Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1997-03-28
2002-07-30
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009370, C436S173000, C600S410000, C600S420000
Reexamination Certificate
active
06426058
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to nuclear magnetic resonance (NMR) techniques for both spectroscopy and imaging. More particularly, the present invention relates to the use of hyperpolarized noble gases (e.g., Xe and He) to enhance and improve NMR and MRI.
BACKGROUND OF THE INVENTION
Nuclear magnetic resonance (NMR) is an established technique for both spectroscopy and imaging. NMR spectroscopy is one of the most powerful methods available for determining primary structure, conformation and local dynamic properties of molecules in liquid, solid and even gas phases. As a whole-body imaging technique, Magnetic Resonance Imaging (MRI) affords images possessing such superb soft tissue resolution that MRI is the modality of choice in many clinical settings. MRI can produce images which allow the clinician to distinguish between a pathological condition and healthy tissue. For example, MR images clearly differentiate tumors from the surrounding tissue. Further, using MRI it is possible to image specific regions within the organism and to obtain anatomical (morphology and pathology) and/or functional information about various processes including blood flow and tissue perfusion. Functional imaging of the brain is now also well documented.
The structural and functional information available through MRI is complemented by whole-body NMR spectroscopy. NMR spectroscopic studies on organisms provides a means to probe the chemical processes occurring in the tissue under study. For example, the location and quantity of intrinsic NMR spectroscopic markers such as lactate and citrate can be studied to gain insight into the chemical processes underlying a disease state (Kurhanewicz, J., et al.,
Urology
45: 459-466 (1995)). NMR spectroscopy can also be used to observe the effects of administered drugs on the biochemistry of the organism or the changes in the drug which occur following its administration (Maxwell, R. J.,
Cancer Surv.
17: 415-423 (1993)). Efforts to improve the information yield from MRI and NMR spectroscopy through increased sensitivity or the use of appropriately designed extrinsic probes have been ongoing since the inception of these techniques.
Sensitivity poses a persistent challenge to the use of NMR, both in imaging and spectroscopy. In proton MRI, contrast is primarily governed by the quantity of protons in a tissue and the intrinsic relaxation times of those protons (i.e., T
1
and T
2
). Adjacent tissues which are histologically distinct yet magnetically similar appear isointense on an MR image. As the proton content of a tissue is not a readily manipulable parameter, the approach taken to provide distinction between magnetically similar tissues is the introduction into the biological system of a paramagnetic pharmaceutical (i.e, contrast enhancing agent) such as Gd(DTPA) (Niendorf, H. P., et al.,
Eur. J. Radiol.,
13: 15 (1991)). Interaction between the proton nuclei and the unpaired spins on the Gd
+3
ion dramatically decrease the proton relaxation times causing an increase in tissue intensity at the site of interaction. Gd(DTPA) and analogous agents are small molecular agents which remain largely confined to the exuccellular compartment and do not readily cross the intact blood-brain barrier. Thus, these agents are of little use in functional brain imaging
Similar to MRI, NMR spectroscopic studies generally rely on detecting NMR active nuclei which are present in their natural abundance (e.g.,
1
H,
31
P,
13
C) (Sapega, A. A., et al.,
Med. Sci. Sports Exerc.,
25: 656-666 (1993)). Additionally, the chemical species under observation must be spectroscopically distinguishable from the other compounds within the window of observation. Thus, sensitivity in NMR spectroscopy is a function of both the abundance and the spectral characteristics of the molecule(s) desired to be studied. The range of NMR spectroscopic studies has been somewhat expanded by the application of exogenous probes which contain NMR active nuclei, for example
19
F (Aiken, N. R., et al.,
Biochim. Biophys. Acta,
1270: 52-57 (1995)).
Noble gases are of interest as tracers and probes for MRI and NMR spectroscopy (Middleton, H, et al.,
Magn. Res. Med.
33: 271 (1995)), however, the sensitivity of MRI and NMR spectroscopy for these molecules is relatively low. A factor which contributes to the lack of sensitivity of these techniques for the noble gases is that the spin polarization, or net magnetic moment, of the noble gas sample is low. For example, a typical molecule at thermal equilibrium at room tempe has an excess of spins in one direction along an imposed magnetic field relative to those in the opposite direction of generally less than 1 in 10
5
. Lower temperatures and higher fields, to the extent that these can be imposed, provide only limited benefit. Alternative approaches rely on disrupting the equilibrium magnetization by forcing molecules in the sample into a polarzed state. Two methods known in the art for enhancing the spin polarization of a population of nuclei are dynamic nuclear polarization and optical pumping.
Dynamic nuclear polarization, originally applied to metals, arises from the cross relaxation between coupled spins. The phenomenon is known as the Overhauser Effect, with early disclosures by Overhauser and others (Ovehauser, A. W., “Polarization of nuclei in metals,”
Phys. Rev.
92(2): 411-415 (1953), Solomon, I., “Relaxation processes in a system of two Spins,”
Phys. Rev.
99(2): 559-565 (1955), and Carver, T. R., et al., “Experimental verification of the Overhauser nuclear polarization effect,”
Phys. Rev.
102(4): 975-980 (1956)). The Nuclear Overhauser Effect between nuclear spins is widely used to determine interatomic distances in NMR studies of molecules in solution.
Optical pumping is a method for enhancing the spin polarization of gases which consists of irradiating an alkali metal, in the presence of a noble gas, with circularly polarized light. The hyperpolarized gases that result have been used for NMR studies of surfaces and imaging void spaces and surfaces. Examples are the enhanced surface NMR of hyperpolarized
129
Xe, as described by Raftery, D., et al.,
Phys. Rev. Lett.
66: 584 (1991); signal enhancement of proton and
13
C NMR by thermal mixing from hyperpolarized
129
Xe, as described by Driehuys, B., et al.,
Phys. Let.
A184: 88-92 (1993), and Bowers, C. R., et al.,
Chem. Phys. Lett.
205: 168 (1993), and by Hartmann-Hahn cross-polarization, as described by Long, H. W., et al.,
J. Am. Chem. Soc.
115: 8491 (1993); and enhanced MRI of void spaces in organisms (such as the lung) and other materials, as described by Albert, M. S., et al.,
Nature
370: 199-201 (1994), and Song, Y.-Q., et al.,
J. Magn. Reson
. A115: 127-130 (1995).
Although hyperpolarized noble gases have proven useful as probes in the study of the air spaces in lungs, the effectiveness or sensitivity of these methods is somewhat compromised for biological materials and organs, such as blood and the parts of the body that are accessible only through the blood. During its residence time in the blood, the hyperpolarized gas is diluted considerably and the delay in transferring the gas from the lung space to the blood consumes much of the time (e.g., T
1
) required for the polarized gas to return to its non-hyperpolarized state. Further complicating the situation, the penetration of the hyperpolarized gas into the interior of red blood cells dramatically reduces the T
1
of the hyperpolarized gas and thus, sorely attenuates the temporal range over which the gas can serve as an effective probe.
A considerable advance in both MRI and NMR spectroscopy could be achieved by the introduction of a versatile hyperpolarized noble gas-based NMR active tracer which could also function as a contrast enhancing agent or otherwise affect, in a spectroscopically discernable manner, sample molecules to which the probe is proximate. Among other applications, such an agent would be useful in conjunction with functional imaging of the brain and also to probe the
Appelt Stephan
Bifone Angelo
Budinger Thomas
Goodson Boyd
Navon Gil
Hartley Michael G.
O'Banion John P.
Ritchey James M.
The Regents of the University of California
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