T1 Agents Research Articles

Multimodal MRI contrast agents

The advent of powerful new imaging tools such as confocal and two-photon microscopy, MRI, PET, SPECT, and ultrasound have provided scientists and clinicians with the ability to acquire in vivo images of anatomy and physiology in whole animals and humans [1–3]. Each of these in vivo imaging techniques possesses unique strengths and weaknesses with varying spatial and temporal resolution limits [4]. Further, the development of sophisticated reporter probes for cell tracking, gene expression, and gene monitoring therapeutic paradigms is rapidly changing the way these techniques are being applied. For example, advances in optical microscopy have revolutionized the way living cells and intact tissues are studied [5]. As a result, cellular events, biochemical processes, and tissue morphogenesis can be followed in developing embryos at submicron resolution. MRI employs nonionizing radiation and has become an integral tool in clinical radiology, and more recently in experimental settings [6–8]. The intensity of the signal in each voxel is dependent on several intrinsic parameters, such as the proton density, longitudinal (R1) and transverse (R2) NMR relaxation rates, and extrinsic parameters, such as magnetic field strength, pulse sequence, and the presence of contrast agents (CAs). CAs for a variety of imaging methods have been in use for decades in diagnostic radiology and developmental biology [9–13]. The application of these CAs is well documented and the fundamental chemical principles for the synthesis and characterization of these complexes are known [14–16]. A rapidly growing body of literature documents the clinical effectiveness of paramagnetic CAs [17–19]. Currently, eight such CAs are in clinical use or clinical trials and more than 30% of all clinical MRI examinations employ CAs [20]. Paramagnetic metal ions, as a result of their unpaired electrons, act as potent relaxation-enhancement agents and decrease the T1 and T2 relaxation times of nearby spins [21]. Some paramagnetic ions decrease T1 without causing substantial line broadening [T1 agents; e.g., Gd(III)], while others induce drastic line broadening (T2 agents; e.g., superparamagnetic iron oxide) [22]. The lanthanide ion Gd(III) has generally been chosen as the metal ion for CAs because it has a high magnetic moment (l = 63 lB ) and a symmetric electronic ground state (S) [23]. Transition metal ions such as high-spin Mn(II) and Fe(III) are candidates owing to their high magnetic moments. The mechanism of T1 relaxation is generally a through-space dipole–dipole interaction between the unpaired electrons of the paramagnetic metal ion and the protons of coordinated or diffusing water molecules. The longitudinal and transverse relaxation rates (Ri) of a CA solution are proportional to the CA’s relaxivity rip (Eq. 1) [20, 23]:

Dynamic imaging with MRI contrast agents: quantitative considerations

Time-resolved MRI has had enormous impact in cognitive science and may become a significant tool in basic biological research with the application of new molecular imaging agents. In this paper, we examine the temporal characteristics of MRI contrast agents that could be used in dynamic studies. We consider "smart" T1 contrast agents, T2 agents based on reversible aggregation of superparamagnetic nanoparticles and sensors that produce changes in saturation transfer effects (chemical exchange saturation transfer, CEST). We discuss response properties of several agents with reference to available experimental data, and we develop a new theoretical model that predicts the response rates and relaxivity changes of aggregation-based sensors. We also perform calculations to define the extent to which constraints on temporal resolution are imposed by the imaging methods themselves. Our analysis confirms that some small T1 agents may be compatible with MRI temporal resolution on the order of 100 ms. Nanoparticle aggregation T2 sensors are applicable at much lower concentrations, but are likely to respond on a single second or slower timescale. CEST agents work at high concentrations and temporal resolutions of 1-10 s, limited by a requirement for long presaturation periods in the MRI pulse sequence.

Gadolinium(III)‐Loaded Nanoparticulate Zeolites as Potential High‐Field MRI Contrast Agents: Relationship Between Structure and Relaxivity

The effects of dealumination, pore size, and calcination on the efficiency (as expressed in the relaxivity) of Gd3+-loaded zeolites for potential application as magnetic resonance imaging (MRI) contrast agents were studied. Partial dealumination of zeolites NaY or NaA by treatment with (NH4)2SiF6 or diluted HCl resulted in materials that, upon loading with Gd3+, had a much higher relaxivity than the corresponding non-dealuminated materials. Analysis of the 1H NMR dispersion profiles of the various zeolites showed that this can be mainly ascribed to an increase of the amount of water inside the zeolite cavities as a result of the destruction of walls between cavities. However, the average residence time of water inside the Gd3+-loaded cavities did not change significantly, which suggests that the windows of the Gd3+-loaded cavities are not affected by the dealumination. Upon calcination, the Gd3+ ions moved to the small sodalite cavities and became less accessible for water, resulting in a decrease in relaxivity. The important role of diffusion for the relaxivity was demonstrated by a comparison of the relaxivity of Gd3+-loaded zeolite NaY and NaA samples. NaA had much lower relaxivities due to the smaller pore sizes. The transversal relaxivities of the Gd3+-doped zeolites are comparable in magnitude to the longitudinal ones at low magnetic fields (<60 MHz). However at higher fields, the transversal relaxivities steeply increased, whereas the longitudinal relaxivities decreased as field strength increased. Therefore, these materials have potential as T1 MRI contrast agents at low field, and as T2 agents at higher fields.

Important Considerations in the Design of Iron Oxide Nanoparticles as Contrast Agents for Tl-Weighted MRI and MRA

Organically coated magnetic monocrystalline iron oxide nanoparticles are being considered as contrast agents for T1-weighted magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) ( 1 Frank H Weissleder R Brady TJ Enhancement of MR angiography with iron oxide: preliminary studies in whole blood phantoms and animals. AJR Am J Roentgenol. 1994; 162: 209-213 Crossref PubMed Scopus (86) Google Scholar , 2 Knollmann FD Böck JC Teltenkötter S et al. Evaluation of portal MR angiography using superparamagnetic iron oxide. J Magn Reson Imaging. 1997; 7: 191-196 Crossref PubMed Scopus (20) Google Scholar , 3 Anzai Y Prince MR Chenevert TL et al. MR angiography with an ultrasmall superparamagnetic iron oxide blood pool agent. J Magn Reson Imaging. 1997; 7: 209-214 Crossref PubMed Scopus (149) Google Scholar , 4 Tobe K Yoshikawa K Seno A et al. Good resolution of contrast-enhanced MRA using USPIO on coronal plane acquisition. Acad Radiol. 1998; 5: S116-S118 Abstract Full Text PDF PubMed Google Scholar ). For such Tl-weighted applications, imaging efficacy is strongly dependent on the physical characteristics of the individual nanoparticles ( 5 Kellar KE Fujii DK Gunther WHH Briley-Sæbø K Spiller M Koenig SH “NC100150,” a preparation of iron oxide nanoparticles ideal for positive-contrast MR angiography. MAGMA. 1999; 8: 207-213 PubMed Google Scholar ). In particular, three stringent physical requirements must be satisfied. First, the magnetic cores must be of an optimal size with essentially a monodisperse size distribution. If the cores are too small, rl (the Tl relaxivity) will be too small for practical applications as T1 agents; if the cores are too large, r2 (the T2 relaxivity) may be so large relative to rl that the T1 efficacy of the particles will be diminished. Second, the high-field magnetization of the cores, typically close to its saturation value, must be sufficient to relax water protons effectively, also implying that the organic coating must not compromise access of solvent to the core. This high-field limit is related to both the total iron content of the cores and their geometry. Third, the nanoparticles cannot become agglomerated in vivo. Given that r2 is very sensitive to agglomeration and rl is not, agglomeration preferentially increases r2, thereby diminishing the efficacy of the nanoparticles as Tl agents.

Technology Transfer in the Transit Industry

The unprecedented advances taking place in the technology industries (computer, electronics, telecommunications) can benefit the transit industry by enabling safer, cleaner, and more reliable transit vehicles; easier maintenance; better customer service; and faster and more efficient scheduling and operations. Without an effective technology transfer process, however, the technologies may not reach the proper audience in the transit organization, or they may fail to elicit the appropriate response from transit staff. The two key elements of successful technology transfer in the transit industry are discussed—effective technology transfer infrastructure and technology transfer (T2) agents. Effective technology transfer infrastructure consists of an organizational culture that is open and flexible, a comprehensive evaluation mechanism, an efficient transfer design, and an effective training program. T2 agents are individuals or organizations that bring new technologies and information to agencies, which then can transform the technology and information into useful products, processes, or programs. Also discussed are intra- and interagency barriers, such as strict adherence to rule books and bureaucratic organizational structures, and examples are provided of how some agencies are addressing these problems.

Relaxivities of different superparamagnetic particles for application in NMR tomography

The development of nuclear magnetic resonance (NMR) imaging technique as a clinical diagnostic modality has prompted the need for a new class of pharmaceuticals, so-called magneto-pharmaceuticals. These drugs must be administered to a patient in order to (1) enhance the image contrast between normal and diseased tissue and/or (2) indicate the status of organ functions or blood flow. A number of different agents have been suggested as potential NMR contrast agents, most of which is highly paramagnetic. Superparamagnetic particles represent an alternative class of NMR contrast agents that usually referred to as T2 or T∗2 contrast agents, opposed to T1 agents such as paramagnetic chelates. Because of their large permanent dipole moments these agents are able to relax neighbouring nuclei faster than paramagnetic ions. The synthesis and measurements of the transverse R2 and longitudinal R1 relaxivities of some ferro-, ferri- and superparamagnetic particles’ suspensions are presented.

A model for MRI contrast enhancement using T1 agents.

Contrast in MRI relies on differences in the local environment of water and is often enhanced by using contrast agents. We present a simple model for evaluating the minimal contrast agent concentration required to produce "satisfactory" contrast enhancement in magnetic resonance images. Previous strategies have been based largely on empirical results for specific systems. The present tissue contrast model (TCM) can be applied to "conventional," targeted, or biochemically responsive agents. The model results are formulated so that only a small number of parameters are required to analyze a given scenario. The TCM is a particularly useful tool in the development of new classes of magnetic resonance contrast media. These agents will have the ability to target specific cells or tissue, and perhaps be able to report on their physiological status. As an example of the applicability of the TCM, we test it against in vivo magnetic resonance microscopy results in frog embryos that have focal cell populations labeled with contrast agent by using calibrated single-cell microinjection techniques.

Adult Learning Styles and Effective Transfer of Information

Effective training and other technology transfer (T2) activities occur when teachers/trainers or T2 agents recognize and use training techniques that correspond to the learning styles of their learner audiences. Learning style is defined as one’s personally preferred way of processing information and experience. It crosses all content areas. It is affected by both intrinsic and extrinsic factors such as stress, world view, and environment. Each learner has the ability to utilize a variety of learning styles, and each teacher has a preferred teaching style based on his or her preferred information processing mode. Each learner learns most comfortably and fastest when his or her preferred learning style meshes with the teaching style of the teacher/trainer. Often teacher/trainers do not have the time, funds, or opportunity to determine their learners’ preferred styles. The effective teacher/trainer utilizes a variety of teaching techniques to engage and convey the most information to the most learners.

Preliminary evaluation of a polyethyleneglycol-stabilized manganese-substituted hydroxylapatite as an intravascular contrast agent for MR angiography.

A blood-persistent particulate paramagnetic contrast agent has been formulated via size stabilization of manganese-substituted hydroxylapatite by a polyethylene glycol (PEG) bearing a terminal diphosphonate. At high PEG surface densities (35-40 mol%), particles with mean diameter 8 +/- 2 nm were obtained. Relaxivities of autoclaved samples (at 20 MHz proton Lamor frequency) were R1 = 18.7 +/- .8 mM-1 sec-1 and R2 = 22.3 +/- .7 mM-1 sec-1. The formulation persisted in rabbit blood with a biphasic clearance profile. Half-lives (with amplitudes in parenthesis) were 4 +/- 1 minutes (55%), and 49 +/- 3 minutes (45%), respectively, for the two phases. A dose of 40 mumol Mn/kg body weight enhanced the signal from rabbit vasculature for more than 45 minutes on MR angiograms. Thus, PEG-modified MnHA particles may find use as T1 agents for MR angiography.

Iron-based second-sphere contrast agents for magnetic resonance imaging: development of a model system and evaluation of iron (III) tris (tironate) complex in rats.

Iron(III) complexes have been developed as magnetic resonance (MR) contrast agents based on the use of ligands capable of providing coordinative saturation at iron and allowing the second-sphere hydrogen bonding of water molecules. Studies of solution-phase binding of a probe ion to a diamagnetic metal catecholate complex and molecular orbital calculations were performed. R1 values were determined. Toxicity studies of iron(III) tris(tironate) were conducted with rats. Excretion studies were performed by analysis of urine samples. MR measurements were made. Second-sphere coordination of a probe ion to a metal catecholate complex occurred in solution. Molecular orbital calculations suggested flexibility in design. Iron(III) tris (catecholate) complexes were shown to have high R1 values. Images of the kidneys and liver showed dose-dependent enhancement in T1-weighted images. The onset of toxicity was at approximately 0.30 mmol/kg. Urine analysis indicated essentially complete clearance (0.1-0.2 mmol/kg) within 24-48 hours. Interactions between water molecules and basic sites within a paramagnetic metal-ligand complex allow for application of suitable complexes as T1 agents.

Macromolecular infarct-specific magnetic resonance contrast agents.

To identify safe and effective magnetic resonance imaging (MRI) agents for infarction, the authors investigate the possibility of using a small population of infarct-avid phosphonates to target macromolecular MRI agents to infarction. Several phosphonylated radiolabeled (gadolinium-153, iron-59) macroaggregates were synthesized. Biodistribution was assessed in a drug-induced rat model of diffuse myocardial infarction (MI). Agents that demonstrated preferential accumulation in infarcted whole hearts were additionally evaluated in occluded and reperfused rabbit hearts. Phosphonylated T2 agents have been thoroughly studied with MRI of MI, and the results are reported. Typically, core size was 11 to 13 nm and particle size was 120 nm. Phosphorus content was < 12% by weight. The relaxivities were R1 of 12 to 20 1/(mM.sec) and R2 of 119 to 270 1/(mM.sec) at 20 MHz in .5% agar. One hour after injection of .03 mmol/kg of the agent into six rabbits (45-minute occlusion with 1-hour reperfusion), the average myocardial tissue agent content was 70 +/- 30 nmol Fe/g (infarct) compared with 9 +/- 2 nmolFe/g (normal); P = .000. Similarly, the infarct zone was clearly discerned by MRI as hypointense on spin echo images, TR/TE = 400/30 msec and 2,000/30 msec with low-dose agent, whereas infarct was barely discernible only on TR/TE = 2,000/90 msec without agent. The magnetic resonance infarcts correlated with histology. Simple phosphonylated macromolecules can be used as low-dose, infarct-specific MRI agents.

Liver contrast media for magnetic resonance imaging. Interrelations between pharmacokinetics and imaging.

In the development of liver CM for MRI, three mainstream approaches have been undertaken: targeting of water-soluble MRI-CM to the hepatocytes, targeting of particles to the Kupffer cells of the liver, and application of macromolecular CM to tumorous tissue. As with the biliary iodinated CM, the physiological function of the liver has been used to target paramagnetic chelates (T1 agents) to the hepatocytes. Gd-EOB-DTPA and Gd-BOPTA are taken up mainly by hepatocytes and excreted into the bile by organic anion transporter (bilirubin transporter), whereas MnDPDP also uses the ability of hepatocytes to excrete metal ions, such as manganese. However, unlike the biliary iodinated CM, besides the specific accumulation in the hepatocytes, the low binding to plasma proteins and the high sensitivity of MRI, combined with the strong increase in relaxivity inside the hepatocellular environment, make the paramagnetic chelates very effective in the detection of liver lesions. Targeting of T2 agents (e.g. SPIO) to the Kupffer cells of the liver also has proved to be very effective in liver lesion detection. However, limited information is available regarding the pharmacokinetics of these particles in man and other problems, such as cardiovascular tolerance and manufacturing, must be overcome before widespread use of particulate CM can be implemented. The third approach is based on the differences in the vessel permeability, the vessel density, and functional lymphatics between normal and tumorous liver tissue when macromolecular CM are administered. This approach, however, is at an early research stage.

Basic physics of MR contrast agents and maximization of image contrast

This review summarizes the physical basis of magnetic resonance (MR) imaging contrast agents, including both T1 agents, such as gadolinium-DTPA (diethylenetriaminepentaacetic acid), and T2 or T2* agents, such as superparamagnetic iron oxides. The maximization of image contrast and lesion visibility with contrast agents is described, and the use of contrast agents in MR angiography and perfusion imaging is discussed.

From the relaxivity of Gd(DTPA)2− to everything else

We resolve the observed magnetic field-dependent relaxivity of Gd(DTPA)2- into inner and outer sphere contributions by comparison with theory. After noting that the outer sphere part, which contributes comparable to both 1/T1 and 1/T2, is identical to the "susceptibility" effect, we demonstrate the transition from the outer sphere relaxivity of small complexes, e.g., Gd(DTPA)2-, to that of large magnetic particulates, e.g., magnetite, used as T2 agents. This transition is expressed as a shift from a quantum to a classical mechanical description of relaxivity. We next show how to extrapolate the inner sphere contribution of Gd(DTPA)2- to similar small agents with greater structural symmetry, e.g., Gd(NOTA)-, by lengthening the electronic relaxation time and to ternary macromolecular complexes of small agents with protein by lengthening the rotational relaxation time. Finally, we indicate how relatively large lipid vesicles containing either small paramagnetic complexes or magnetized particulates may be considered analogs of Gd(DTPA)2-, with analogous inner and outer sphere contributions.