Volumetric assessment of myocardial viability in rats using 3D double contrast enhanced T1 and T2-weighted MRI

Objective: Volumetric evaluation of the myocardial viability post-infarction in rats using 3D in vivo MR imaging at 7 T using injection of an extracellular paramagnetic contrast agent and intravascular superparamagnetic iron oxide nanoparticles in the same imaging session. Materials and methods: Five hours after induction of permanent myocardial infarction in rats (n=6), 3D in vivo T1- and T2-weighted MR Imaging was performed prior to and after Gd-DOTA injection (0.2 mmol/kg) and prior to and after nanoparticle injection (5 mg Fe/kg) to assess infarct size and myocardial viability. Results: 3D MR Imaging using a successive contrast agent injection showed a difference of infarct size after Gd-DOTA injection on T1-weighted images compared to the one measured on T2-weighted images after Gd-DOTA and nanoparticle injection. Conclusion: The use of 3D T1- and T2-weighted MR Imaging using a double contrast agents protocol made possible the accurate characterization of myocardial infarction volume and allowed the detection of myocardial viability post-infarction in rats     

Dose and scanning delay using USPIO for central nervous system macrophage imaging

Rationale and objectives: In experimental allergic encephalomyelitis (EAE), central nervous system (CNS) macrophage imaging is achievable by MRI using AMI-227 an ultra-small particle iron oxide contrast agent at a dose of 300 μmol/kg Fe. The objective was to test the feasibility at the human recommended dose of 45 μmol/kg Fe.Methods: Two groups of EAE rats were tested with AMI-227 using 45 and 300 μmol/kg Fe respectively. Following i.v. injection of AMI-227, they were scanned after a delay of 4–6 and 20–24 h.Results: With a high dose of AMI-227, all animals showed low signal intensity related to iron-loaded macrophages in the CNS. At low dose no abnormalities were found in the CNS. Furthermore, a delay of 4–6 h failed to demonstrate abnormalities even at high dose.Conclusions: Dose, scanning delay after administration and blood half-life are major parameters for T2^* CNS macrophage imaging.     

Optimising the design of paramagnetic MRI contrast agents: influence of backbone substitution on the water exchange rate of Gd-DTPA derivatives

Among other factors influencing the residence time of the coordinated water (τ _M ) of paramagnetic contrast agents, the steric hindrance around the gadolinium ion seems to play a beneficial role. Such a crowding can be achieved by substituting the Gd-DTPA backbone on the C4 position. Several Gd-DTPA complexes carrying diverse groups at this position have thus been synthesised and characterised: Gd(S)-C₄-Me-DTPA, Gd(S)-C₄-n-Bu-DTPA, Gd(S)-C₄-iBu-DTPA, Gd(S)-C₄-iPr-DTPA, and Gd-C₄-diMe-DTPA. τ _M has been measured through the evolution of the water oxygen-17 transverse relaxation rate as a function of the temperature. The data show a reduction of τ _M of Gd(S)-C₄-Me-DTPA, Gd(S)-C₄-n-Bu-DTPA, Gd(S)-C₄-iBu-DTPA, Gd(S)-C₄-iPr-DTPA, and Gd-C₄-diMe-DTPA (τ _M ³¹⁰=91,82, 108,98, and 57 ns respectively, as compared to Gd-DTPA (τ _M ³¹⁰=143 ns)). At 310 K, the nuclear magnetic dispersion relaxation profiles of water protons are very similar for the five complexes which present longitudinal relaxivities slightly higher than those of Gd-DTPA. Regarding zinc transmetallation, C4-monosubstituted derivatives are more stable than Gd-DTPA. These results confirm that a judicious substitution of the DTPA skeleton allows for an acceleration of the coordinated water exchange rate. This observation can be useful for the design of vectorised contrast agents for molecular imaging.     

Complete elimination of the hepatobiliary mr contrast agent Gd-EOB-DTPA in hepatic dysfunction: An experimental study using transport-deficient,mutant rats

Mutant Wistar rats (TR^– rats) are characterized by a defect in the canalicular transport system for organic anions in the hepatocytes. Anionic hepatobiliary contrast agents for X-ray and MR imaging usually depend on this transport system for biliary secretion. The current study investigated in rats whether Gd-EOB-DTPA, a hepatocyte-directed MR contrast agent, can be completely eliminated in the absence of biliary excretion, and whether urinary elimination may compensate for the hepatic dysfunction. In TR^/t- rats elimination of Gd-EOB-DTPA almost completely depended on renal excretion: following intravenous administration of 25µmol kg^–1 Gd-EOB-DTPA only 2.4±0.4% of the injected dose underwent biliary excretion. Nevertheless only 2% of a 10-fold higher dose (250µmolkg^–1 Gd-EOB-DTPA) was still detected in the body 24 hours p.a., and less than 0.5% 7 days p.a. (no statistically significant differences as compared to values in control rats). In TR^– rats, renal and liver signal intensities on T1-weighted MR images returned to baseline within 24 hours following administration of 25µmol kg^–1 Gd-EOB-DTPA. In control rats, return to baseline values was observed already 6 hours after injection of the contrast agent. In conclusion, the hepatobiliary MR contrast agent Gd-EOB-DTPA is effectively and completely cleared from the body even in the virtual absence of biliary excretion. The urinary elimination pathway is able to fully compensate for the deficient hepatic transport system.     

1H-NMRD and17O-NMR assessment of water exchange and rotational dynamics of two potential MRI agents: MP-1177 (an extracellular agent) and MP-2269 (a blood pool agent)

The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-l-aspartyl-lysine-derived-DTPA [GdL]⁴⁻, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An¹⁷O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant ofk _ex ²⁹⁸ =(0.39±0.02)×10⁶ s⁻¹, identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An¹⁷O-NMR study of [GdL]⁴⁻ gives a water exchange rate constant ofk _ex ²⁹⁸ =(4.2±0.1)×10⁶ s⁻¹, identical to that for [Gd(DTPA)]²⁻. The water exchange rate on [GdL]⁴⁻ did not decrease considerably when bound to albumin, the lowest limit isk _ex,GdL-BSA=k _ex,GdL/2. Both approaches yield identical rotational correlation times for [GdL]⁴⁻, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]⁴⁻ using the different approaches (values ranged between 1.0 and 23.0 ns).     

Gadolinium-containing copolymeric chelates—a new potential MR contrast agent

Rationale and objectives: To develop and partially characterize a new class of potential blood pool magnetic resonance (MR) contrast agents.Methods: Various copolymeric chelates of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) were prepared with differing molecular weights of polyethylene glycol (PEG) or polypropylene glycol (PPG) as linkers between the monomeric chelate units. Gadolinium content of the polymeric chelates was determined by atomic absorption spectra. Relaxivity of the polymeric chelates was measured at 1.5 Tesla and compared with Gadolinium-DTPA. MR angiography (MRA) was performed in rabbits comparing Gd-DTPA with Gd-copolymers.Results: The gadolinium content of the copolymeric chelates ranged from 2.95 to 22.2% on weight basis. The molecular weight of the PEG linkers in the copolymers ranged from about 150 to about 3400. Ther ₁ (1/T1, mM⁻¹ s⁻¹) for Gd-DTPA=4.1. Ther ₁ values for the different Gd-containing polymers ranged from 3.8 to 5.8, with the lowestr ₁ for the polymer prepared with the lowest-molecular-weight complex. The higher-molecular-weight complexes resulted in moderately higher relaxivity. MRA with Gd-copolymers, in rabbits, showed markedly greater vascular enhancement relative to an equivalent dose of Gd-DTPA. Vascular enhancement was much more sustained with the copolymeric agent and confined to vascular space; i.e. no appreciable background tissue enhancement—a reflection of distribution into extravascular fluid space—was observed.Conclusions: Relative to Gd-DTPA monomers, PEG-containing Gd-DTPA polymeric complexes provided moderate increases in relaxivity but markedly greater efficacy during in vivo MRA. In vitro relaxivity studies of Gd-copolymers showed only an approximately 50% increase inr ₁ relaxivity compared with Gd-DTPA. The PEG-containing complex's lack of rigidity may have diminished the effect of spin diffusion on relaxation, thereby accounting for this modest increase. The greater efficacy of Gd-copolymers during in vivo MRA may reflect compartmentalization within the vascular space and possibly enhanced relaxation of the macromolecular copolymers in the blood. Gd-copolymers are promising agents that merit additional study.     

A double-blind study to evaluate the efficacy and tolerability of a higher dose (0.3 mmol per kg bw) of gadodiamide injection as a contrast medium for MRI

Gadodiamide injection was administered intravenously to 48 patients with known or suspected central nervous system (CNS) lesions undergoing magnetic resonance imaging (MRI). Two parallel groups were examined to evaluate the efficacy and safety of single doses of 0.1 and 0.3mmol per kg bw. The principal measures of efficacy were diagnostic yield of MR images, the overall contrast enhancement and the contrast index (CI). Adverse events and serum bilirubin level were the main safety parameters. Nineteen patients in each dose group displayed contrast enhancement of the MR image (1.5 T Siemens Gyroscan MR unit;T ₁ TR/TE=560–650/15–25 ms;T ₂:TR/TE=2200–3100/22–90 ms). The CI increased by 47.3% in the 0.1 mmol/kg bw group and by 86.5% in the 0.3 mmol per kg bw group compared to the pre-contrast scan. Four patients in the 0.1 mmol per kg bw group and seven in the 0.3 mmol per kg bw group had their management changed by new information from the post-contrast scan and four patients in each dose group had their diagnosis altered following the post-contrast scan. Two patients in the 0.3 mmol per kg bw group experienced injection-associated discomfort. There were no other adverse events reported during the 24 h follow-up period. No clinically significant changes in serum bilirubin or other parameters of blood chemistry or haematology were observed. The study demonstrates that the safety profile of gadodiamide injection 0.3 mmol per kg bw is similar to that of 0.1 mmol per kg bw and that, at both doses, gadodiamide injection is a safe and effective contrast medium for use in patients undergoing MRI on the CNS. Slightly more patients had an improvement in diagnostic yield with the 0.3 mmol per kg bw dose and the CI was increased to a greater extent in this group, showing that when greater contrast is required the higher dose of gadodiamide injection may be considered. Further studies in selected patient groups, and with the use of different doses in the same patient are necessary to evaluate the diagnostic value of higher doses.     

Mixed micelles containing lipophilic gadolinium complexes as MRA contrast agents

Mixed micelles for MRA are multicomponent systems containing a phospholipid, a biocompatible non-ionic surfactant (e.g. Synporonic^(k) F-108) and a lipophilic gadolinium complex. A variety of lipophilic gadolinium complexes were designed taking into account features such as: (i) nature of ligand (cyclic versus acyclic); (ii) lipophilic moiety; (iii) global charge of the complex; and (iv) nature of bond connecting the complex to the lipophilic moiety. All the lipophilic gadolinium complexes after formulation as mixed micelles show high relaxivities in water and in blood (rat). Mixed micelles containing gadolinium complexes bearing only one aliphatic chain cannot be used as MRA contrast agents because they have a high haemolytic effect. Furthermore, in rats they are quickly eliminated from the blood stream. These drawbacks are completely circumvented using gadolinium complexes bearing two aliphatic chains. Mixed micelles containing such complexes show high relaxivities. no haemolytic effect and long blood permanence. This makes them promising candidates as MRA contrast agents. However, elimination, which occurs exclusively through the liver, is not complete, even after 7 days. Complexes containing labile (e.g. ester) bonds between the lipophilic moieties and the chelate subunit are eliminated through both the liver and the kidneys. However, elimination is stiil not complete after 7 days.     

Magnetic resonance evaluation of autonomous thyroid nodules treated by percutaneous ethanol injection

Magnetic resonance (MR) imaging was used to evaluate the effect of ultrasound-guided percutaneous ethanol injection (PEI) of autonomous thyroid nodules (ATNs). Nine patients affected with ATN (3.7–32.2 mL volume) underwent PEI (4–19 mL ethanol, subdivided in 3–6 weekly procedures). MR imaging (1.5 T) was performed before each alcoholization and 1 month after the last PEI procedure with the following parameters:T ₁-(550/12) andT ₂-weighted (2200/160) spin-echo images; 4-mm slices, 10% gap; coronal planes. A further seven patients with normal thyroid function, who had undergone PEI 6–18 months before, underwent an MR examination with the same parameters. The signal-to-noise ratio (S/N) of ATN and extranodular gland, as well as ATN volume, were evaluated on theT ₂-weighted images. OnT ₁-weighted images, ATNs appeared mostly hypointense before treatment, with hyperintense areas during treatment, and were lightly hyperintense 6–18 months after treatment. S/N onT ₂-weighted images: extranodular gland 3.5–9.2; ATNs, before treatment 13.2–19.7, before the last procedure 7.7–11.6, 1 month after the last procedure 5.6–10.9; previously treated ATNs, 4.3–8.2. No significant volume reduction was observed with MR 1 month after the last procedure. The MR examination time was about 15 minutes. In conclusion, the effect of PEI on ATNs can be evaluated with an MR examination that is not very time consuming.     

Characterization of late radiation effects in the rat thoracolumbar spinal cord by MR imaging using USPIO

The aim of this study was to detect late radiation effects in the rat spinal cord using MR imaging with ultra-small particles of iron oxide (USPIO) contrast agent to better understand the development of late radiation damage with emphasis on the period preceding neurological signs. Additionally, the role of an inflammatory reaction was assessed by measuring macrophages that internalized USPIO. T₂-weighted spin echo MR measurements were performed at 7T in six rats before paresis was expected (130–150 days post-irradiation, early group), and in six paretic rats (150–190 days post-irradiation, late group). Measurements were performed before, directly after and, only in the early group, 40 h after USPIO administration and compared with histology. In the early group, MR images showed focal regions in grey matter (GM) and white matter (WM) with signal intensity reduction after USPIO injection. Larger lesions with contrast enhancement were located in and around edematous GM of three animals of the early group and five of the late group. Forty hours after injection, additional lesions in WM, GM and nerve roots appeared in animals with GM edema. In the late paretic group, MR imaging showed WM necrosis adjacent to areas with large contrast enhancement. In conclusion, detection of early focal lesions was improved by contrast administration. In the animals with extended radiation damage, large hypo-intense regions appeared due to USPIO, which might be attributed to blood spinal cord barrier breakdown, but the involvement of blood-derived iron-loaded macrophages could not be excluded.