Albumin binding, relaxivity, and water exchange kinetics of the diastereoisomers of MS-325, a gadolinium(III)-based magnetic resonance angiography contrast agent.

The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 consists of two slowly interconverting diastereoisomers, A and B (65:35 ratio), which can be isolated at pH > 8.5 (TyeklAr, Z.

Structural, kinetic, and thermodynamic characterization of the interconverting isomers of MS-325, a gadolinium(III)-based magnetic resonance angiography contrast agent.

The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 comprises a GdDTPA core with an appended phosphodiester moiety linked to a diphenylcyclohexyl group to facilitate noncovalent binding to serum albumin and extension of the plasma half-life in vivo. The chiral DTPA ligand (R) was derived from L-serine, and upon complexation with gadolinium, forms two interconvertible diastereomers, denoted herein as isomers A and B.

Fibrin-targeted contrast agent for improvement of in vivo acute thrombus detection with magnetic resonance imaging.

Objective: Plaque rupture leading to thrombosis and occlusion is a major source of acute coronary syndromes. Methods for accurate detection of thrombosis in veins or arteries may expand our capacity to predict clinical complications and guide therapeutic decisions. We sought to demonstrate the feasibility of in vivo acute thrombus detection using a fibrin-targeted gadolinium based magnetic resonance contrast agent (EP-1242).

When are two waters worse than one? Doubling the hydration number of a Gd-DTPA derivative decreases relaxivity.

The synthesis of a novel ligand, based on N-methyl-diethylenetriaminetetraacetate and containing a diphenylcyclohexyl serum albumin binding group (L1) is described and the coordination chemistry and biophysical properties of its Gd(III) complex Gd-L1 are reported. The Gd(III) complex of the diethylenetriaminepentaacetate analogue of the ligand described here (L2) is the MRI contrast agent MS-325. The effect of converting an acetate to a methyl group on metal-ligand stability, hydration number, water-exchange rate, relaxivity, and binding to the protein human serum albumin (HSA) is explored.

In vivo magnetic resonance imaging of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent.

Background: The advent of fibrin-binding molecular magnetic resonance (MR) contrast agents and advances in coronary MRI techniques offers the potential for direct imaging of coronary thrombosis. We tested the feasibility of this approach using a gadolinium (Gd)-based fibrin-binding contrast agent, EP-2104R (EPIX Medical Inc), in a swine model of coronary thrombus and in-stent thrombosis.

Methods And Results: Ex vivo and in vivo sensitivity of coronary MR thrombus imaging was tested by use of intracoronarily delivered Gd-DTPA-labeled fibrinogen thrombi (n=6).

Interstitial MR lymphography with MS-325: characterization of normal and tumor-invaded lymph nodes in a rabbit model.

Objective: The aim of our study was to evaluate the performance of a new blood-pool contrast agent, MS-325, in depicting regional lymph nodes when injected interstitially and in allowing the subsequent classification of the lymph nodes as normal or tumor-bearing (VX2 tumor).

Materials And Methods: Six New Zealand white rabbits underwent adapted fast three-dimensional (3D) MR imaging before implantation of VX2 tumor cells in the flank and again 3 weeks after the implantation. For each imaging session, 0.

The effect of a phosphodiester linking group on albumin binding, blood half-life, and relaxivity of intravascular diethylenetriaminepentaacetato aquo gadolinium(III) MRI contrast agents.

Amphiphilic gadolinium complexes were investigated as potential magnetic resonance imaging (MRI) contrast agents. A series of complexes was synthesized in order to study the effect of hydrophilic phosphodiester groups on albumin binding, relaxivity, and blood half-life in rats. Thus, compound 11a, a diethylenetriaminepentaacetato aquo gadolinium(III) (Gd-DTPA) derivative with an octyl substituent, was synthesized and compared to 5b, the analogous octyl derivative containing a phosphodiester linkage between the gadolinium chelate and the alkyl chain.

Contrast-enhanced magnetic resonance imaging (MS-325) in a murine model of systemic lupus erythematosus.

Rationale And Objectives: To investigate whether inflammatory activity can be evaluated by MRI with an intravascular compound (MS-325) in Desoxyribonuclease I (Dnase1)-deficient mice, which show classical symptoms of systemic lupus erythematosus.

Methods: Dnase1-deficient and normal mice (both groups n = 10) underwent MRI with a body weight adapted dose of MS-325 on a 1.5 T whole body scanner equipped with a dedicated surface coil.

The interaction of MS-325 with human serum albumin and its effect on proton relaxation rates.

MS-325 is a novel blood pool contrast agent for magnetic resonance imaging currently undergoing clinical trials to assess blockage in arteries. MS-325 functions by binding to human serum albumin (HSA) in plasma. Binding to HSA serves to prolong plasma half-life, retain the agent in the blood pool, and increase the relaxation rate of water protons in plasma.

Enzyme-Activated Gd Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement.

Clinically relevant relaxivity enhancement of a magnetic resonance imaging (MRI) contrast agent has been achieved by using prodrug Gd complexes (see picture, DTPA=diethylenetriaminepentaaceto). Enzymatic cleavage of lysine residues from the prodrug exposes a group that has a high affinity to human serum albumin and promotes enhanced relaxivity, thus enabling the detection of targets at submicromolar concentrations.

Magnetic resonance angiography at 0.3 T using MS-325.

Preliminary results on MS-325 versus ProHance enhanced magnetic resonance angiography (MRA) at low field strength in a rabbit model are reported. MS-325-enhanced images were acquired in vivo and compared with pre-contrast as well as conventional contrast-enhanced images. Visual image quality observations correlated with measurements of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR).

Blood pool agent strongly improves 3D magnetic resonance coronary angiography using an inversion pre-pulse.

The ability of a blood pool contrast agent to enhance MR coronary angiography was defined. The proximal coronary vessels of pigs were imaged before and after administration of Gd-DTPA bound covalently to bovine serum albumin (0.2 mmol/ kg).

Three-dimensional MRI of coronary arteries using an intravascular contrast agent.

To assess the effectiveness of an intravascular contrast agent, MS-325, for enhancing the vascular signal in coronary MR angiograms, six minipigs were studied using a three-dimensional, gradient-echo sequence with retrospective respiratory gating. To suppress the myocardial signal, preparatory RF pulses were applied before data acquisition. With the administration of MS-325, the blood signal-to-noise ratio increased by 97-276%, depending on the region of interest in which the blood signal was measured and the precontrast imaging sequence structures.

MS-325: albumin-targeted contrast agent for MR angiography.

Purpose: To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents.

Materials And Methods: Protein binding in human plasma was measured by means of ultrafiltration. T1 relaxation times (20 MHz) were measured in human plasma or ex vivo samples from rabbits and monkeys injected with 0.

Preclinical evaluation of the pharmacokinetics, biodistribution, and elimination of MS-325, a blood pool agent for magnetic resonance imaging.

Rationale And Objectives: The authors evaluate MS-325, a new albumin-targeted magnetic resonance imaging (MRI) contrast agent, for its pharmacokinetics, biodistribution, and elimination characteristics in multiple animal species.

Methods: Studies were performed in rats, rabbits, and nonhuman primates at intravenous doses ranging from 0.025 to 0.

Intravascular contrast agent improves magnetic resonance angiography of carotid arteries in minipigs.

This study was designed to optimize three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) sequences and to determine whether contrast-enhanced MRA could improve the accuracy of lumen definition in stenosed carotid arteries of minipigs. 3D TOF MRA was acquired with use of either an intravascular (n = 13) and/or an extravascular contrast agent (n = 5) administrated at 2 to 4 weeks after balloon-induced injury to a carotid artery in 16 minipigs. Vascular contrast, defined as signal intensity differences between blood vessels and muscle normalized to the signal intensity of muscle, was compared before and after the injection of each contrast agent and between the two agents.

Detection and characterization of primary liver cancer in rats by MS-264-enhanced MRI.

A new MR contrast agent, MS-264 (Gd(1RS)-1-(p-butylbenzyl)-DTPA), was developed to achieve hepatobiliary specificity and its potential evaluated for detecting and characterizing liver tumors in rats with chemically induced hepatocellular carcinoma (HCC). In seven rats with 66 HCC lesions, enhancements of different abdominal organs and tumors were compared on T1-weighted images after intravenous administration of Gd-DTPA (0.3 mmol/kg) and MS-264 (0.

Targeted relaxation enhancement agents for MRI.

The design, relative merits, and initial applications of targeted relaxation enhancement agents, a new form of MRI contrast media, are briefly discussed. These agents are designed to bind reversibly to target macromolecules in a tissue of interest, thus enhancing water proton relaxation efficiency and MRI contrast. Initial applications for targeted agents include blood pool and hepatobiliary imaging.

Iron stores and the international variation in mortality from coronary artery disease.

Possible roles for iron in coronary artery disease (CAD) have emerged, including contributions to atherogenesis and/or the vulnerability of the myocardium to ischemia/reperfusion events. The value of hepatic storage iron as a potential risk factor for CAD was evaluated independently and in combination with various lipoprotein indices using CAD mortality data from 11 countries along with available data on liver iron stores. CAD mortality rates were found to be best correlated with the liver iron-serum cholesterol product in both men (r = 0.

Exercise as prevention: do the health benefits derive in part from lower iron levels?

The mechanism by which exercise, a key component of modern preventative medicine, protects man from strikingly different diseases such as heart disease and cancer, is largely a mystery. It is proposed that exercise-induced reductions in iron levels, either through iron loss or enhanced iron storage, could be responsible for some of the beneficial effects. Possible roles for iron in coronary artery disease and cancer have recently emerged, particularly as a catalyst for oxygen free radical-induced tissue damage.