Diagnostic procedures using 129Xe spectroscopy...

Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent

Reexamination Certificate

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Reexamination Certificate

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06696040

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to magnetic resonance spectroscopy methods utilizing chemical shifts of hyperpolarized
129
Xe.
BACKGROUND OF THE INVENTION
MRI using hyperpolarized noble gases has been demonstrated as a viable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. The contents of this patent are hereby incorporated by reference as if recited in full herein. Albert et al. proposed several techniques of introducing the hyperpolarized gas (either alone or in combination with another substance) to a subject, such as via direct injection, intravenous injection, and inhalation. See also “
Biological magnetic resonance imaging using laser
-
polarized
129
Xe
,” Nature, pp. 199-201 (Jul. 21, 1994). Other researchers have since obtained relatively high-quality images of the lung using pulmonary ventilation of the lung with both hyperpolarized
3
He and
129
Xe. See J. R. MacFall et al., “
Human lung air spaces: Potential for MR imaging with hyperpolarized He
-3,” Radiology 200, 553-558 (1996); and Mugler et al., “
MR Imaging and spectroscopy using hyperpolarized
129
Xe gas: Preliminary human results
” Mag Res Med 37, 809-815 (1997). See also E. E. de Lange et al., “
Lung Airspaces: MR Imaging evaluation with hyperpolarized Helium
-3
gas
, ” Radiology 210, 851-857 (1999); L. F. Donnelly et al., “
Cystic fibrosis: combined hyperpolarized
3
He
-
enhanced and conventional proton MR imaging in the lung—preliminary observations
,” Radiology 212, 885-889 (1999); and H. P. McAdams et al., “
Hyperpolarized
3
He
-
enhanced MR imaging of lung transplant recipients: Preliminary results
,” AJR 173, 955-959 (1999).
These researchers and others have investigated vascular and tissue imaging using inhaled or injected hyperpolarized gases to observe and detect abnormalities in body cavities.
129
Xe may additionally be used to detect abnormalities within tissues because of its high solubility (relative to
3
He) and lipophilic nature. Despite these advantages, hyperpolarized
129
Xe cannot readily or typically achieve the signal strength readily attainable with hyperpolarized
3
He. Hyperpolarized
129
Xe has an inherently shorter lifespan even under the best of conditions due to depolarizing interactions between
129
Xe nuclei. When hyperpolarized
129
Xe additionally interacts with body tissues, its lifetime is reduced further as will be discussed hereinbelow.
129
Xe can be administered to a patient by several means, such as by inhalation and injection. During inhalation delivery, a quantity of hyperpolarized
129
Xe is inhaled by a subject (a subject breathes in the
129
Xe gas) and the subject then holds his or her breath for a short period of time, i.e. a “breath-hold” delivery. This inhaled
129
Xe gas volume then exits the lung space and is generally taken up by the pulmonary vessels and associated blood or pulmonary vasculature at a rate of approximately 0.3% per second. For example, for an inhaled quantity of about 1 liter of hyperpolarized
129
Xe, an estimated uptake into the body is about 3 cubic centimeters per second or a total quantity of about 40 cubic centimeters of
129
Xe over about a 15 second breath-hold period. Accordingly, it has been noted that such uptake can be used to generate images of pulmonary vasculature or even organ systems more distant from the lungs. See co-pending and co-assigned U.S. patent application Ser. No. 09/271,476 to Driehuys et al, entitled “Methods for Imaging Pulmonary and Cardiac Vasculature and Evaluating Blood Flow Using Dissolved Polarized
129
Xe,” the contents of which are hereby incorporated by reference as if recited in full herein.
Many researchers are also interested in the possibility of using inhaled
129
Xe for imaging white matter perfusion in the brain, renal perfusion, and the like. While inhaled delivery
129
Xe methods are suitable, and indeed, preferable, for many MR applications for several reasons such as the relatively non-invasive characteristics attendant with such a delivery to a human subject, inhalation or ventilation-based deliveries may not be the most efficient method to deliver a sufficiently large dose to more distant (away from the pulmonary vasculature) target areas of interest. In addition, due to the dilution of the inhaled
129
Xe along the perfusion delivery path, relatively large quantities of the hyperpolarized
129
Xe are typically inhaled in order to deliver a small fraction of the gas to the more distal target sites or organ systems. For example, the brain typically receives only about 13% of the total blood flow in the human body. Thus, the estimated 40 cc's of hyperpolarized
129
Xe taken up into the pulmonary vessels from the 1-liter inhalation dose may be reduced to only about 5 cc's by the time it reaches the brain.
Further, the hyperpolarized state of the gas is sensitive and can decay relatively quickly due to a number of relaxation mechanisms. Indeed, the relaxation time (generally represented by a decay constant “T
1
”) of the
129
Xe in the blood, absent other external depolarizing factors, is estimated at T
1
=4.0 seconds for venous blood and T
1
=6.4 seconds for arterial blood at a magnetic field strength of about 1.5 Tesla. See Wolber et al., Proc Natl Acad Sci USA 96:3664-3669 (1999). The more oxygenated arterial blood provides increased polarization life over the relatively de-oxygenated venous blood. Therefore, for about a 5-second transit time, the time estimate for the hyperpolarized
129
Xe to travel to the brain from the pulmonary vessels, the
129
Xe polarization is reduced to about 37% of its original value. In addition, the relaxation time of the polarized
129
Xe in the lung itself is typically about 20-25 seconds due to the presence of paramagnetic oxygen. Accordingly,
129
Xe taken up by the blood in the latter portion of the breath-hold cycle can decay to about 50% of the starting polarization (the polarization level of the gas at the initial portion of the breath-hold cycle). Thus, generally stated, the average polarization of the
129
Xe entering the pulmonary blood can be estimated to be about 75% of the starting inhaled polarization value. Taking these scaling effects into account, the delivery to the brain of the inhaled
129
Xe can be estimated as about 1.4 cc's of the inhaled one liter dose of
129
Xe polarized to the same polarization level as the inhaled gas (0.75×0.37×5 cc's). This dilution reduces signal delivery efficiency; i.e. for remote target areas (such as the brain), the quantity of delivered
129
Xe signal is typically severely reduced to only about 0.14% of that of the inhaled
129
Xe. Since MR imaging requires high signal strength to achieve a clinically useful spatial resolution in the resulting image, inhalation delivery may not produce clinically desirable images of distal or remote target organs or regions. However, much smaller quantities, for example on the order of approximately 0.01 cc's of
129
Xe, polarized to about 10%, are sufficient to provide signal information for MR spectroscopy.
An alternative method for delivering hyperpolarized
129
Xe is injection.
129
Xe injection can be accomplished by suspending the hyperpolarized gas in a carrier or by direct gaseous injection. See international patent application PCT/US97/05166 to Pines et al, the contents of which are hereby incorporated by reference as if recited in full herein. In this application, Pines et al describes suitable injectable solutions in which to suspend hyperpolarized gases for in vivo use to effectively target regions or areas of the body. See also co-pending U.S. patent application Ser. No. 09/804,369 to Driehuys et al., entitled “Diagnostic Procedure Using Direct Injection of Gaseous Hyperpolarized
129
Xe and Associated Systems and Products,” the contents of which are hereby incorporated by reference as if recited in full herein. Generally stated, this patent application describes methods and an associated apparatus for injecting hyperpolarized
129
Xe directly into the vasculatu

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