Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1998-03-18
2001-06-05
Hollinden, Gary E. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009370, C534S007000, C436S173000, C600S420000
Reexamination Certificate
active
06241966
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to techniques of nuclear magnetic resonance imaging. In particular, the present invention relates to, among other things, the detection and imaging of a noble gas by nuclear magnetic resonance spectrometry.
Current views as to the molecular basis of anesthetic action are mostly derived from experimental work carried out in vitro. Interpretation of many of the results of these studies are extremely controversial, e.g., changes in lipid structure are observed at exceedingly high, indeed toxic, concentrations of anesthetic. Changes observed in vitro, from animals whose physiology has been altered, or from animals administered non-clinical doses of anesthetics might not reflect the effects of these agents clinically. It is believed that significant progress can be made by employing direct non-invasive methods for the detection and characterization of anesthetics in living animals. Both lipid solubility and protein binding undoubtedly do play a role, but new ideas are now needed.
Attempts have been made to bring powerful nuclear magnetic resonance (NMR) techniques to bear on this problem. (References 1-3). Wyrwicz and co-workers pioneered the use of fluorine-19 (
19
F) NMR spectroscopy to observe fluorinated anesthetics in intact tissues and recorded the first
19
F NMR spectra from the brain of a live anesthetized rabbit. (References 1, 4). These early studies demonstrated the feasibility of studying the fate of anesthetics in live mammals. Burt and collaborators also used halothane and other fluorinated anesthetics for monitoring membrane alterations in tumors by
19
F NMR. (References 5-6). In recent years, several groups have conducted
19
F NMR studies which have shed light on the molecular environment of anesthetics in the brains of rabbits and rats. (References 3, 7). Using a surface coil placed on top of the calvarium during halothane inhalation, two overlapping spectral features observed by d'Avignon and coworkers, perhaps 0.1-0.2 ppm apart, could be resolved through their different transverse relaxation times (T
2
). (Reference 3). The biexponential dependence of the spin-echo amplitude on echo delay reported in this study demonstrated that anesthetics in different molecular environments could be discerned in the brain i vivo using
19
F NMR. Such environments, separated by chemical shifts of only about 0.1 ppm, had previously been reported by Wyrwicz et al. in high resolution studies of excised neural tissue. (Reference 4).
Notwithstanding such attempts to use other compounds for NMR imaging, state-of-the-art biological magnetic resonance imaging (MRI) has remained largely restricted to the water proton,
1
H
2
O, NMR signal. The natural abundance of water protons, about 80-100M in tissue, and its large magnetic moment make it ideal for most imaging applications. Despite its tremendous value as a medical diagnostic tool, however, proton MRI does suffer several limitations. Most notably, the water protons in lung tissue, and the protons in lipids of all interesting biological membranes, are notoriously NMR invisible as a result of the short T
2
in such environments. (References 8-9). Other
1
H signals and signals from other biologically interesting nuclides are either present in too low a concentration (10
−3
to 10
−1
M, compared to ca. 100M for H
2
O) or have undesirable NMR characteristics. In studying dynamic processes with
1
H
2
O, one must sacrifice much of the proton signal to exploit differences in effective spin density resulting from T
1
and/or T
2
spatial variation. (Reference 10).
Various noble gases are known to be effective anesthetic agents. For example, Xenon is approved for use in humans, and its efficacy as a general anesthetic has been shown. Attempts have previously been made to take advantage of the properties of Xenon for purposes of medical imaging, but success has heretofore been extremely limited, and techniques have been impractical at best. For example, the
127
Xe isotope was used in early ventilation studies of the lung. (References 11-12). Unfortunately, the poor image quality attained limited its clinical use. Xenon has, however, been used as a contrast enhancement agent in computed tomography (CT) studies of the brain, (References 13-14), and as a tracer for regional cerebral blood flow (rCBF) measurements. (Reference 15).
An isotope of Xenon, Xenon-129 (
129
Xe), has non-zero nuclear spin (i.e., ½) and therefore is a nucleus which, in principle, is suited to study by nuclear magnetic resonance techniques. Despite the apparent potential for use of Xenon in magnetic resonance imaging, its small magnetic moment, and the low number densities of gas generally achievable, have heretofore been insuperable obstacles to practicable magnetic resonance (MR) imaging of
129
Xe at normal, equilibrium (also known as “Boltzmann”) polarizations, P (P~10
−5
in 0.5-1.5 Tesla (T) clinical imaging systems). However, unlike the water proton (
1
H) employed as the nucleus in conventional NMR techniques, the nuclear magnetic resonance signals obtainable from
129
Xe are extraordinarily sensitive to local environment and therefore very specific to environment.
Certain aspects of the behavior of
129
Xe, and other noble gas isotopes having nuclear spin, in various environments have been studied and described. For example, Albert et al. have studied the chemical shift and transverse and longitudinal relaxation times of Boltzmann polarized
129
Xe in several chemical solutions. (Reference 16). Albert et al. and others have also shown that oxygen can affect longitudinal relaxation time T
1
of
129
Xe. (References 17-18). Miller et al. have also studied the chemical shifts of
129
Xe and
131
Xe in solvents, proteins, and membranes. (Reference 2). However, none of these publications provides any indication of a method by which
129
Xe could be used for nuclear magnetic resonance imaging.
It is known in the art that the polarization of certain nuclei, such as noble gas nuclei having nuclear spin, may be enhanced over the equilibrium or Boltzmann polarization, i.e., hyperpolarized. Such techniques include spin exchange with an optically pumped alkali metal vapor and metastability exchange.
The physical principles underlying the hyperpolarization of noble gases have been studied. (Reference 19). For example, Happer et al. have studied the physics of spin exchange between noble gas atoms, such as Xenon, with alkali metals, such as Rubidium. (Reference 20). Others have studied spin exchange between Helium and alkali metals. (References 21-22, 49). Other publications have described physical aspects of spin exchange between alkali metals and noble gases. (References 23-24). The technique of using metastability exchange to hyperpolarize noble gases has been studied by Schearer et al. and by Hadeishi et al. (References 26-31).
Other publications, by Cates et al. and Gatzke et al., describe certain behaviors of frozen, crystalline
129
Xe that has been hyperpolarized. (References 32-33). Cates et al. and others describe spin-exchange rates between Rubidium and
129
Xe at high Xenon pressures as measured by magnetic resonance apparatus. (References 34-35). These publications, however, relate to
129
Xe behavior in highly controlled physical systems and provide no description concerning how
129
Xe might be used to produce images by nuclear magnetic resonance.
Raftery et al. have described optically pumped
129
Xe as an adsorption probe for the study of surface structure by analysis of NMR spectra. (References 36-37). Long et al. have also observed the chemical shift of laser polarized Xenon adsorbed to a polymer surface. (Reference 38).
U.S. Pat. Nos. 4,856,511 and 4,775,522 to Clark describe a nuclear magnetic resonance technique for detecting certain dissolved gases in an animal subject. Gas compositions described as useful for this technique include fluorine compounds such as perfluorocarbons. Other gases suggested to be potentially useful for the technique of Clark inclu
Albert Mitchell S.
Balamore Dilip
Cates, Jr. Gordon D.
Driehuys Bastiaan
Happer William
Hollinden Gary E.
Myers Bigel Sibley & Sajovec P.A.
The Trustees of Princeton University
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