breath hold, ∼20 s) has been shown. As of today, calibration curves according to the particular experimental conditions are necessary. This work aims to clarify whether the Pr[MOE-DO3A] probe in conjunction with1H-NMR spectroscopy allows non-invasive absolute temperature measurements with high accuracy. The measurement results from two different representative media, distilled water and human plasma, show a slight but significant dependence of the calibration curves on the surrounding medium. Calibration curves in water and plasma were derived for the temperature dependence of the chemical shift difference (F) between Pr[MOE-DO3A]s OCH3 and water withF=−(27.53±0.04)+(0.125±0.001)*T andF=−(27.61±0.02)+(0.129±0.001)*T. respectivel, withF in ppm andT in °C. However, the differences are minuscule even for the highest spectral resolution of 0.001 ppm/pt, so that they are indistinguishable under practical conditions. The estimated temperature errors are ±0.18°C for water and ±0.14°C for plasma and with that only slightly worse than the measurement accuracy of the fiber-optical temperature probe (±0.1°C). It can be concluded that the results obtained indicate the feasibility of the1H spectroscopy method in conjunction with the Pr[MOE-DO3A] probe for absolute temperature measurements, with a maximum accuracy of ±0.2°C.