MR Agents Research Articles

Synthesis and Characterization of New Porphyrazine-Gd(III) Conjugates as Multimodal MR Contrast Agents

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high-resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein, we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) complexes are conjugated to a fluorescent tetrapyrrole, namely, a porphyrazine (pz). Zinc metalated pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, Zn-Pz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.

Multivalent Protein Polymer MRI Contrast Agents: Controlling Relaxivity via Modulation of Amino Acid Sequence

Magnetic resonance imaging is a noninvasive imaging modality with high spatial and temporal resolution. Contrast agents (CAs) are frequently used to increase the contrast between tissues of interest. To increase the effectiveness of MR agents, small molecule CAs have been attached to macromolecules. We have created a family of biodegradable, macromolecular CAs based on protein polymers, allowing control over the CA properties. The protein polymers are monodisperse, random coil, and contain evenly spaced lysines that serve as reactive sites for Gd(III) chelates. The exact sequence and length of the protein can be specified, enabling controlled variation in lysine spacing and molecular weight. Relaxivity could be modulated by changing protein polymer length and lysine spacing. Relaxivities of up to approximately 14 mM(-1) s(-1) per Gd(III) and approximately 461 mM(-1) s(-1) per conjugate were observed. These CAs are biodegradable by incubation with plasmin, such that they can be easily excreted after use. They do not reduce cell viability, a prerequisite for future in vivo studies. The protein polymer CAs can be customized for different clinical diagnostic applications, including biomaterial tracking, as a balanced agent with high relaxivity and appropriate molar mass.

Abstract 4000: Cellular MRI of human breast cancer cells labeled with gadofluorine M

Abstract The ability to non-invasively locate and quantify tumor cell number at a metastatic site would be of considerable interest in pre-clinical and clinical metastasis research. To this end, our objective is to develop positive-contrast cellular magnetic resonance imaging (MRI) for use in quantifying tumor cell number at a metastatic site in vivo. The goals of the current study were to characterize the in vitro labeling of MDA-MB-231-luc-D3H2LN human breast cancer cells with a novel positive contrast MR agent Gadofluorine M (GdF), and to demonstrate the detectability of GdF-labeled cells in vitro at clinical strength MRI (1.5 and 3Tesla) scanners. Briefly, cells (1.5 × 107cells) were loaded by simple incubation for 24h with GdF at concentrations ranging from 25μM to 10mM. GdF-loading from 25μM to 1000μM did not result in significant changes in metabolic activity. Higher GdF-loading concentrations, 2500μM and 10mM, resulted in a 16% and 21% reduction in metabolic activity, respectively. The lowest GdF-loading concentration used (25μM) resulted in a significant (9-fold) increase in MR signal enhancement which then plateaued from 100μM to 1000μM. T1-relaxometry of cell pellets demonstrated a similar statistical trend in relaxation rates of cell pellets for all loading conditions, and at both field strengths. Inductively-coupled plasma atomic emission spectroscopy was performed on the cell pellet extracts to assess the average amount of GdF that had accumulated per cell at each incubating concentration. Since the relaxivity of an MR contrast agent can be affected by its intracellular location, we assessed whether internalized GdF-cc (GdF analog where the mannose moiety was replaced with carbocyanine) was cytosolic or compartmentalized into endosomes, via immunostaining for mannose-6-phosphate receptor. Using confocal fluorescence microscopy, we found that GdF is largely cytosolic and did not co-localize to late endosomes, an optimal situation for achieving maximum positive-contrast by T1-shortening since endosomal compartmentalization can lessen the enhancement seen in MR images. From these results, we have determined that the GdF loading concentration of 1000μM permits the highest payload for detection by cellular MRI in clinical field strength scanners. Information from this proof-of-principle study will support future work to develop positive-contrast cellular MRI as a new approach to quantitative imaging of metastatic cells in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4000.

Molecular MRI of Intracranial Thrombus in a Rat Ischemic Stroke Model

Intracranial thrombus is a principal feature in most ischemic stroke, and thrombus location and size may correlate with outcome and response to thrombolytic therapy. EP-2104R is a fibrin-specific molecular MR agent that has previously been shown to enhance extracranial and venous sinus thrombi in animal models and, recently, in clinical trials. In this study, we examined whether this fibrin-specific MR probe could noninvasively characterize intracranial arterial thrombi. Embolic stroke was induced in adult rats by occlusion of the right internal carotid artery with an aged thrombus. We used diffusion-weighted imaging, time of flight angiography, and high-resolution 3-dimensional T1-weighted MRI at 4.7 T before and after use of contrast agents EP-2104R (n=6) and gadopentetate dimeglumine (n=5). In all animals, MR angiography revealed a flow deficit and diffusion-weighted imaging showed hyperintensity consistent with ischemia. Using EP-2104R-enhanced MRI, we saw occlusive thrombi and vessel wall enhancement in all 6 animals with high contrast to noise relative to blood, whereas gadopentetate dimeglumine-injected animals showed no occlusive thrombus or vessel wall enhancement. The concentration of gadolinium in the thrombus after EP-2104R was 18 times that in the blood pool. EP-2104R-enhanced MRI successfully identifies intracranial thrombus in a rat embolic stroke model.

Bimodal MR–PET Agent for Quantitative pH Imaging

Bimodal MR–PET Agent for Quantitative pH Imaging

New Dual Mode Gadolinium Nanoparticle Contrast Agent for Magnetic Resonance Imaging

BackgroundLiposomal-based gadolinium (Gd) nanoparticles have elicited significant interest for use as blood pool and molecular magnetic resonance imaging (MRI) contrast agents. Previous generations of liposomal MR agents contained gadolinium-chelates either within the interior of liposomes (core-encapsulated gadolinium liposomes) or presented on the surface of liposomes (surface-conjugated gadolinium liposomes). We hypothesized that a liposomal agent that contained both core-encapsulated gadolinium and surface-conjugated gadolinium, defined herein as dual-mode gadolinium (Dual-Gd) liposomes, would result in a significant improvement in nanoparticle-based T1 relaxivity over the previous generations of liposomal agents. In this study, we have developed and tested, both in vitro and in vivo, such a dual-mode liposomal-based gadolinium contrast agent.Methodology/Principal FindingsThree types of liposomal agents were fabricated: core-encapsulated, surface-conjugated and dual-mode gadolinium liposomes. In vitro physico-chemical characterizations of the agents were performed to determine particle size and elemental composition. Gadolinium-based and nanoparticle-based T1 relaxivities of various agents were determined in bovine plasma. Subsequently, the agents were tested in vivo for contrast-enhanced magnetic resonance angiography (CE-MRA) studies. Characterization of the agents demonstrated the highest gadolinium atoms per nanoparticle for Dual-Gd liposomes. In vitro, surface-conjugated gadolinium liposomes demonstrated the highest T1 relaxivity on a gadolinium-basis. However, Dual-Gd liposomes demonstrated the highest T1 relaxivity on a nanoparticle-basis. In vivo, Dual-Gd liposomes resulted in the highest signal-to-noise ratio (SNR) and contrast-to-noise ratio in CE-MRA studies.Conclusions/SignificanceThe dual-mode gadolinium liposomal contrast agent demonstrated higher particle-based T1 relaxivity, both in vitro and in vivo, compared to either the core-encapsulated or the surface-conjugated liposomal agent. The dual-mode gadolinium liposomes could enable reduced particle dose for use in CE-MRA and increased contrast sensitivity for use in molecular imaging.

Comparison of Gadofluorine-M and Gd-DTPA for Noninvasive Staging of Atherosclerotic Plaque Stability Using MRI

Inflammation and neovascularization play critical roles in the stability of atherosclerotic plaques. Whole-body quantitative assessment of these plaque features may improve patient risk-stratification for life-threatening thromboembolic events and direct appropriate intervention. In this report, we determined the utility of the MR contrast agent gadofluorine-M (GdF) for staging plaque stability and compared this to the conventional agent Gd-DTPA. Five control and 7 atherosclerotic rabbits were sequentially imaged after administration of Gd-DTPA (0.2 mmol/kg) and GdF (0.1 mmol/kg) using a T(1)-weighted pulse sequence on a 3-T MRI scanner. Diseased aortic wall could be distinguished from normal wall based on wall-to-muscle contrast-to-noise values after GdF administration. RAM-11 (macrophages) and CD-31 (endothelial cells) immunostaining of MR-matched histological sections revealed that GdF accumulation was related to the degree of inflammation at the surface of plaques and the extent of core neovascularization. Importantly, an MR measure of GdF accumulation at both 1 and 24 hours after injection but not Gd-DTPA at peak enhancement was shown to correlate with a quantitative histological morphology index related to these 2 plaque features. GdF-enhanced MRI of atherosclerotic plaques allows noninvasive quantitative information about plaque composition to be acquired at multiple time points after injection (within 1 and up to 24 hours after injection). This dramatically widens the imaging window for assessing plaque stability that is currently attainable with clinically approved MR agents, therefore opening the possibility of whole-body (including coronary) detection of unstable plaques in the future and potentially improved mitigation of cataclysmic cardiovascular events.

The Effect of the Amide Substituent on the Biodistribution and Tolerance of Lanthanide(III) DOTA-Tetraamide Derivatives

Recent advances in the design of MRI contrast agents have rendered the lanthanide complexes of DOTA-tetraamide ligands of considerable interest, both as responsive MR agents and paramagnetic chemical exchange saturation transfer agents. The potential utility of these complexes for in vivo applications is contingent upon them being well tolerated by the body. The purpose of this study was to examine how the nature of the amide substituent, and in particular its charge, affected the fate of these chelates postinjection. Complexes of 6 DOTA-tetraamide ligands were prepared in which the nature of the amide substituent was systematically altered. The 6 ligands formed 3 series: a phosphonate series that included tri-cationic, mono-anionic, and poly-anionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tri-cationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either Gd or Lu, and the biodistribution profiles in rats recorded 2 hours postinjection. Biodistribution profiles were initially acquired at low doses to minimize adverse effects. All the complexes studied were found to be excreted primarily through the renal system, with the majority of the dose being found in the urine. None of the complexes exhibited substantial uptake by bone, liver, and spleen, except for a complex with 4 phosphonate groups that exhibited significant bone targeting capabilities. Increasing the dose of each complex to that of a typical MR contrast agent was found to render all 3 tri-cationic complexes studied here acutely toxic. In contrast, no ill effects were observed after administration of similar doses of the corresponding anionic complexes. The absence of uptake by the liver and spleen indicate that irrespective of the ligand structure and charge, these complexes are not prone to dissociation in vivo. This is in agreement with previously published work that indicates high kinetic inertness for this class of compounds. At low doses, all complexes were well tolerated; however, for applications that require higher doses, the structure and charge of the ligand becomes a fundamentally important parameter. The results reported herein demonstrate the importance of incorporating negatively charged groups on amide substituents if a DOTA-tetraamide complex is to be employed at high doses in vivo.

On the potential causal relationship between gadolinium‐containing MRI agents and nephrogenic systemic fibrosis

THERE IS GROWING INTERNATIONAL CONCERN related to the possibility that gadolinium-containing MRI agents are or may be associated with nephrogenic systemic fibrosis (NSF). Nephrogenic systemic fibrosis is known to be a rare multisystem fibrosis disorder that primarily affects the skin but may affect other organs of patients with renal insufficiencies. The opinions expressed in recent publications vary related to the determination of whether intravenous gadolinium-containing MR agents are definitely, possibly, or conditionally associated with the development of NSF. The literature has a range of opinions, a few of which are described here. A recent article in the American Journal of Roentgenology concludes that the development of NSF is strongly associated with gadodiamide administration in the clinical setting of either acute hepatorenal syndrome or dialysis-dependent chronic renal insufficiency (1). A different opinion, stated in the guest editorial published in this issue, stresses that the exposure to gadolinium-containing agents is not currently a proven prerequisite for the onset of NSF (2). Also, in their recent review of 3D contrast-enhanced MR angiography, Zhang et al (3) suggest that gadolinium-based contrast agents do not pose a risk for nephrotoxicity. However, in a letter to the editor that is currently in press with JMRI (4), this suggestion has been challenged. The authors of the letter to the editor note that gadolinium-based contrast agents might induce NSF, a newly identified, debilitating, and potentially fatal disorder (5) in patients with renal insufficiencies. They urge practitioners to stay updated about this emerging disorder and to follow appropriate recommendations. In an article published in this issue, Lin and Brown (6) state that the causal link between high dose gadolinium-containing agents and NSF has not been proven. That article refers to the U.S. Food and Drug Administration (FDA) recommendation that cautious use of any gadolinium in patients with advanced renal failure be applied. This article also recommends that if contrast-enhanced MR examination is necessary, the dose should be limited and dialysis should be promptly performed (7). In addition, the American College of Radiology has just issued guidelines for the utilization of gadolinium-containing MRI contrast agents in patients with renal disease (8). Clearly, consensus is needed concerning the risks and recommended safety guidelines for contrast-enhanced MRI studies. Through JMRI and the society, ISMRM, and its members whom we serve, we have both the opportunity and the responsibility to communicate new and accurate information. This can involve maintaining a balance between disseminating reports with documented credibility related to any MRI issue—including contrast enhancement—while not prematurely raising anxiety with data that are or may be currently incomplete or evolving. With the goal of achieving this balance, JMRI is pleased to participate in and enable peer review for scientific articles and data that result from the special round table discussion and poster session that have been developed for the annual ISMRM/ESMRMB meeting in Berlin on the topic of the potential causal relationship between gadolinium-containing MRI agents and nephrogenic systemic fibrosis (NSF). The round table discussion is scheduled for Tuesday, May 22, 13:30–15:30 hours, and the poster session is scheduled for Thursday, May 24, 14:50–15:30 hours. We anticipate reviewing and potentially publishing in JMRI a summary of conclusions and recommendations that come from these sessions, together with peer-reviewed, revised, and accepted scientific papers on the subject, which we hope to group together in a special section, or possibly in a special issue of JMRI. I encourage each interested ISMRM member's active participation in dialogue related to this topic, including the round table discussion and poster session in Berlin this month. Letters to the editor are welcome! Together we seek the finest scientific data and the finest clinical investigations that can result in appropriate guidelines or boundary conditions for the safe utilization of gadolinium-containing MRI contrast agents in all patients, especially those with severe renal disease.

Amplification strategies in MR imaging: Activation and accumulation of sensing contrast agents (SCAs)

We review new strategies for the development of Gd3+-based T1-relaxation agents and paramagnetic chemical exchange saturation transfer (PARACEST) "sensing" contrast agents (SCAs) designed specifically to detect small molecules or enzymatic activity in living systems. The first class of agents exhibits molecular "sensing" properties as a result of water coordination sphere effects, cleavage, or synthesis of reactive precursor compounds that recombine with macromolecules with the resultant formation of immobilized or rotationally constrained paramagnetic cations. This effect results in changes of water proton relaxation times. The second class (PARACEST) comprises a family of lanthanide-based paramagnetic compounds suitable for CEST imaging. The need for both types of MR agents is justified by efforts to utilize magnetic resonance imaging (MRI) to visualize fine structures in living tissue, and to increase the molecular specificity of MRI.

Initial clinical experience with oral manganese (CMC-001) for liver MR imaging

Recently, a new oral liver-specific manganese-based MR agent (CMC-001) has been introduced. This contrast medium is delivered to the liver in high concentrations in the portal vein and very low doses in the hepatic artery, as only small amounts of manganese enter the general circulation. It is taken up by the hepatocytes and excreted in the bile. Our initial experience with the new MR contrast medium in a variety of patients is reported. A total of 20 patients (11 males and 9 females) were studied with MR imaging 2 h after oral ingestion of the contrast agent. Sixteen patients were referred for evaluation of focal liver lesion(s), whereas in the remaining four patients, evaluation of the biliary tract was requested. In the 17 patients without biliary obstruction, there was an increased signal intensity of the liver parenchyma, whereas in the three patients with biliary obstruction, the uptake was delayed. There was excellent visualization of the biliary system on the T1-weighted images in the 16 patients without biliary obstruction referred for evaluation of a focal liver lesion. In seven patients, the uptake was patchy. In patients with focal liver lesions or biliary tract diseases, it is possible to increase the signal intensity of the liver parenchyma after the oral intake of CMC-001. In patients without biliary tract obstruction, the biliary system is easily visualized. Oral manganese seems to be useful in hepatobiliary MRI. Further research is strongly warranted.

Osmolarity: a decisive parameter of bowel agents in intestinal magnetic resonance imaging

The aim was to evaluate the importance of the osmolarity of different oral agents for bowel distension and the level of related adverse events. The longitudinal design included the exposition of different oral MR agents on two separate occasions. Four groups of volunteers were randomly given 350 ml gastrografin of three different concentrations and water. On the second occasion they received mannitol, iohexol or iodixanol with equivalent osmolarities, but the control group (water) received mannitol. We recorded the outcomes as the degree of bowel distension determined as the mean bowel section area and the total level of discomfort recorded from a visual analogue scale (VAS). The statistical analysis included scatter plots with the best-fitted line with linear regression to study the association between osmolarity and section area and the association between osmolarity and adverse events. A dose-response association was found between increasing osmolarity levels and bowel area in square centimeters (P = 0.00001). A similar dose-response association existed between increasing levels of osmolarity and adverse events (P = 0.001). Osmolarity appears to be more important for bowel distension than the physico-chemical characteristics of the nonabsorbable oral agents. The optimum osmolarity level is determined by the patient's tolerance of the adverse events.

Synthesis and Magnetic Relaxation Properties of Paramagnetic Gd-complexes of New DTPA-bis-amides. The X-ray Crystal Structure of [Gd(L)(H2O)]？H2O (L = DTPA-bis(4-carboxylicphenyl)amide)

A new type of DTPA-bis-amides (L1-L4) and their Gd(III)-complexes of the type [Gd(L)(H 2 O)]·nH 2 O (5: L1; 6: L2; 7: L3; 8: L4) have been prepared and characterized by analytical and spectroscopic techniques. The X-ray crystal structure of 8 has been determined for structural confirmation. The coordination geometry adopts a tricapped trigonal prism geometry with L4 acting as a chelate octadentate and a water molecule in the coordination sphere. Crystals are monoclinic, P2 1 , a = 14.468(3), b = 19.235(4), c = 13.527(2) A, β = 107.245(3)°, V = 3595.2(11) A 3 , Z = 4, D calc = 1.570. Significant increases in relaxivities are observed with 6 and 7 as compared with that of Omniscan®, a commercial MR agent: R1 = 12.46 mM -1 s -1 , R2 = 8.76 mM -1 s -1 for 6; R1 = 12.77 nm -1 s -1 , R2 = 7.60 mM -1 s -1 for 7; R1 = 4.9 mM -1 s -1 , R2 = 4.8 mm -1 s -1 for Omniscan®. In the case of 5, however, both Rl and R2 are found to be lower to show 2.09 mM -1 s -1 and 1.82 mM -1 s -1 , respectively.

Toward the Design of MR Agents for Imaging β-Cell Function.

The chemistry of Gd(3+)-based MRI agents has advanced considerably during the past decade toward agents with higher relaxivity and agents that respond to physiology and/or metabolism. This review describes various approaches that have been taken toward the development of responsive contrast agents and discusses the importance of fast water exchange for advancement of targeted Gd(3+)-based agents with higher sensitivity. The recent discovery of Eu(3+) complexes having extraordinarily slow water exchange has opened a new avenue in contrast agent design based upon the chemical exchange saturation transfer (CEST) mechanism. These new paramagnetic complexes called PARACEST agents offer new possibilities of imaging biological functions such as tissue pH and metabolite levels. The lower detection limits that may apply to each class of contrast agent (Gd(3+)-based versus PARACEST) are discussed and the extent to which they may be applied to the imaging of β-cells is considered.

Cyanine Dyes as Contrast Agents in Biomedical Optical Imaging

As light exhibits highest penetration into living tissue in the near-infrared (NIR) region between 700 and 900 nm, tissue probing with NIR light provides the opportunity to detect tumors or other abnormalities up to several centimeters below the tissue surface (1). To gain a deeper understanding of physiological and molecular processes in vivo, an important role is increasingly attributed to the acquisition of optical signals generated by exogenously administered fluorescent probes (2–4). Particularly, NIRabsorbing cyanine dyes are potentially suited as fluorescent contrast agents, e.g. for fluorescence-guided endoscopy or optical mammography (1). The fact, that fluorescent dyes can be detected at low concentrations and nonionizing, harmless radiation can be applied repeatedly to the patient renders this technology particularly attractive. In the area of organic dyes, the class of cyanine dyes has proven to be most promising for biomedical applications (5). Thus, the objective of our work is the synthesis of novel cyanine dyes and their characterization as fluorescent contrast agents. Following different concepts, a hydrophilic indotricarbocyanine, which is supposed to act as extracellular contrast agent similar to MR agents, was studied on the one hand. In a different approach we demonstrate that receptor-mediated intracellular tumor targeting using cyanine dye-labeled peptides, which are structurally derived from natural ligands of heptahelical receptors, is a feasible way to achieve specific accumulation and high contrasts in animal tumors. One particular approach was adapted from the radiodiagnostic agent OctreoScan® and involved the use of the peptide octreotate which is known to effectively bind to the somatostatin receptor (SSTR).

Gd3+ complexes with slowly exchanging bound-water molecules may offer advantages in the design of responsive MR agents.

Slow water exchange in Gd3+ complexes is generally considered detrimental to their use as MR contrast agents. The objective of this work was to demonstrate how this feature may serve as a useful template for the design of responsive MR agents. Lanthanide (Ln) complexes of two 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA)-tetraamide phosphonate (1) and phosphonate ester (2) ligands were studied by multinuclear (1H, 13C, 31P, and 17O) nuclear MR spectroscopy. The inner-sphere water lifetime in the Ln(2) complexes was much longer (tauM298 = 0.8-1.3 ms) than in the corresponding Ln(1) complexes. This allowed direct detection of the bound-water molecule in europium(2) in water at 40 degrees C by 1H nuclear MR. The water relaxivity of gadolinium(2) was independent of pH between 8.5 and 6.0, whereas the relaxivity of gadolinium(1) increased more than twofold in this pH range. T1-weighted images of phantoms containing gadolinium(1) at different pH values demonstrate the efficacy of this complex as a pH-sensitive MR contrast agent.

Splanchnic vessels

Splanchnic vessels

Contrast Media Research

This selective review highlights research in contrast media development and application in the field of diagnostic radiology in 1998 and 1999. The focus is on research published in Investigative Radiology, supplemented with work from other publications in the few areas not extensively covered by the journal. Studies continue to be performed, although at a low level, examining safety issues. Most preclinical investigations have focused on MR and ultrasound agents. In MR, the research effort is concentrated on the development of targeted agents; in ultrasound, work is focused on the characterization of basic contrast mechanisms. The demonstration of clinical applications is still dominated by work with MR, both in disease models and human investigations. The use of extracellular gadolinium chelates to enhance visualization of blood vessels (the field of contrast-enhanced MR angiography) is the largest single new clinical application of contrast media to emerge in several years. New clinical applications continue to be pursued with contrast media in CT, ultrasound, and x-ray angiography. As intravenously injected ultrasound contrast agents come to market, trials demonstrating clinical applications and subsequent scientific publications will increase in number.

Development of a novel nonaromatic small-molecule MR contrast agent for the blood pool.

The ideal contrast agent for MR angiography should be safe, efficacious, blood-persistent, and easily excreted. The binding of small Gd chelates to macromolecules has been shown to provide a mechanism of proton relaxation enhancement in MR images through longer rotational correlation times of the macromolecule-bound Gd-chelate complexes (1,2). Several effective macromolecules bearing such covalently attached Gd chelates have been synthesized and evaluated previously for MRA applications. These, however, either proved unsafe (protein precipitants) or had undesirably long blood retention, ie, were not easily excreted (3-6). Reversible noncovalent binding of small Gd chelates to serum albumin (via hydrophobic interactions) produces an efficacious, blood persistent alternative to macromoleculebased MR blood-pool agents without attendant clearance problems (7,8). A prime requirement for this approach is the presence of a lipophilic component on the Gd chelate that can undergo reversible protein binding. An MR blood-pool agent, MS-325, which takes advantage of the binding of aromatic side chains on a Gd-chelate compound to albumin, is under development (2,7,8). We now report the results of our attempt to develop a nonaromatic small Gd 3+ chelate as a contrast agent for MR angiography (ie, MP-2269, a water-soluble MR agent that binds blood proteins reversibly to yield an efficacious blood-pool agent).

Comparison between Gd-DTPA, Gd-EOB-DTPA, and Mn-DPDP in induced HCC in rats: A correlation study of MR imaging, microangiography, and histology

The behaviour of two liver-specific contrast MR agents, Gd-EOB-DTPA and Mn-DPDP and one nonspecific contrast agent, Gd-DTPA, was compared in a rat model of chemically induced hepatocellular carcinoma (HCC). The study included contrast enhanced MR imaging and the corresponding microangiography and histology. Analysis of the MR images showed similar degrees of maximum relative liver enhancement: 47.5 ± 8.2% for Gd-EOB-DTPA (0.03 mmol/kg) at 5 min postinjection and 52.5 ± 14.4% for Mn-DPDP (0.025 mmol/kg) at 15 min; both exceeded the value obtained with Gd-DTPA (34.8 ± 13.6%, at 5 min), even at 0.3 mmol/kg. Gd-EOB-DTPA caused a similar “negative” enhancement of all types of HCC, independent of their differentiation and vascularization, i.e., lesion-to-liver contrast-to-noise ratio (CNR) of differentiated and undifferentiated HCC increased negatively from, respectively, 1.9 ± 1.1 and −5.1 ± 3.1 before contrast to −5.2 ± 2.4 and −11.8 ± 4.8 at 5 min after contrast. On Mn-DPDP enhanced images, the undifferentiated HCCs showed up negatively (CNR −5.5 ± 4.7 before contrast to −13.7 ± 10 at 15 min after contrast), whereas the more differentiated tumors showed up positively (CNR from 2.3 ± 2.0 before contrast to 12.5 ± 3.5 at 24 hr postcontrast) due to active uptake and delayed elimination of Mn-DPDP.