Paramagnetic macrocyclic complexes as contrast agents for MR imaging: proton nuclear relaxation rate enhancement in aqueous solution and in rat tissues

Paramagnetic macrocyclic chelates show promise as magnetic resonance (MR) imaging contrast agents due to stability and relaxivity comparable to those of DTPA-type chelates. For the three copper and manganese macrocyclic complexes studied in aqueous solution, T1 and T2 relaxivities ranged from 0.14 to 5.88 mM-1sec-1 at 6.25 MHz. In rats, the intravenous administration of 16 mumol/kg of Mn(cyclam) caused the liver T1 relaxation rate to double at 15 minutes after injection. T1 measurements by pulsed MR imaging and manganese analyses on excised tissue showed that both relaxation rate (1/T1) and manganese content of liver and kidney increase linearly with the dosage of Mn(cyclam). The linear relationship between 1/T1 and manganese content can be considered an "in tissue" relaxivity plot for the agent. The resulting relaxivity is 54 mM-1sec-1 in liver, compared with 3.1 mM-1sec-1 in aqueous solution. Although this work is preliminary, the implication for medical MR imaging applications is that macrocyclic contrast agents can be effective at approximately one-tenth the current typical dose used for gadolinium DTPA.     

NMR spin-lattice relaxation in tissues with high concentration of paramagnetic contrast media: evaluation of water exchange rates in intact rat muscle

High concentrations of GdDTPA in extracellular water of tissue cause the intrinsic relaxation rate of water to become greater than the coupling rate between intracellular and extracellular water compartments. The fast exchange limit is no longer valid and distinctly nonexponential spin-lattice recovery is observed. T1 relaxation recovery was characterized by a double exponential curve when striated rat muscle was immersed in a highly concentrated (110 Mm) isotonic solution of GdDTPA. When the water exchange rate through cell membranes in intact muscle tissue was calculated (using a two-compartment exchange model) and compared to similar data determined from T2 Carr-Purcell-Meiboom-Gill experiments, a significant discrepancy was found.     

Dyke Award. Europium-DTPA: a gadolinium analogue traceable by fluorescence microscopy

A lanthanide series chelate, europium(Eu)-DTPA, was synthesized to serve as a histochemical analogue for the widely used MR contrast agent gadolinium(Gd)-DTPA. Eu and Gd, being neighboring elements on the periodic table, share many fundamental properties, including ionic radius, valence, and chemical reactivity. Eu-DTPA, however, possesses one important physical property not shared by Gd-DTPA: luminescence under ultraviolet light. The feasibility of detecting Eu-DTPA in animal tissues under fluorescence microscopy was systematically evaluated and documented. Distinctive orange-red luminescence of Eu-DTPA could be observed in the kidneys, livers, dura, choroid, and pituitary glands of rats after intravascular injection. No luminescence was detected in areas of brain beyond an intact blood-brain barrier. When the brain was locally injured by an experimental laceration, however, leakage of Eu-DTPA was detected. Electron probe microanalysis confirmed the parallel presence or absence of simultaneously injected Eu-DTPA and Gd-DTPA in all tissues studied. Fluorescence microscopy with Eu-DTPA has thus been validated as a method for tracing the distribution of Gd-DTPA at the microscopic level.     

Steric control of CO binding in a totally synthetic heme protein model

A family of totally synthetic models for the carbon monoxide adducts of heme proteins has been synthesized and applied to the elucidation of the role of steric effects in the relative detoxification of carbon monoxide. The complexes are designed such that a sheltered void of controllable dimensions encompasses the CO binding site. Systematic variations in the available space for the iron-bound CO produce a wide range of equilibrium binding constants (K_CO). An x-ray structure determination of a CO adduct complex having a crowded CO site reveals that the Fe—CO linkage is bent, and further, the distortion involves both displacement of the Fe—C vector from the normal to the N₄ plane and bending of the Fe—C—O angle.     

Use of a paramagnetic substance, colloidal manganese sulfide, as an NMR contrast material in rats

Paramagnetic pharmaceuticals ( magnetopharmaceuticals ) that are suitably distributed into specific organ systems or diseased sites might be clinically useful for tissue contrast enhancement in nuclear magnetic resonance images. To determine whether an insoluble magnetopharmaceutical might be useful in such service, we investigated the effect of a colloidal preparation of manganese sulfide ( MnSC ) upon liver and lung spin-lattice relaxation times (T1) in rats following intravenous administration. NMR tissue sample measurements were made at 24 MHz, ahd showed that after MnSC treatment, liver T1 values--and to a lesser extent lung T1 values--were depressed below control values. Liver manganese content (as determined by flame atomic absorption spectrophotometry) increased in proportion to the dose of MnSC , and the reciprocal of the liver T1 values also increased in proportion to the dose of MnSC .