We have developed a new class of magnetic resonance imaging contrast agents with large proton relaxation enhancements and high molecular relaxivities. The reagents are built from the polyamidoamine form of Starburst dendrimers in which free amines have been conjugated to the chelator 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid. The dendrimer gadolinium poly-chelates have enhancement factors, i.e., the ratio of the relaxivity per Gd(III) ion to that of Gd(III)-diethylenetriaminepentaacetic acid, of up to 6. These factors are more than twice those observed for analogous metal-chelate conjugates formed with serum albumins, polylysine, or dextran. One of the dendrimer-metal chelate conjugates has 170 gadolinium ions bound, which greatly exceeds the number bound to other macromolecular agents reported in the literature, and has a molecular relaxivity of 5,800 (mM.s)-1, at 25 MHz, 20 degrees C, and pH of 7.4. We observed that these dendrimer-based agents enhance conventional MR images and 3D time of flight MR angiograms, and that those with molecular weights of 8,508 and 139,000 g/mole have enhancement half lives of 40 +/- 10 and 200 +/- 100 min, much longer than the 24 +/- 4 min measured for Gd(III)-diethylenetriaminepentaacetic acid. Our results suggest that this new and powerful class of contrast agents have the potential for diverse and extensive application in MR imaging.

Dendrimer‐based metal chelates: A new class of magnetic resonance imaging contrast agents

Field-Cycling NMR Relaxometry

The properties of water in biological systems have been studied for well over a century by a wide range of physical techniques, but progress has been slow and erratic. Protein hydration--the perturbation of water structure and dynamics by the protein surface--has been a particularly rich source of controversy and confusion. Our aim here is to critically examine central concepts in the description of protein hydration, and to assess the experimental basis for the current view of protein hydration, with the focus on dynamic aspects. Recent oxygen-17 magnetic relaxation dispersion (MRD) experiments have shown that the vast majority of water molecules in the protein hydration layer suffer a mere twofold dynamic retardation compared with bulk water. The high mobility of hydration water ensures that all thermally activated processes at the protein-water interface, such as binding, recognition and catalysis, can proceed at high rates. The MRD-derived picture of a highly mobile hydration layer is consistent with recent molecular dynamics simulations, but is incompatible with results deduced from intermolecular nuclear Overhauser effect spectroscopy, dielectric relaxation and fluorescence spectroscopy. It is also inconsistent with the common view of hydration effects on protein hydrodynamics. Here, we show how these discrepancies can be resolved.

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Protein hydration dynamics in solution: a critical survey

The properties of water in biological systems have been studied for well over a century by a wide range of physical techniques, but progress has been slow and erratic. Protein hydration-the perturbation of water structureand dynamics by the protein surface-has been a particularly rich source of controversy and confusion. Our aim here is to critically examine central concepts in the description of protein hydration, and to assess the experimental basis for the current view of protein hydration, with the focus on dynamic aspects. Recent oxygen-17 magnetic relaxation dispersion (MRD) experiments have shown that the vast majority of water molecules in the protein hydration layer suffer a mere twofold dynamic retardation compared with bulk water. The high mobility of hydration water ensures that all thermally activated processes at the protein-water interface, such as binding, recognition and catalysis, can proceed at high rates. The MRD-derived picture of a highly mobile hydration layer is consistent with recent molecular dynamics simulations, but is incompatible with results deduced from intermolecular nuclear Overhauser effect spectroscopy, dielectric relaxation and fluorescence spectroscopy. It is also inconsistent with the common view of hydration effects on protein hydrodynamics. Here, we show how these discrepancies can be resolved.

Protein hydration dynamics in solution: a critical survey - Discussion

NMR field-cycling spectroscopy: principles and a]lications

Power supplies used in field‐cycling nuclear resonance experiments are described. These are used to switch an air coil from high field to low field as rapidly as possible, then back to high field after a short time. This sequence must be repeated every few seconds or minutes. An example of a simple regulator is described, and methods of output switching with relays are discussed. A circuit is described which delivers up to 10 kG (15 A) in a 2.6 cm i.d. superconducting coil with a switching speed of 5×105 G/sec and an accuracy probably as great as 1 G. Speed is achieved by automatic connection, during up or down switching, of energy storage capacitors across the magnet, operating at much higher voltage than the steady‐state voltage level across the magnet and pass transistors.

Precision High Speed Current Regulators for Occasionally Switched Inductive Loads

Moderately high resolution NMR of rare spins in solids is described, using a modified Hartmann–Hahn double resonance experiment Resolution is achieved by high power resonant decoupling of abundant spins, and the Hartmann–Hahn condition is achieved by irradiation of the rare spins off resonance, which preserves their chemical shift in the rotating frame The rare spins are saturated with an additional weak variable frequency rf field Following this cross‐polarization period is a period when strong gated rf is applied off resonance to the abundant spins This permits time‐shared observation of the abundant spin magnetization, which reflects saturation of the rare system during the previous cycle At the same time it serves to replenish the rare spin magnetization because it is off resonance Transition between the two modes is adiabatic This method distorts the rare‐spin line shape, but a related model experiment is also described which would not do so This method is expected to be more useful than that

Hermann E. Bleich

Papers

Precision High Speed Current Regulators for Occasionally Switched Inductive Loads

Modified Hartmann–Hahn double NMR in solids for high resolution at low gyromagnetic ratio: CaF2 and quadrupole interaction in MgF2