Showing papers in "Contrast Media & Molecular Imaging in 2008"

68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals

Abstract: PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced (11)C and (18)F. An alternative is the use of metallic positron emitters. Among them (68)Ga deserves special attention because of its availability from long-lived (68)Ge/(68)Ga generator systems which render (68)Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga(3+) is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable (68)Ga(3+)complexes and convenient coupling to biomolecules. (68)Ga coupling to small biomolecules is potentially an alternative to (18)F- and (11)C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the (99)Mo/(99m)Tc-based radiopharmacy, still the mainstay of nuclear medicine.

Development and validation of a smoothing-splines-based correction method for improving the analysis of CEST-MR images.

Abstract: Chemical exchange saturation transfer (CEST) imaging is an emerging MRI technique relying on the use of endogenous or exogenous molecules containing exchangeable proton pools. The heterogeneity of the water resonance frequency offset plays a key role in the occurrence of artifacts in CEST-MR images. To limit this drawback, a new smoothing-splines-based method for fitting and correcting Z-spectra in order to compensate for low signal-to-noise ratio (SNR) without any a priori model was developed. Global and local voxel-by-voxel Z-spectra were interpolated by smoothing splines with smoothing terms aimed at suppressing noise. Thus, a map of the water frequency offset (‘zero’ map) was used to correctly calculate the saturation transfer (ST) for each voxel. Simulations were performed to compare the method to polynomials and zero-only-corrected splines on the basis of SNR improvement. In vitro acquisitions of capillaries containing solutions of LIPOCEST agents at different concentrations were performed to experimentally validate the results from simulations. Additionally, ex vivo investigations of bovine muscle mass injected with LIPOCEST agents were performed as a function of increasing pulse power. The results from simulations and experiments highlighted the importance of a proper ‘zero’ correction (15% decrease of fictitious CEST signal in phantoms and ex vivo preparations) and proved the method to be more accurate compared with the previously published ones, often providing a SNR higher than 5 in different simulated and experimentally noisy conditions. In conclusion, the proposed method offers an accurate tool in CEST investigation. Copyright © 2008 John Wiley & Sons, Ltd.

Cobalt nanoparticles as a novel magnetic resonance contrast agent--relaxivities at 1.5 and 3 Tesla

Abstract: Two samples of polymer-coated cobalt nanoparticles were synthesized and dispersed in agarose gel and water. The relaxivities r1 and r2 of the two samples were obtained at different temperatures (25, 37 and 40 degrees C) and magnetic field strengths (1.5 and 3 T). The average cobalt core diameters of the two samples were 3.3 and 3.9 nm (measured by transmission electron microscopy); the corresponding average total diameters (cobalt core + polymer coating) were 13 and 28 nm (measured by dynamic light scattering). The larger particles had the higher r1 relaxivity, whilst r2 was similar for the two samples. There was no significant change in r1 or r2 relaxivities with temperature but r1 at 1.5 T was approximately double the value at 3 T. The highest relaxivities were obtained at 1.5 T with values for r1 and r2 of 7.4 and 88 mM(-1) s(-1), respectively. These values are similar to those reported for iron oxide with larger core size, suggesting the potential of the cobalt nanoparticles for development and future use as a negative contrast agent.

Imaging of angiogenesis using Cadence™ contrast pulse sequencing and targeted contrast agents

Abstract: Objectives Low-power multipulse contrast ultrasound imaging provides a promising tool to quantify angiogenesis noninvasively when used with contrast agents targeted to vascular markers expressed by the angiogenic endothelium. Targeted ultrasound contrast agents, with a diameter on the order of micrometers, cannot extravasate and therefore are targeted solely to receptors expressed by the vascular endothelium. The aim of this study was to evaluate the potential of a low-power multipulse imaging sequence, CadenceTM contrast pulse sequencing (CPS), combined with targeted contrast agents to quantify angiogenesis. Material and Methods Targeted microbubbles were prepared by conjugating echistatin via biotin–avidin linkage to the surface of a phospholipid microbubble shell. The density of echistatin present on the shell was confirmed with flow-cytometry and quantified by total fluorescence. The binding of targeted microbubbles was evaluated in vitro by quantifying the adherence of targeted microbubbles to rat aortic endothelial cells, compared with control (nontargeted) microbubbles. The circulation time and adherence of targeted microbubbles was evaluated in vivo in a Matrigel model in rats and compared with control microbubbles using CPS in addition to a destructive ultrasound pulse. Results Using only the low-power CPS pulse, the echo intensity produced in the neovasculature of the Matrigel pellet was significantly greater with targeted microbubbles than with the control contrast agent (p < 0.001). Combining CPS with the destructive pulse, the processed image was significantly different in intensity (p < 0.001) and spatial extent between targeted and control agents (p < 0.001). When the morphology of the histological sample and ultrasound image correlated, the microvessel density count and the percentage of the circular area enhanced by ultrasound were correlated (p < 0.05). Conclusion Low-power multipulse imaging in combination with targeted echistatin-bearing microbubbles facilitated a noninvasive, quantitative evaluation of early angiogenesis during real-time imaging. The addition of high-intensity destructive pulses facilitated estimation of the spatial extent of angiogenesis. Copyright © 2008 John Wiley & Sons, Ltd.

Incorporation of an apoE-derived lipopeptide in high-density lipoprotein MRI contrast agents for enhanced imaging of macrophages in atherosclerosis.

Abstract: Magnetic resonance (MR) imaging is becoming a pivotal diagnostic method to identify and characterize vulnerable atherosclerotic plaques. We previously reported a reconstituted high-density lipoprotein (rHDL) nanoparticle platform enriched with Gd-based amphiphiles as a plaque-specific MR imaging contrast agent. Further modification can be accomplished by inserting targeting moieties into this platform to potentially allow for improved intraplaque macrophage uptake. Since studies have indicated that intraplaque macrophage density is directly correlated to plaque vulnerability, modification of the rHDL platform may allow for better detection of vulnerable plaques. In the current study we incorporated a carboxyfluoresceine-labeled apolipoprotein E-derived lipopeptide, P2fA2, into rHDL. The in vitro macrophage uptake and in vivo MR efficacy were demonstrated using murine J774A.1 macrophages and the apolipoprotein E knock-out (apoE−/−) mouse model of atherosclerosis. The in vitro studies indicated enhanced association of murine macrophages to P2fA2 enriched rHDL (rHDL–P2A2) nanoparticles, relative to rHDL, using optical techniques and MR imaging. The in vivo studies showed a more pronounced and significantly higher signal enhancement of the atherosclerotic wall 24 h after the 50 µmol Gd/kg injection of rHDL–P2A2 relative to administration of rHDL. The normalized enhancement ratio for atherosclerotic wall of rHDL–P2A2 contrast agent injection was 90%, while that of rHDL was 53% 24 h post-injection. Confocal laser scanning microscopy revealed that rHDL–P2A2 nanoparticles co-localized primarily with intraplaque macrophages. The results of the current study confirm the hypothesis that intraplaque macrophage uptake of rHDL may be enhanced by the incorporation of the P2fA2 peptide into the modified HDL particle. Copyright © 2008 John Wiley & Sons, Ltd.

Efficient stem cell labeling for MRI studies

Abstract: Iron oxide particles are especially suited for cell tracking experiments due to their extraordinarily molar relaxivity as compared with other paramagnetic nuclei. We have compared different iron oxide particles (Sinerem, Endorem and magnetic microspheres) for their suitability to label embryonic stem cells (D3 cell line). In addition to detectability thresholds, particular attention has been paid to the evaluation of long-term stability of the labelling procedure (up to 4 weeks) as well as to toxic and other adverse effects on cell viability. Comparative studies were performed using neural progenitor cells (C17.2) and dendritic cells. The present study indicates strong dependence of the label efficiency and stability on the iron oxide particles and cell lines in use. Copyright © 2008 John Wiley & Sons, Ltd.

Positive MRI Enhancement in THP-1 Cells with Gd2O3 Nanoparticles

Abstract: There is a demand for more efficient and tissue-specific MRI contrast agents and recent developments involve the design of substances useful as molecular markers and magnetic tracers. In this study ...

A dual CT-MR dendrimer contrast agent as a surrogate marker for convection-enhanced delivery of intracerebral macromolecular therapeutic agents.

Abstract: The feasibility of using Gd dendrimer-based macromolecules (Gd-G8 dendrimer) as a dual CT and MR contrast agent for monitoring convection-enhanced delivery of therapy in the brain is evaluated both in vitro and in vivo with optimal dosing established. In vitro CT attenuation values of the Gd-based agents ( approximately 6.0 HU mM(-1)) were approximately 1.6 times greater than iodine-based agents and the attenuation of the Gd-DTPA was comparable to Gd-G8 dendrimer. Visible enhancement was observed on both CT and MR using Gd-G8 dendrimer over a range of 23-78 mM; however, a concentration of at least 47 mM in Gd was required for adequate delineation of the injection site on both CT and MR. MR offers greater sensitivity than CT in estimating the volume of distribution (V(d)) and effectively quantified the agent's concentration and diffusion using T(1) mapping at much lower concentrations of Gd (<10 mM in [Gd]).

Magnetic labeling of non‐phagocytic adherent cells with iron oxide nanoparticles: a comprehensive study

Abstract: Small particles of iron oxide (SPIO) and ultrasmall particles of iron oxide (USPIO), inducing a strong negative contrast on T2 and T2*-weighted MR images, are the most commonly used systems for the magnetic labeling of cultured cells and their subsequent detection by magnetic resonance imaging (MRI). The purpose of this work is to study the influence of iron incubation concentration, nanoparticle size and nanoparticle coating on the magnetic labeling and the viability of non-phagocytic adherent cells in culture. The magnetic labeling of 3T6 fibroblasts was studied by T2-weighted MRI at 4.7 T and by dosing—or cytochemical revealing—of iron through methods based on Perl's Prussian blue staining. Cells were incubated for 48 h with increasing iron concentrations of SPIO (25–1000 µg Fe/ml Endorem®). Sinerem®, a USPIO (20–40 nm) coated with neutral dextran, and Resovist® (65 nm), a SPIO bearing an anionic carboxydextran coating, were compared with Endorem® (dextran-coated, 80–150 nm) as magnetic tags. The iron loading of marrow stromal cell primary cultures (MSCs) isolated from rat femurs was compared with that of 3T6 fibroblasts. The SPIO-labeling of cells with Endorem® was found to be dependent on the iron incubation concentration. MSCs, more sparsely distributed in the culture, exhibited higher iron contents than more densely populated 3T6 fibroblast cultures. A larger iron loading was achieved with Resovist® than with Endorem®, which in turn was more efficient than Sinerem® as a magnetic tag. The magnetic labeling of cultured non-phagocytic adherent cells with iron oxide nanoparticles was thus found to be dependent on the relative concentration of the magnetic tag and of the cells in culture, on the nanoparticle size, and on the coating type. The viability of cells, estimated by methods assessing cell membrane permeability, was not affected by magnetic labeling in the conditions used in this work. Copyright © 2008 John Wiley & Sons, Ltd.

Accurate pre-operative localization of pathological parathyroid glands using 11C-methionine PET/CT

Abstract: Objective The pre-operative technique most routinely used to localize pathological parathyroid glands (PPG), prior to minimal access surgery (MAS), relies on 99mTc-sestamibi (MIBI) scintigraphy. Positron emission tomography (PET) using the radiolabelled amino acid 11C-methionine as the tracer agent offers a technological alternative to localize PPG. In this study we evaluated the sensitivity of 11C-methionine PET/CT (MET-PET/CT) for PPG detection and the extent to which MET-PET/CT images may contribute to the planning of surgical procedures. Design Thirty patients were included, 22 with primary hyperparathyroidism and eight with secondary hyperparathyroidism. Patients suspected of suffering from parathyroid hyperplasia underwent a complete surgical exploration of the neck region. In those suspected of parathyroid adenoma, surgery was limited to the presumed localization described by MET-PET/CT. To specifically address the additional benefit of the MET-PET/CT in terms of surgical planning and procedure, the surgeon classified the patients into two categories depending on the type of benefit, or the reason for the absence of benefit, occurring in each case. We also compared the sensitivity of MET-PET/CT and MIBI scintigraphy. Results The total number of lesions removed was 46 (24 adenomatous and 22 hyperplastic). Globally, MET-PET/CT provided additional benefit to surgery in 15 out of 30 cases (50%). The sensitivity of 11C-methionine PET/CT and MIBI scintigraphy was respectively 92% and 95% for adenoma, and 68% and 59% for hyperplasia, on the basis of available resected lesions. Conclusion MET-PET/CT appears a reliable technique to guide MAS of parathyroid glands. Copyright © 2008 John Wiley & Sons, Ltd.

First ex-vivo MRI co-localization of two LIPOCEST agents.

Abstract: One of the major advantages of the CEST methodology deals with the possibility of visualizing more probes in the same MR image voxels. This is a unique property within the contrast media that act on the 1H-NMR signal of water protons, and it might considerably improve the potential of the technique. In addition to displaying sufficiently different resonance frequencies of their mobile protons, it is also important that the CEST agents designed for this application are highly sensitive. LIPOCEST agents represent the most sensitive class of CEST systems developed so far. On this basis, two LIPOCEST samples, a spherical one and an osmotically shrunken nonspherical one, endowed with markedly different resonance frequencies of their intraliposomal water protons, 3 ppm and 15 ppm, respectively, were prepared and tested both in vitro and in ex-vivo on a bovine muscle used as tissue-surrogate. The response of the two agents did not interfere each other, thus allowing the multiple visualization of the two agents present at nanomolar concentrations in the same image voxels. Copyright © 2008 John Wiley & Sons, Ltd.

Aerosols and gaseous contrast agents for magnetic resonance imaging of the lung.

Abstract: Magnetic resonance imaging of lungs and the investigation of pulmonary pathologies with this technique are limited by low proton spin density, degraded magnetic homogeneity and motion. Inhaled contrast agents (gases or aerosols) can improve the diagnostic value of MRI for lung. Paramagnetic contrast agents such as gadolinium chelates aerosol or dioxygen gas increase the relaxivity of proton in lung parenchyma and can be used to assess the ventilated fraction of the bronchoalveolar space. Similarly, inhalation of non proton-MRI nuclei such as perfluorinated gas or hyperpolarized gases ((3)He or (129)Xe) can provide functional ventilation image. In this review paper, the principles, the practical implementation, the limitations and possible safety issues of these different techniques are summarized. The main pre-clinical and clinical applications of these approaches based on oral contrast agents are reviewed and illustrated with cutting-edge lung MRI studies.

In vivo MR imaging of magnetically labeled mesenchymal stem cells transplanted into rat liver through hepatic arterial injection.

Abstract: Objective The aim of this study was to evaluate in vivo magnetic resonance imaging (MRI) for tracking the magnetically labeled mesenchymal stem cells (MSCs) transplanted into rat liver through hepatic arterial injection. Materials and Methods MSCs, harvested from the bone marrow of Wistar rats and expanded by the adhesion method, were labeled with both Feridex and 4′,6-diamidino-2-phenylindole (DAPI). Cell transplantation was performed by injection of 1 × 106 labeled cells (n = 20) or unlabeled cells (n = 10) via hepatic artery into rat livers treated with 2% carbon tetrachloride to induce acute liver necrosis. MR imaging was performed on a clinical 1.5 T MR scanner with a T2*-weighted gradient-echo sequence immediately before and at 1 h, 3 days, 7 days and 14 days after transplantation, and the signal-to-noise ratios (SNRs) were measured in liver, spleen, kidney and muscle. After MR examination, the animals were sacrificed, and the liver, kidney, lung and muscle were prepared for fluorescence observation and Prussian Blue staining. Results In the group treated with labeled cells, the SNR of the liver after cell transplantation was 3.12 ± 0.43 at 1 h, 7.98 ± 1.05 at 3 days and 11.46 ± 1.41 at 7 days. These values were significantly lower than the pre-transplantation SNR (14.40 ± 0.37). In the group treated with unlabeled cells, no significant difference could be found between after and before transplantation liver SNRs. Prussian Blue staining showed iron particles, contained within the cytoplasm and distributed in the liver parenchyma, which corresponded to the DAPI-stained fluorescent nuclei under the fluorescence microscope. Conclusion The magnetically labeled MSCs transplanted into rat liver through hepatic arterial injection can be detected and monitored in vivo with a 1.5 T clinical MR scanner for up to 7 days after cell transplantation. Copyright © 2008 John Wiley & Sons, Ltd.

In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications.

Abstract: Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

Kidney volume quantification using contrast-enhanced in vivo X-ray micro-CT in mice.

Abstract: The present study sought to establish a standard in vivo imaging procedure for mouse kidney anatomy evaluation using contrast-enhanced high-resolution X-ray microtomography (micro-CT). Micro-CT estimation of kidney volume was compared with ex vivo measurement by micro-CT and water displacement. Control values were obtained in four strains (BALB/c, C3H/HeN, 129/Sv and C57BL/6J) of healthy male and female mice aged 22 +/- 2 weeks. An excellent correlation was found between in vivo and ex vivo kidney volumes (n = 26 mice; 52 kidneys; r = 0.96). In vivo measurement systematically overestimated ex vivo kidney volume by 28 +/- 4%, while there was no significant difference between the ex vivo micro-CT value and the true kidney volume on water displacement (2.3 +/- 2.1%). In vivo kidney volume also correlated strongly with kidney weight and in vivo kidney length (n = 52 mice; 104 kidneys; r = 0.84, r = 0.92 respectively). Differences between strains were observed for kidney volume when comparing either kidney volume or kidney weight to body weight. In conclusion, this study demonstrated that contrast-enhanced micro-CT enables accurate in vivo measurement of kidney volume, length and thickness in mice. Reference parameters are reported for four strains. The technique provides a useful follow-up research tool for mouse phenotyping and renal disease studies.

In vitro characterization of phosphatidylglyceroglycerol-based thermosensitive liposomes with encapsulated 1H MR T1-shortening gadodiamide.

Abstract: Thermosensitive liposomes (TSL) with encapsulated proton (1H) magnetic resonance (MR) contrast agents have been proposed for noninvasive online temperature monitoring during tumor treatment using chemotherapy combined with hyperthermia (HT). The technique exploits the fact that water exchange between the TSL interior and exterior is increased and/or the encapsulated 1H MR contrast agent is released near the gel-to-liquid crystalline phase transition temperature (Tm) of TSL and thus shortens the 1H MR relaxation time of tissue. In this work, newly developed, phosphatidylglyceroglycerol (DPPGOG)-based TSL with encapsulated 1H MR longitudinal relaxation time (T1)-shortening gadodiamide (Gd-DTPA-BMA) were characterized in vitro by measuring the temperature dependence of the T1 of these gadodiamide-containing DPPGOG-TSL samples between 30 and 50 degrees C. The measurements revealed that the T1 nonlinearly slightly decreased with increasing temperature from 30 to 37 degrees C, mainly due to increased water exchange between the gadodiamide-containing DPPGOG-TSL interior and exterior with the exception of negligible gadodiamide release. This implies that gadodiamide-containing DPPGOG-TSL were stable at temperatures < or =37 degrees C, which was also confirmed by an independent stability study. From 37 to 44 degrees C, the T1 nonlinearly markedly decreased with increasing temperature since encapsulated gadodiamide was rapidly released. Above 44 degrees C, gadodiamide was completely released and the T1 was directly proportional to temperature while heated from 44 to 50 degrees C and cooled from 50 to 30 degrees C, respectively. Additionally, gadodiamide release was theoretically quantified and this calculated concentration was consistent with the actually released amount directly obtained from the cooling course of empty DPPGOG-TSL with completely released gadodiamide.

A new method for the aqueous functionalization of superparamagnetic Fe2O3 nanoparticles.

Abstract: A new methodology for the synthesis of hydrophilic iron oxide nanoparticles has been developed. This new method is based on the direct chemical modification of the nanoparticles' surfactant molecules. Using this methodology both USPIO (ultrasmall super paramagnetic iron oxide) (hydrodynamic size smaller than 50 nm) and SPIO (super paramagnetic iron oxide) (hydrodynamic size bigger than 50 nm) were obtained. In addition, we also show that it is possible to further functionalize the hydrophilic nanoparticles via covalent chemistry in water. The magnetic properties of these nanoparticles were also studied, showing their potential as MRI contrast agents.

Manganese cell labeling of murine hepatocytes using manganese(III)‐transferrin

Abstract: Manganese(III)-transferrin [Mn(III)–Tf] was investigated as a way to accomplish manganese-labeling of murine hepatocytes for MRI contrast. It is postulated that Mn(III)–Tf can exploit the same transferrin-receptor-dependent and -independent metabolic pathways used by hepatocytes to transport the iron analog Fe(III)–Tf. More specifically, it was investigated whether manganese delivered by transferrin could give MRI contrast in hepatocytes. Comparison of the T1 and T2 relaxation times of Mn(III)–Tf and Fe(III)–Tf over the same concentration range showed that the r1 relaxivities of the two metalloproteins are the same in vitro, with little contribution from paramagnetic enhancement. The degree of manganese cell labeling following incubation for 2–7 h in 31.5 µm Mn(III)–Tf was comparable to that of hepatocytes incubated in 500 µm Mn2+ for 1 h. The intrinsic manganese tissue relaxivity between Mn(III)–Tf-labeled and Mn2+-labeled cells was found to be the same, consistent with Mn(III) being released from transferrin and reduced to Mn2+. For both treatment regimens, manganese uptake by hepatocytes appeared to saturate in the first 1–2 h of the incubation period and may explain why the efficiency of hepatocyte cell labeling by the two methods appeared to be comparable in spite of the ∼16-fold difference in effective manganese concentration. Hepatocytes continuously released manganese, as detected by MRI, and this was the same for both Mn2+- and Mn(III)–Tf-labeled cells. Manganese release may be the result of normal hepatocyte function, much in the same way that hepatocytes excrete manganese into the bile in vivo. This approach exploits a biological process—namely receptor binding, endocytosis and endosomal acidification—to initiate the release of an MRI contrast agent, potentially conferring more specificity to the labeling process. The ubiquitous expression of transferrin receptors by eukaryotic cells should make Mn(III)–Tf particularly useful for manganese labeling of a wide variety of cells both in culture and in vivo. Published in 2008 by John Wiley & Sons, Ltd.

Identification of residual ischemia, infarction, and microvascular impairment in revascularized myocardial infarction using 64-slice MDCT.

Abstract: This study aimed to assess the potential of 64-slice MDCT in characterizing revascularized infarcted myocardium at the cellular and microvascular levels. Pigs (n=7) underwent 2 h left anterior descending coronary artery occlusion/reperfusion. In acute (2-4 h) and subacute (1 week) infarction, first-pass perfusion (FPP) (1 ml/kg of 300 mg/ml Omnipaque) was performed using a cine (rotation time 60 s/bpm) non-ECG gated sequence (mAS/kV=100/120). Delayed contrast enhanced images (DE) (mAS/kV=650/120) were acquired every 2 min for 10 min to determine the kinetics of Omnipaque and to define infarcted myocardium and microvascular impairment (representing microvascular obstruction and/or no- or low-reflow phenomenon). Maximum upslope, maximum attenuation and time to the peak were measured from FPP plots. 2,3,5-Triphenyltetrazolium-chloride (TTC) was used to define true infarction in the excised hearts. Hyperenhanced myocardium on DE was measured and compared with TTC. The contrast media caused minor beam hardening and X-ray scatter on FPP. The above-mentioned perfusion parameters significantly differed between remote and acute infarction. Infarcted myocardium showed two patterns of enhancement on DE, hyperenhanced rim representing the perfused infarction and hypoenhanced core representing a microvascular impaired region, with significantly different attenuation. The extent of infarction on DE-MDCT decreased over the course of 1 week and did not differ from TTC. Post-processed FPP semi-quantitative images showed a decline in myocardial blood volume and flow in acute revascularized infarction. In conclusion, modern MDCT has the potential to identify residual ischemia on FPP and microvascular impairment and infarction on DE images. (Less)

Application of MRI phase-difference mapping to assessment of vascular concentrations of BMS agent in mice.

Abstract: Direct quantitation of contrast agent concentration can be performed using dynamic susceptibility contrast MRI. This method is based on phase imaging and administration of paramagnetic agents such as gadolinium-chelates. This technique has only been applied on humans or primates. However, numerous research models have been developed on small animals like mice. For this reason, the aim of this work was the application of this MRI technique, allowing the direct quantitation of the contrast agent concentrations in vivo, in the mouse vascular system at high field. For this purpose, Dy–DOTA has been preferred to Gd–DOTA due to a lower T2* effect. Dy-DOTA shifts in Larmor frequency were measured by phase difference mapping, using fast gradient-echo imaging at short echo times. Such an acquisition sequence allowed the limitation of susceptibility artifacts at high magnetic fields and phase wrapping. As demonstrated in a phantom oriented parallel to the static magnetic field, it is possible to measure contrast agent concentrations between 0 and 10 mm with an uncertainty of about 100 µm. Finally, the method was applied on living mice at 4.7 T. After the bolus injection, the evolution of contrast agent concentrations was assessed in brain blood vessels parallel to B0. Long-term disappearance of contrast agent was monitored at high spatial resolution every 15 s. Alternatively, lower resolved images at 0.72 s time-resolution allowed preliminary assessment of arterial input functions. The feasibility of quantitative bolus-tracking in small rodents opens the way for comprehensive descriptions of flow and over time-dependent biological processes, especially in pathological murine models. Copyright © 2008 John Wiley & Sons, Ltd.

MR imaging assessment of the kinetics of P846, a new gadolinium-based MR contrast medium, in ischemically injured myocardium

Abstract: The objectives of the study were: (1) to compare the kinetics of a new gadolinium-based low-diffusibility magnetic resonance (MR) contrast medium, P846 and Gd-DOTA in left ventricular (LV) blood and in normal and ischemically injured myocardium using inversion recovery echo-planar imaging (IR-EPI) and (2) to compare the enhancement pattern after injection of P846 with Gd-DOTA, using T1-weighted spin-echo imaging (T1-SE). Sixteen rats were subjected to left descending artery (LAD) occlusion for 30 min, followed by 2.5 h reperfusion. MR imaging was performed before and after administration of the contrast medium in two different groups of animals: one group (n = 8) received 0.05 mmol kg(-1) P846 and the other (n = 8) 0.1 mmol kg(-1) Gd-DOTA. A blipped IR-EPI and a multislice T1-SE were performed before injection and for 90 min after injection. T1-values were derived by fitting regional signal intensity on the IR-EPI images, the R1, DeltaR1 (R(1postcontrast) - R(1precontrast)) and DeltaR1 ratios were calculated in LV blood, normal and injured myocardium. On SE-T(1), the signal intensity ratio (SI) and extent of injury were measured. True infarct size was measured using histochemical staining. Changes in DeltaR(1) were 4.8 times greater with 0.05 mmol kg(-1) P846 than with 0.1 mmol kg(-1) Gd-DOTA in LV blood (6.3 +/- 0.9 vs 0.9 +/- 0.1 s(-1), p < 0.0001), normal (1.7 +/- 0.2 vs 0.34 +/- 0.03 s(-1), p < 0.0001) and ischemically injured myocardium (5.4 +/- 0.4 vs 1.6 +/- 0.1 s(-1), p < 0.0001). MR imaging experiments showed that the signal enhancement with P846 is longer (90 min), which might be explained by a lower diffusion of P846 compared with Gd-DOTA (30 min). P846 differentiates viable and nonviable myocardium. Despite lower gadolinium dose, P846 permits differentiation of viable and nonviable myocardium owing to a high contrast and a long imaging window with conventional t1-weighted SE sequence.

Improved fluorescence of indocyanine green in vitro and in vivo after simple cooling procedures.

Abstract: Indocyanine green (ICG) is a contrast agent used for detecting angiogenesis with optical imaging (OI). The purpose of this study was to investigate whether cooling procedures increase the signal yield of ICG with OI. Test samples of 0.05 and 0.02 mM ICG in 40% DMSO and 60% DMEM underwent OI at four different temperatures (5, 37, 55 and 75°C). In addition, six athymic rats with an antigen-induced arthritis of the knee and ankle joints underwent OI before and after injection of ICG (10 mg/ml, dose 15 mg/kg) on two separate days with and without cooling of the joints. The fluorescent signals of the test samples and arthritic joints were measured and evaluated for significant differences before and after cooling with a t-test. In vitro studies showed a strong negative correlation between ICG temperature and fluorescent signal. The mean fluorescent signal of arthritic joints (measured in efficiency) was 0.345 before ICG-injection, 4.55 after ICG-injection and before cooling and 9.71 after ICG-injection and after cooling. The fluorescent signal enhancement of arthritic joints with ICG-enhanced OI images increased significantly after cooling (p = 0.02). The signal yield of ICG can be significantly increased by cooling the target pathology. The primary underlying cause of the temperature dependence of ICG is enhanced collisional quenching with increasing temperature. This simple cooling method may be immediately helpful to increase the fluorescence signal yield in current ICG-enhanced OI-studies in patients. Copyright © 2008 John Wiley & Sons, Ltd.

New synthesis of a high molecular weight ligand derived from dota; thermodynamic stability of the MRI contrast agent formed with gadolinium

Abstract: The new total synthesis in four steps of the compound P1041 is reported. This compound is a high molecular mass ligand (MW 6.32 kDa) derived from dota in which the four substituents are hydroxylated and contain amidic groups. The attribution of the nine protonation constants of P1041 is based on the comparison with the behaviour of the precursor ligands dota and tced, a tetracarboxylated derivative of dota. From these results, the studies of the systems P1041/Na+ and P1041/Gd3+ lead to the determination of the stability constants corresponding to the three species Na(P1041)Hh (h = 0, 2 or 4) and to the five complexes Gd(P1041)Hh (h = 0, 2, 3, 4 or 5). The complexing ability of P1041 towards Gd3+ is compared with those of dota and tced. At physiological pH = 7.4, the very stable species Gd(P1041)H (currently named P792 in the literature) of this rapid clearance blood pool agent is predominant. Copyright © 2008 John Wiley & Sons, Ltd.