Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1999-10-05
2002-03-12
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320, C424S009360, C436S173000
Reexamination Certificate
active
06355225
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to compositions for improving magnetic resonance imaging (“MRI”), magnetic resonance spectroscopy (“MRS”), and magnetic resonance spectroscopy imaging (“MRSI”) and more particularly to contrast agents that have particular affinity for certain tissues and can therefore be used as contrast agents. Still more particularly, the present invention relates to paramagnetic contrast agents that comprise stable fullerene molecules adapted to dissolve in aqueous solutions.
BACKGROUND OF THE INVENTION
Magnetic Resonance Imaging (hereinafter “MRI”) is a powerful imaging tool that produces results analogous to x-ray images without requiring the application of harmful radiation. The nuclei of many atoms have a property called spin, which is associated with a small magnetic moment. In the absence of an external magnetic field, the distribution of the orientations of these magnetic moments is random. In the presence of a static external magnetic field, the nuclear magnetic moments precess about the field direction, producing a net alignment in the field. MRI works by exciting the molecules of a target object using a harmless pulse of radiofrequency (“RF”) energy to excite molecules that have first been aligned using a strong external magnetic field and then measuring the molecules' rate of return to an equilibrium state within the magnetic field following termination of the RF pulse.
For example, in NMR imaging, a patient is placed in a static field and a short radio frequency pulse is applied via a coil surrounding the patient. The radio frequency or RF signal is selected for the specific nuclei (e.g.
1
H) that are to be resonated. The RF pulse causes the magnetic moments of these nuclei to align with the new field and to precess in phase. On termination of the pulse, the moments return to the original distribution of alignments with respect to the static field and to a random distribution of precession phases, thereby giving off a nuclear magnetic resonance signal that can be picked up by a receiving coil. The NMR signal represents a proton density map of the tissue being studied.
Two additional values can be determined when the RF pulse is turned off and the nuclear magnetic moments are relaxing or returning to equilibrium orientations and phases. These are T
1
and T
2
, the spin-lattice and spin-spin relaxation times. T
1
represents a time characteristic of the return to equilibrium spin distribution, i.e. equilibrium alignment of the nuclear magnetic moments in the static field. T
2
, on the other hand, represents a time characteristic of the return to random precession phase distribution of the nuclear magnetic moments. Hence, the NMR signal that is generated may contain information on proton density, T
1
and T
2
. The visually readable images that are generated as output are the result of complex computer data reconstruction on the basis of that information.
Because successful imaging depends on the ability of the computer to recognize and differentiate between different types of tissue, it is not uncommon to apply a contrast agent to the tissue prior to making the image. The contrast agent alters the response of the aligned protons to the RF signal. Good contrast agents interact differently with different types of tissue, with the result that the effect of the contrast agent is greater on certain body parts, thus making them easier to differentiate and image. Various contrast agents are known for various medical imaging techniques, including X-ray, magnetic resonance and ultrasound imaging. Magnetic resonance contrast agents generally function by modifying the density or the characteristic relaxation times T
1
, T
2
and T
2
* of the water protons, which results in resonance signals from which the images are generated.
A paramagnetic substance is one that contains one or more fundamental particles (i.e. electrons or protons) with a spin whose effect is not cancelled out by another particle with like spin. These particles create a small magnetic field that can interact with neighboring nuclear magnetic dipoles to cause a reorientation of the dipole, i.e. a change in nuclear spin and precession phase. Because of their ability to affect relaxation times, many paramagnetic substances have potential as contrast agents. Since the magnetic field created by an electron is much greater than that created by a proton, however, in practice only ions, molecular radicals or metal complexes or cluster complexes that are paramagnetic as a result of containing one or more unpaired electrons are used as paramagnetic MRI contrast agents.
The use of paramagnetic metal ions, such as Mn(II), as contrast agents in MRI was first proposed by Lauterbur et al. in 1978. Since that time, a wide range of paramagnetic metal ion chelate complexes have been proposed. Metal ions that are reasonably stable and possess the highest magnetic moment, such as Mn
2+
, Fe
3+
, and Gd
3+
, are the most commonly employed, but any paramagnetic transition metal ion will also work. More recently the use of superparamagnetic particles as MRI contrast agents has been described in U.S. Pat. No. 4,863,715.
While metal ion contrast agents are often used in MRI, they are not suitable for all applications. For example, they are not particularly useful in certain body areas such as the gastrointestinal (GI) tract. In addition, these contrast agents can be toxic and chemically reactive in vivo. Hence, the majority of contrast agent research has focused on developing non-toxic, stable chelates for binding these metal ions. Attempts have been made to achieve tissue-specific MRI contrast enhancement, to decrease toxicity, or to enhance stability and/or relaxivity by coupling of the paramagnetic chelates, or metal complexing groups, to various macromolecules or biomolecules such as polysaccharides, proteins, antibodies or liposomes. Thus, for example, U.S. Pat. No. 4,647,447 discloses the use of salts of Gd(III) chelates of DTPA (diethylenetriamine pentaacetic acid). Current commercial products are based on Gd(III) chelates of DTPA, DOTA (1,4,7,10-tetraazacyclododecane -N, -N′, -N″, -N′″, -tetraacetic acid), and other modifications or derivatives of these chelates. In addition to metal chelates, the use of these metal ions as colloidal oxides or sulfides and as small superparamagnetic clusters has also been investigated.
Nevertheless, each of these approaches still requires the placement in the body of elements that have a degree of toxicity. Because the body may not readily eliminate these toxic elements, there is a potential health risk associated with their use.
In the search for a highly effective, non-toxic contrast agent, fullerene molecules have received attention. Researchers have speculated that fullerenes might be used to safely encapsulate and carry medically useful metals to different parts of the body where they could then be used for diagnostic or therapeutic purposes. In this capacity, the fullerene would act as a carrier for a metal atom or ion and maintain the same functionality as the metal chelates described above. For example, U.S. Pat. No. 5,688,486 discloses using fullerene molecules as cages or carriers for diagnostic or therapeutic entities. In particular, molecules are disclosed that enclose or support metal atoms or ions, preferably those that are paramagnetic or a radioisotope or have a large x-ray cross-section. Most of the compounds disclosed in the '486 patent, however, still include undesirable and potentially toxic metals.
The '486 patent makes brief reference to paramagnetic compounds comprising carbon mesh. Regarding such compounds, the '486 patent states that, “In certain imaging modalities the macromolecular mesh may itself function as a contrast agent.” The sole disclosure cited in the '486 patent that provides any disclosure of specific paramagnetic fullerene compounds that do not contain a metal ion is Krusic et al., Science, 254:1183-1185 (1991). Krusic teaches that benzyl and methy
Alford John M.
Wilson Lon J.
Conley & Rose & Tayon P.C.
Hartley Michael G.
Wm. Marsh Rice University TDA Research, Inc.
LandOfFree
Fullerene contrast agent for magnetic resonance imaging and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Fullerene contrast agent for magnetic resonance imaging and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fullerene contrast agent for magnetic resonance imaging and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2820078