JP2002525188A - Magnetic resonance imaging method - Google Patents

Abstract

(57) [Summary] To identify an artery from a vein in an MR image. The present invention provides a method for magnetic resonance imaging of local blood oxygenation, the method comprising the steps of introducing T into a vascular network of a human or non-human animal subject with vascular tissue. ₍₂₎ administering a blood pool contrast agent, detecting a magnetic resonance signal from at least a part of the vascular network of the subject where the contrast agent is distributed, processing the signal, and processing the signal to at least a part of the vascular network; Generating an indication of the oxygen partial pressure (pO ₂ ) at

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to magnetic resonance imaging, and more particularly to improving imaging of blood oxygenation, and more particularly to a magnetic material used for manufacturing a contrast medium used in such an imaging method.

In magnetic resonance angiography, a method of imaging a vascular network by magnetic resonance (MR), it is necessary to distinguish arteries from veins. Conventional MR contrast agents with a long blood half-life, that is, conventional MR contrast agents that remain in the circulating blood for a long period of time, are generally:
Veins and arteries are similarly augmented. Therefore, arteries cannot be distinguished from veins in MR images.

[0003] The present invention relies on the use of a contrast agent that has the effect of reducing water protons T ₁ and T ₂ and is retained in the blood plasma, ie, is hardly distributed in the stroma or crosses the cell membrane. ing. Resides in the blood, subsequent to such contrast agents referred to as "T ₂ blood pool agent", there are two different contributions to T ₂ reduced to water protons in the blood, i.e., it passes through a contrast agent in the blood Diffusion through the magnetic field gradient due to the difference in magnetization between the inside and outside of the red blood cell. The second of these contributions depends on the oxygenation status of hemoglobin in red blood cells. In the veins, hemoglobin is deoxygenated, so that red blood cells are paramagnetic, while hemoglobin in the arteries is oxygenated, and thus red blood cells are diamagnetic (diamagnetic). In this way, the difference in magnetization between the inside of the red blood cells and the external contrast agent containing plasma is different for arteries and veins, and T ₂ ^* accordingly. The difference in magnetization contributes only to T ₂ reduction, does not contribute to T ₁ reduction, MR signal intensity from the vein will be different from the MR signal intensity from the artery.

[0004] Further, the difference in the enhancement of the venous signal with respect to the arterial signal is widened. Since blood flow in the vein is generally slower and less pulsed, the signal loss due to intra-voxel dephasing (spin divergence) is greater in veins than in arteries.

[0005] T ₂ blood pool contrast agent and contrast agent designations, the T ₂ reducing effect, than the T ₁ reducing effect, it is not intended that a high effect on the overall MR signal intensity. That, T ₁ reducing effect, because the result of increasing the MR signal intensity is also effective in the arterial as well veins. In other words, T ₂ blood pool contrast agent has "positive" contrast agent, i.e. a function that increases the MR signal intensity in the region distributed.

[0006] Thus, in one aspect, the present invention provides a method for imaging local blood oxygenation by magnetic resonance, comprising the steps of: for example, mammals, reptiles, or administering a T ₂ blood pool contrast agent into the vasculature or vascular network within the subject avian), preferably uniformly distributed in the contrast agent is the subject of the blood pool Waiting for the contrast agent to be detected, detecting a magnetic resonance signal from at least a portion of the vascular network of the subject in which the contrast agent is distributed, processing the signal to reduce oxygen in at least a portion of the vascular network. Partial pressure (
Generating a representation of (pO ₂ ) (eg, an image showing pO ₂ ) to identify, for example, differences between veins and arteries or to identify areas undergoing ischemia (local anemia) including.

[0007] If the concentration of T ₂ contrast agent in the blood increases, the by the contrast agent be reduced susceptibility paramagnetic erythrocytes deoxygenated blood R2 * ^(i.e., 1 / T 2 ^_*) is reduced, Then, R2 ^* goes high and the magnetization in plasma exceeds the magnetization in red blood cells. However, the blood that has been oxygenated arterial R2 ^* generally increases with increasing T ₂ contrast agent concentration. In the absence of contrast agent, a concentration range exists because R2 ^* of deoxygenated blood is greater than that of oxygenated blood, and over that concentration range R2 ^* is substantially reduced in both oxygenated and deoxygenated blood. In other words, there is a range of “matching susceptibility”.

Thus, in both the upper and lower states of the matched susceptibility concentration range, the intensity of the MR signal from the oxygenated blood and the intensity of the MR signal from the deoxygenated blood are different, and the vein and the artery are MR images. Can be distinguished. Below the consistent susceptibility density range, MR
In the image, oxygenated blood is represented brighter than deoxygenated blood. Above the consistent susceptibility range, oxygenated blood appears darker than deoxygenated blood.

[0009] In the method of the present invention, T ₂ contrast agent is preferably administered as its dose, and the difference between R2 ^* of R2 ^* and deoxygenated blood oxygenated blood (arterial) (iv) the minimum A concentration in the blood greater than, for example, a total blood concentration of 0.4 mM (Fe) or higher, preferably 0.5 mM (Fe), for an aggregated paramagnetic (superparamagnetic) iron oxide (SPIO) contrast agent. And more preferably 0.5 to 2 mM Fe, evenly distributed in the blood pool (for example, after a period of 10 to 100 minutes, preferably 15 to 30 minutes after administration). For humans this is 1-8 mg Fe
/ Kg (body weight).

[0010] Secondary matched susceptibility concentration, eg 0.05-0.5 mM for SPIO contrast agent
Fe (or more preferably 0.05 to 0.3 mM Fe) or (using a magnetic field strength of, for example, 1 to 1.5 T (magnetic flux density: Tesla) used for medical use)
Distinguishing the vein from the artery and assessing the difference between R2 ^* in the vein and artery for 0.2-10 mM Gd against the gadolinium chelated blood pool contrast agent (eg, 0.8-4 mM Gd). Improving is feasible.

[0011] At the secondary matched susceptibility concentration, the arteries and static
Dipole transverse relaxation time (T₂) Can be used
. The dosage of the contrast agent in this embodiment of the invention desirably is the blood T₂To
It should be low enough not to change significantly, but the blood T ₁ Should be high enough to significantly reduce In this way, relatively small
Sana T₂Sensitive to differences and short T₁Use MR acquisition sequence that is sensitive to values
Is brighter than a vein (longer T₂With arteries)
Generally, it is possible to obtain an image with brighter blood vessels. Particularly preferably
, A relatively short TR (eg, TR is the blood T₂Non-spoil with smaller)
A type of gradient echo sequence is used. Spoiling (before each excitation
Remove lateral magnetism), T₁Usually suitable for MR angiography to optimize sensitivity
Used. However, by not spoiling, the available magnetism (Mz
) And hence the signal strength is the intrinsic T of the blood.₂Modulated by Longer T₂Is
, Oxygenated blood T₂Is the deoxygenated blood T₂Mxy (in the xy plane)
And hence the signal strength. As a result, oxygenated blood is deoxidized
It will appear brighter in the MR image than in the raw blood. "Driven" sequence
By using the `` equilibrated '' type, the total loss transverse magnetism precedes the excitation pulse.
In the direction of the main magnetic field (Mz). In addition, spoiled sequences and non-spoiled
It is possible to remove the image data set for the textual sequence. Sports
In an Il image, arteries and veins have essentially equivalent signal strengths (T₂Feeling
On the other hand, arteries appear brighter than veins in non-spoiled images
. Removing these two would enhance the ability to distinguish arteries from veins.
You. For this technique, paramagnetic contrast agents are preferred over superparamagnetic.

[0012] As noted above, increasing the _{T 2} Construction concentration, R2 ^* is increased in oxygenated blood. The extent of this increase depends on the contrast agent concentration, oxygenation (pO ₂ ), and hematocrit (volume ratio of red blood cells to total blood).

[0013] Hematocrit is measured by taking a blood sample. However, alternatively, for oxygenated arterial blood, it can be assumed that oxygenation is at about 97%, with R2 ^* and R1 for arterial blood (1/2 depending on contrast agent concentration).
Measurement of T ₁ ) makes it possible to determine hematocrit, measurement of R2 ^* on venous blood makes it possible to determine the level of oxygenation of venous blood and to estimate the oxygen uptake of specific visceral organs And

Viewed from another aspect, the present invention provides a method for imaging local blood oxygenation by magnetic resonance, the method comprising the steps of imaging a human or non-human animal with vascular tissue. applying a T ₂ blood pool contrast agent into the vasculature or vascular network within the specimen,
Detecting a magnetic resonance signal from at least a portion of the subject's vascular network where the contrast agent is distributed and processing the signal to enhance a difference between a vein and an artery.

[0015] Since the magnetic plasma of blood following administration to the vascular structure of the T ₂ contrast agents depends on the magnetic properties of the local concentration of contrast agent during the arterial and venous or between normal tissue and the ischemic tissue The difference between the MR signal intensities depends on the dose and, in echo imaging techniques, on the echo time (TE). Thus, in one embodiment of the present invention, _two MRs are detected and processed by the MR signal, one being a larger T2 enhancement than the other.
Generate images and compare those images. Thereby, areas of lower or higher blood oxygenation are selectively visualized. Such comparison is optionally performed after normalization of one or both images to enhance selective visualization, e.g., by setting the image intensity for the selected area of interest to be identical in both images. This may include subtracting one image.

[0016] Relatively larger T₂Enhanced image and smaller T₂The enhanced image is a conventional MR image.
Imaging sequence, for example, sequentially or alternately (interleaved sequence)
Echo sequences that include shorter or longer echo times generated by the
Can be obtained using However, in a particularly preferred embodiment, double echo
The sequence involves two images generated with earlier and later echoes
Can be used. Thus, double echo sequences can be used to advantage and
The first (short TE) echo of the vein and artery (or normal and ischemic tissue)
To give almost the same signal strength while transmitting the second (long TE) echo of the vein.
The signal intensity is higher than that of the artery. To subtract the first image from the second image
Thus, an artery or a vein can be selectively visualized. To tissues or organs
The relative frequency of oxygenation of the flowing blood and blood flowing from the tissue or organ (pO ₂ ), The oxygen consumption of the tissue or organ can be evaluated.
Blood pO₂Is, for example, a known pO₂And calibration values determined for contrast agent concentration values
Can be determined quantitatively, semiquantitatively or qualitatively.

[0017] Thus when viewed from a further aspect, the present invention provides a method of magnetic resonance imaging of a subject a human or non-human animal, administering T ₂ blood pool contrast agent into the vascular network of the subject , said generating at least a portion of the at least two images of the object, the first image of the image is greater T ₂ emphasized as compared with the second image of said image, said first and second A method of magnetic resonance imaging comprising comparing two images, e.g., obtaining an image providing an indication of local blood oxygenation in the subject by subtracting one image from another image. It is to provide.

In the method of the present invention, the optimal echo time required to maximize the signal strength between oxygenated and deoxygenated blood can be calculated for a given difference in R2. Assuming that signal strength (SI) is proportional to exp ^(-R2 * TE), the relative difference in SI between blood having different ^{_{R2: ΔSI = A * (exp}} (-R2 1 * TE) -exp _(-R2 ² * TE))
Given by Here, A is a constant, and each is a relaxation rate of arterial blood and venous blood.

[0019] Taking the partial derivative with respect to _TE: TE opt ₌ obtain _{ln (R2 1 / R2 2)} / (R2 1 -R2 2). _{Here, TE opt} is optimized TE to the maximum SI difference between the blood having a corresponding relaxation rate R2 ₁ and R2 _2.

As an example, using typical R2 values for oxygenated blood and deoxygenated blood respectively: R2 ₁ = 230 s ⁻¹ and R2 ₂ = 130 s ⁻¹ are TE _opt = ln (230/130) / ( 230-130) -5.7 ms.

It can be seen from the above that not only the relative difference in R2 between the artery and the vein, but also the optimized TE for the maximum SI difference between the artery and the vein depends on the absolute value of the relaxation rate.

In the method of the present invention, the contrast agent dosage is preferably between plasma and deoxygenation (venous).
It is adjusted so as to substantially cancel the magnetic difference with blood. Thus, an appropriate dose depends on the subject's blood pool volume, the subject's total number of red blood cells, the magnetic susceptibility of the contrast agent, and the strength of the magnetic field of the magnet in the MR imaging apparatus. These first ones are easily estimated to a sufficient level of precision, the second is measurable or estimable, the third is easily measurable, and the fourth is Is known for each device.

It is known that the susceptibility difference Δχ between red blood cells and plasma in venous blood having about 40% hematocrit is about 8 × 10 ⁻⁸ cgs / cm ³ . 1.5T
This corresponds to a magnetization difference ΔM of 1.2 A / m. WO9
The magnetization at 1.5 T of the PEGylated superparamagnetic fine particle contrast agent described in 7/25073 is 4.5 A / m / mM Fe. As a result, administration of a contrast agent that provides a plasma concentration of 0.26 mM Fe reduces ΔM to about zero and minimizes R2 in venous blood. If, blood iron concentration is higher than or concentration or equivalent to minimize _{^{R2 * (1 / T 2 *}} ) relaxation rates of the venous blood, blood in the veins has a large T ₂ values than those in the arterial Therefore, different MR signal strengths will be given.
Optimum value of the blood iron concentration to distinguish between veins and arteries with determined depending on the actual T ₂ and value of T ₁ of such blood, also depends on the MR imaging sequences used.

For a given species of subject, generally speaking, the R2 ^* value for oxygenated and deoxygenated blood is measured by the magnetic field strength of the main magnet of the MR imager to be used. The blood contrast agent concentration should be such that the two R2 ^* values are sufficiently different so that a difference in signal intensity between venous blood and arterial blood can be observed (Embodiment 3 (FIG. 2) and Embodiment 4 (FIG. 3)).

Approximating the blood pool volume as 80 mL / kg body weight for mammals such as humans, this corresponds to a dose of about 1 mg Fe / kg. Therefore, the dose range for a human subject is preferably 0.2 to 8 mg Fe / kg body weight, more preferably 0.5 to 6 mg / kg, and still more preferably 1 to 5 mg / kg. .

Thus, in a further aspect, the present invention provides a method of magnetic resonance imaging of a mammalian, preferably human, subject, the method comprising the steps of introducing T into the vascular network in the subject. applying a ₂ blood pool superparamagnetic iron oxide contrast agents, the generating at least a portion of the T ₂ enhancement (e.g. T ₂ weighted) magnetic resonance imaging in a subject, wherein the said contrast agent 0.2 Includes modifications administered at doses in the range of ８8 mg Fe / kg body weight, or preferably, in the range of 1-5 mg / kg, and the like.

The imaging method of the present invention can be defined as optionally including only the steps following administration of the contrast agent. Except for distinguishing between venous and arterial blood or between normal and ischemic tissues, the method of the present invention allows one to study lung function. Similarly, the methods of the invention can be used to study the structure and function of the kidney and the structure and development of tumors. Image contrast agent provides a contrast enhancement of the vessel, aberrant blood supply can be used to detect an area of the lung with, but the T ₂ enhancement signal from deoxygenated blood, such as tumor Or it can be used to detect areas in the lungs where oxygen inhalation is abnormal, such as as a result of a start-up failure.

Thus, in a further aspect, the present invention provides a method for magnetic resonance imaging of lung function in a human or non-human subject, the method comprising: administering _two blood pool contrast agent, wherein at least a portion of the T ₂ of the of the subject lungs - that form the dependent magnetic resonance images and include identifying regions of abnormal MR signal intensity at that intrapulmonary In.

[0029] T ₂ blood pool contrast agents used in the method of the present invention, without substantial effect on pO ₂ in the red blood cells, intended to selectively increase the magnetization of the plasma, any physiologically acceptable A paramagnetic, superparamagnetic, ferromagnetic, or ferrimagnetic material. Such materials have a blood half-life (eg, as measured in pigs) of at least 15 minutes, preferably at least 30 minutes, more preferably at least 1 hour. Generally, the contrast agent is a water-soluble or water-dispersible agent such as a polychelate of a transition metal or a lanthanide series element (preferably a dendritic polychelate), or 1 to 80
Microparticles having a particle size of 00 nm, preferably 5-500 nm, particularly preferably on or as their surface, for example polyalkylene oxides (e.g. polyethylene glycol) or glycosaminoglycans (heparin, dermatan, It is a particulate agent having a blood retention agent such as hyaluronic acid, keratan, chondroitin, etc. The particulate agent can be a solid (eg, a single substance or aggregate containing a matrix and a magnetic material), or even liquid particles of a water-insoluble liquid material. Generally, the particulate material is more preferably a water-soluble material. Less than 2.3, especially 2.
SPI0s with _r 2 / _{r 1} ratio of less than 0 are particularly preferred.

A magnetic property of a contrast agent of particular interest is its magnetic susceptibility. Therefore, when the contrast agent is paramagnetic, its paramagnetic center is preferably a high susceptibility lanthanide series metal ion having a high T ₁ relaxation such as Gd or Eu. Examples of gadolinium-based agents include gadolinium polychelates based on polylysine poly-GdDTPA and cascade polymers or dendrimers. Magnetic susceptibility of superparamagnetic material significantly higher than that of the superparamagnetic material, it is particularly preferable that include or superparamagnetic T ₂ contrast agent is a superparamagnetic material, such as a mixed oxide of iron such as iron oxide or magnetite. Superparamagnetic contrast agents are also preferred because they are generally well magnetized by the strength of the magnetic fields used in chemical imaging. In contrast, the magnetization induced by a chelate-based contrast agent depends on the magnetic field.

A number of susceptibility agents are described in patent literature by companies such as Nicomed, Sterling, Advanced Magnetics, Silica Gel, BASF, Sterling Winthrop, MBI, The General Hospital Corporation, Meito Sangyo and the like. Have been. Exemplary _{T 2} blood pool agent is PEG superparamagnetic materials disclosed in WO97 / twenty-five thousand and seventy-three by Nikomudo imaging Eiesu.

Thus, from a further aspect, the invention relates to a method of forming a physiologically acceptable paramagnetic, ferrimagnetic, ferromagnetic, or more preferably superparamagnetic material in accordance with the present invention. Provided for use in the production of a contrast medium for use in a diagnostic method comprising:

The method of the present invention typically allows arteries and veins to be identified by signal strength (
Generates at least a partial image of the vascular tissue of the subject
While doing so, it is not always so. Including arteries and / or veins
The region of interest can be selected, for example, from a pre-contrast image,
R2 for^*And / or R₁The value determines post-contrast and is
Thus, the pO due to the organ into which such blood vessels have been introduced or derived₂or
Is operated to produce a graph or simple numerical value indicating oxygen consumption. Similarly, p
O₂(Or oxygen consumption) is quantitative or semi-quantitative, eg, absolute pressure (or volume) value
Alternatively, it can be determined by the percentage of the achievable oxygenation level and the like. Therefore,
In a preferred embodiment, the image has a pixel color or shading in the visualized vascular network of pO. ₂ Or it can be produced in a state that is directly dependent on the oxygenation percentage. In this way,
For example, such selective coloring of veins leading from pulmonary function back to the heart from the lungs
It can be visualized by shading or shading. In an alternative embodiment, R2^*Value is visual
A vascular network that can be visualized is assigned oxygenation to one color or shade value, and oxygenation to the other.
Simply include oxygenated or deoxygenated blood when assigned to deoxygenation
Can be used to characterize.

The invention will now be further described with reference to the following examples and drawings. Example 1 Contrast Agent An aqueous PEG suspension of PEG (polyethylene glycol) -modified superparamagnetic particulate contrast agent can be made by the method described in Embodiment 12 of WO 97/25073. The properties of this contrast agent are as follows. [Fe] = 30.2 mg Fe /
mL; density 1.0589 g / mL; r ₁ = 19.3 s ⁻¹ mM ⁻¹ ; r ₂ = 3
^{_{1.2s -1 mM -1; r 2 /}} r 1 = 1.61 (20MHz, 37 ℃), saturation magnetization (Msat) = 84emu / g Fe .

Example 2 Effect of Contrast Agent Concentration T₂ ^*Is based on a sample of porcine venous blood containing various concentrations of the contrast agent of Embodiment 1.
And measured under a magnetic field of 1.5T. As can be considered from FIG.₂ ^* Increases initially and then decreases with increasing contrast agent concentration. Maximum T₂ ^* Values occur in the concentration range 2-10 μg Fe / mL.

Example 3 Imaging A dose of 4 mg Fe / kg of the contrast agent in Embodiment 1 was administered to 80 kg healthy volunteers. Thirty minutes after administration of the contrast agent, the inguinal region of the volunteer had RT = 10 ms and T
The image was imaged on a Philips Gyroscan NT 1.5T RM device using a T1-FFE imaging sequence at E = 4 ms. The vena cava and iliac veins were clearly visible, but the arterial vasculature had significantly lower signal intensity (see FIG. 2).

Example 4 Effect of Iron Concentration R2 ^* Relaxation (unit s ⁻¹ ) is measured at 300 MHz (7 T) using the contrast agent of Example 1 in fully oxygenated and fully deoxygenated human blood. Was done. The results are plotted in FIG. In oxygenated blood, R ₂ ^* is increased in a constant with increasing iron concentration. In deoxygenated blood on the other hand, R ₂ ^* is then initially decreases with increasing iron concentration, reached the minimum value of about 2 mM Fe, it starts to increase thereafter. At all iron concentrations above 1 mM Fe, R ₂ ^* is higher for oxygenated blood than for deoxygenated blood.

Example 5 Effect of contrast agent on fully oxygenated and deoxygenated blood The effect of the contrast agent of Example 1 on oxygenated and deoxygenated whole blood is 1.5 Tesla (human body) model (Philips NT, Philips Medical Systems, The Netherlands). Human whole blood was obtained from a blood bank (Oslo, Norway). All blood was 5000 IU of heparin sodium as an anticoagulant
(Corresponding to 1.35 ml heparin / 450 ml blood). All blood was freshly obtained from blood banks and stored at 4 ° C. prior to use. All samples were analyzed for 72 hours after blood collection.

[0039] Blood deoxygenation was achieved by adding sodium dithionite to the blood sample immediately prior to imaging (however, the exact frequency of deoxygenation was not determined in this example). Fully oxygenated blood was obtained by gently stirring oxygen into the sample.

A double echo 3D gradient echo sequence was used to calculate the R2 ^* relaxation rate of a blood sample. The sequence parameters are as follows: TR = 13m
s, flip = 40 degrees, TE1 = 1.7 ms, TE2 = 10 ms, slice thickness = 2 mm, matrix = 256 * 256, field of view = 250 mm.

R2^*The relaxation rate is calculated from the signal intensity difference between the images acquired by the first and second echoes.
Was calculated. R2^*Assuming a single exponential decay of signal strength as a function of relaxation rate,
, R2^*Can be represented as follows: R2^*(S^-1) = Ln (SI₁/ SI₂) / (TE₂−TE₁) Where SI₁= 1st echo (TE₁= 1.7 ms) and the signal strength ₂ = Is the second echo (TE₁= 10 ms).

FIG. 4 shows R as a function of contrast agent for fully oxygenated and deoxygenated blood.
2 shows the variation for ^* . At the lowest concentration investigated (0.1 mM Fe),
Deoxygenated blood has a slightly larger R2 ^* than oxygenated blood. At higher concentrations,
R2 ^* of oxygenated blood increased more rapidly than to deoxygenated blood. At the highest contrast agent concentration investigated (0.5 mM Fe), the difference in R2 ^* between oxygenated and deoxygenated blood was found to be about 100 s- ¹ . This difference could be easily observed in the image, as can be seen in FIG. The dramatic effect of changing blood hematocrit was also noted. Sample 1 and sample 3 are both deoxygenated at the same contrast agent concentration. However, sample 1 has a hematocrit of 53% and sample 3 has a hematocrit of 23%. Due to the subtraction of the first echo image from the second echo image, the resulting subtracted image (FIG. 6) shows a larger signal from oxygenated blood than from deoxygenated blood because oxygenated blood Due to a greater signal drop from the first to the second echo.

Example 6 Effect of Concentration of Contrast Agent on R2 ^* of Human Whole Blood and Percentage of Blood Oxygenation In this study, the observed MR signal at 1.5 T for whole blood of a person containing the contrast agent of Example 1 The effect of oxygenation on strength was investigated. A quiescent in vivo model was prepared containing whole blood to which the contrast agent of Example 1 was added over a concentration range of 0 to 1.13 mM Fe. Multiple samples are either oxygen enriched or deoxygenated (by dithionite) and have 0, 25, 50, 75, and 100%
Of oxygenation level. The resulting R2 ^* value reported as a function of oxygenation concentration is reported. The blood was fully oxygenated by carefully exposing it to oxygen agitation for several hours. Deoxygenation was achieved by adding dithionite to blood samples. The oxygenation percentage, hemoglobin concentration, and hematocrit percentage of all samples were determined by automated blood pH / gas analyzer (AVL).
995). Plasma samples were analyzed for total iron (Fe) concentration by inductively coupled plasma atomic emission spectroscopy (ICP-AES).

All imaging was performed using a 3D-FFE shift echo sequence for 1.5
T (Philips Gyroscan ACS-NT). shift·
The echo sequence was used to generate a total of 10 echoes. These echoes were obtained by shifting the TE from 3 ms to 13 ms in steps of 1 ms. Region of interest (RO
I) was defined for each sample in each image formation series. Average signal strength (
SI) and the standard deviation of the average intensity were recorded. A parameter R2 ^* map was generated on a pixel-by-pixel basis from the shifted echo image after image smoothing (for noise reduction). R2 ^* was obtained from the data set using the formula SI = Aexp (-R2 ^* TE), where A is a constant and TE is the echo time. Standard 3D-F
FE sequence (TR / TE / Philip = 13.9ms / 3.1ms / 35 °
) Was also used.

FIG. 7 shows an MR image of a model in a stationary state. This image is 3D-FFE
Obtained using a sequence. The effect of blood oxygenation on signal enhancement is clearly evident. Note that signal intensity (SI) at low contrast agent concentrations is higher for oxygenation compared to deoxygenated blood, but reversed at higher contrast agent concentrations (SI is higher for deoxygenated blood) Should. FIG. 8 shows the correlation between R2 ^* and contrast agent concentration as a function of blood oxygenation confirming the effects found in the MR images of FIG. At contrast agent concentrations below about 0.5 mM Fe, R2 ^* is higher in deoxygenated blood compared to oxygenated blood. Higher contrast agent concentrations (eg, about 0.8 m
R2 ^* is higher in oxygenated blood than in deoxygenated blood. In the intermediate concentration range, the relationship between R2 ^* and oxygenation is not well defined, and arteries and veins are expected to display similar R2 ^* values.

FIG. 9 shows the correlation between R2 ^* and oxygenation as a function of contrast agent concentration. At clinically relevant oxygenation levels (greater than 50%), a nearly linear correlation between R2 ^* and oxygenation levels exists at both lower and higher contrast agent concentration levels.

Example 7 MR Angiography in a Pig Model The purpose of this study was to demonstrate that lateral relaxation R2 ^* between arteries and veins was observed in a pig model after administration of a clinical dose of the Example 1 contrast agent. The question was whether to get it. A contrast agent at a dose of 4 mg Fe / kg was injected into the ear vein of a healthy pig. Immediately after injection, a 3D gradient echo sequence (3D FFE; TR /
TE / Philip = 36 ms / 20 ms / 20 °, slice thickness = 1 mm; field of view = 310 * 310 mm). All images were flow compensated to ensure that there was no flow dependent contribution to the difference in arterial / venous signal strength. FIG. 10 shows the acquired MR image.

The signal intensity of the vena cava (solid arrow) is higher than that of the aorta (dashed arrow).

It is important to note that pig hematocrit is significantly lower than humans (typically 25-30% vs. 40-50% humans). As a result, the arterial-venous R2 ^* difference after administration of the contrast agent of Example 1 is expected to be significantly smaller in the pig model than in the human case. The hematocrit dependence of arterial-venous R2 ^* differences is due to the fact that R2 ^* in fully oxygenated blood increases with increasing hematocrit. This is caused by a higher concentration of red blood cells at higher hematocrit and a higher plasma concentration of contrast agent.

As a result, the difference in SI between artery and vein is expected to be more pronounced in humans (as can be seen from Example 3 above).

Example 8 R2 in Blood Containing SPI0 Contrast Agent and Gadolinium Chelate Contrast Agent ^* Comparison The purpose of this study was to include SPI0 contrast agents or chelating paramagnetic metal ion contrast agents.
R2 in the whole blood of a person with^*Is to compare the effects of blood oxygenation on
Was. Because the study was performed in vitro, the chelate ion contrast leachables were problematic
Instead, the ECF agent GdDTPA was used. GdDTPA is better than SPI0
It has a significantly lower magnetic moment, so it can be used in intracellular and fine cells in deoxygenated blood.
The extracellular magnetization equalization is significantly higher than GdDTPA compared to the SPI0 contrast agent of Example 1.
Occurs at higher concentrations.

[0052] Fresh human whole blood with a hematocrit of 44% was aspirated into six equivalent sample tubes. The contrast agent of Example 1 was added to three of the samples,
Contrast agent concentrations were added over a wide range of 1.00 to 2.99 mM Fe. GdDTPA was added to three of the samples to give a gadolinium concentration of 1.
One blank sample was prepared, ranging from 22 to 3.58 mM Gd. Percent oxygenation, hemoglobin concentration, and hematocrit percentage of all samples were measured using an automated blood pH / gas analyzer (AVL 995).
Plasma samples were analyzed for total iron (Fe) concentration by inductively coupled plasma automated emission spectrophotometer (ICP-AES).

The samples have a longitudinal relaxation rate (R1) at 300 MHz, as shown in Table 2 below, for samples 1 and 4, for samples 2 and 5, and for samples 3 and 6 were prepared so as to be equivalent to each other.

[0054]

[Table 1] These blood samples were either fully oxygenated (by carefully stirring oxygen into the sample) or fully deoxygenated (by addition of dithionite).

NMR spectrophotometry was performed at 300 MHz (7.05 T) on a Varian VXR300S spectrometer equipped with a 5 mm 1H-broadband computer interchangeable probe. The blood sample was a 5 mm NMR tube (Norell 508-U)
P). The temperature was adjusted to 37 ° C. using an ethylene all temperature standard. After the initial shim with the spin D ₂ O sample, the shim value was maintained unchanged. The samples were analyzed without spinning and with the lock disconnected. Data is acquired as soon as the frequency of the water resonance stops moving significantly, and a long delay between the introduction of the sample into the magnet and the data acquisition is desirable because cell sedimentation leads to artificial changes in linewidth. Absent.

FIGS. 11 and 12 show the relationship between Example 1 and the contrast agent concentration of GdDTPA in oxygenated and deoxygenated blood versus line width. FIG. 11 shows that the contrast agent concentration of Example 1 was about 2 mM at 7.05T, which gave the minimum line width to fully deoxygenated blood.
Fe is shown. From FIG. 12 it is clear that at the highest concentration of GdDTPA investigated (3.58 mM Fe), the concentration giving the minimum line width has not yet been reached.

Compared to the minimum line width dose of 2 mM Fe for SPI0 agent, gadolinium
Significantly higher concentrations are necessary to adequately offset the susceptibility effect in deoxygenated blood.
It is important. This is Gd⁺³Is induced by such a high magnetic field strength (7.
05T) is even lower than for SPI0. In effect, gadolinium
(Or any other paramagnetic compound), the minimum linewidth concentration is independent of the magnetic field strength
The reason is that both paramagnetic ions and paramagnetic deoxyhemoglobin
Is increased linearly with the magnetic field strength. Gd³⁺Has a magnetic susceptibility of 2.
5 × 10^-2cgs / mol (= 2.5 × 10^-8cgs / (cm³× mM Gd
)). Magnetic susceptibility of fully deoxygenated blood is 2 * 10^-7cgs / cm ³ Assuming that Gd³⁺Has a minimum line width concentration of 7.9 mM Gd
. When this is converted to whole blood concentration ([Gd]_bAnd [Gd]_pWith whole blood and plasma Gd
[Gd] when the concentration is Hct is a hematocrit value._b= [Gd]_p*
(1-Hct) Gd concentration of 4.4 mM Gd in fully deoxygenated blood
Are found to be needed to offset the susceptibility effect. SPI0
The minimum line width concentration depends on the magnetic field strength because the magnetic mode of SPI0 particles
In the medical field (particles are essentially magnetically saturated at 1T)
Is almost independent of the magnetic field strength, but the magnetization by deoxyhemoglobin is
This is because both increase linearly. As a result, the concentration that gives the minimum line width is the magnetic field
Increases with strength.

[0058] Higher concentrations of paramagnetic agent to superparamagnetic agent may reduce R2 in deoxygenated blood.^*About
It can be concluded that it is necessary to obtain a substantial reduction to Paramagnetic sharp
It is important to note that the oxygenation-dependent effect of the salt is independent of the magnetic field.
is there. This is because the magnetization of both deoxyhemoglobin and paramagnetic ions is linear.
Due to the fact that it has field dependence. In the case of superparamagnetic agents, the oxygenation effect is a strong magnetic field
Dependency. The lower the magnetic field, the lower the linewidth concentration (susceptibility in deoxygenated blood)
The concentration at which the effect is completely eliminated) is lower. R2 to isolate artery from vein ^* To take advantage of the difference in^*The absolute difference in as large as possible
This is very important. This is because the concentration of the magnetically active substance is above the "matched" concentration.
Need to do that. For the contrast agent of Example 1, the required concentration is probably
, Within the clinically tested dosage range at the relevant magnetic field strength. Gadolinium
For substances based on the required dose is considerably higher, (arterial / venous separation
Does not matter) may be only achievable with a "first pass" concentration. Only
The low concentration of gadolinium chelate, while the blood signal intensity in T1-weighted images,
And then increase T to obtain the differential enhancement between artery and vein as described above. ₂ By taking advantage of the differences, there is still a way to distinguish arteries from venous blood
Very useful.

Example 9 Effect of Contrast Agent Concentration and Percentage of Blood Oxygenation on R2 ^* in Whole Blood of a Person
The effect of oxygenation on the MR signal intensity observed at T was investigated. The study was performed in vitro, exudates were not a problem, and GdDTPA (ECF rather than blood pooling agent) was used. A resting in vivo model was prepared containing whole blood to which GdDTPA was added over a concentration range of 0-9.4 mM Gd. Multiple samples were either fully oxygenated (by careful stirring of oxygen in the sample for several minutes) or fully deoxygenated (by addition of dithionite). . The resulting R2 ^* value obtained as a function of GdDTPA concentration and oxygenation was measured. The oxygenation percentage, hemoglobin concentration, and hematocrit percentage of all samples were measured by an automated blood pH / gas analyzer (AVL 99).
5) was measured. The plasma sample is analyzed by an inductively coupled plasma atomic emission spectrophotometer (
(ICP-AES) for total iron (Fe) concentration.

All imaging was performed using a 3D-FFE shift echo sequence for 1.5
T (Philips Gyroscan ACS-NT). shift·
The echo sequence was used to generate a total of 10 echoes. These echoes were shifted in 1 ms steps by the first TE at 3 ms and the last TE at 13 ms. Regions of interest (ROI's) were defined for each sample in each successive image formation. The average signal strength (SI) and the standard deviation of the average strength were recorded. A parameter R2 ^* map was generated on a pixel-by-pixel basis from the shifted echo image after image smoothing (for noise reduction). R2 ^* is calculated using the equation SI = Aexp (-R2 ^* TE) where A is a constant and TE is the echo time.
Fitted from the data set.

FIG. 13 shows a curve of R2 ^* versus Gd concentration in oxygenated and deoxygenated blood. The effect of blood oxygenation on R2 ^* is clearly discriminated. In fully oxygenated blood, an almost linear relationship exists between R2 ^* and Gd concentration. On the other hand,
In deoxygenated blood, an initial decrease in R2 ^* occurs with increasing Gd concentration. A minimum R2 ^* is achieved at a gadolinium concentration of about 6-7 mM.
The curve shape shows only that the minimum R2 ^* occurs at a significantly higher contrast agent concentration.
Similar to that found for PIO contrast agents.

FIG. 14 shows an image of the model (2D-FFE, TR = 100 ms, TE
= 8 ms, flip = 30 °). The inner circle contains the oxygenated blood sample, and the outer circle is the oxygenated sample. Note that at low Gd concentrations, a clear difference in signal intensity is observed between oxygenated and deoxygenated blood, with oxygenated blood conferring higher signal intensity. . At higher concentrations, the situation is reversed and deoxygenated blood gives higher signal strength. The low concentration effect makes gadolinium enhanced MRI an attractive method of separating arteries from veins.

Example 10 Contrastingly Contrast Concentration Concentration Concentration Combined with Non-Spoiled Gradient Echo Imaging Whole human blood with 0.25 mM Fe, Example 1's contrast agent, added to the model Were placed in three vials. The blood in one vial is fully oxygenated, the second vial is 50% oxygenated, and the third vial is fully deoxygenated.

The contrast agent concentration corresponded to a human 1 mg Fe / kg body weight dose.

The model was imaged using a 1.5 Tesla Philips Gyroscan ACS / NT magnetic resonance imager. In collecting the image of FIG. 15, a spoiled FFE sequence was used (TR = 100 ms / TE = 8 ms / flip = 20 °). In acquiring the image of FIG. 16, a non-spoiled FFE sequence was used (TR = 14 ms / TE = 8.8 ms / flip = 35 °). In spoiled images, the signal intensities for all three blood samples are essentially equivalent. In non-spoiled images, there is a large signal intensity difference between oxygenated and deoxygenated blood.

[Brief description of the drawings]

FIG. 1. T ₂ ^* (in relation to water protons) as a function of contrast agent concentration in venous blood.
FIG.

FIG. 2 shows a halftone image showing a magnetic resonance image of the human inguinal region created using the method according to the invention.

FIG. 3 is a plot of R2 ^* (ie, 1 / T ₂ ^* ) versus iron concentration obtained at 300 MHz in fully oxygenated and fully deoxygenated blood.

FIG. 4 is a plot of the R2 relaxation rate of oxygenated and deoxygenated human whole blood as a function of contrast agent concentration at 1.5 Tesla, where R2 ^* is TE1 = 1.7 ms and TE2 = 10 ms. Calculated using the double echo gradient echo sequence of

FIG. 5 illustrates the contrast agent 0 of Example 1. Model images showing the effect of oxygenation on blood signal by mM Fe administration (Sample 1 contains fully deoxygenated blood with 53% hematocrit, Sample 2 contains fully oxygenated blood with the same hematocrit, Sample 5 contains plasma (zero hematocrit), image sequence: 3
FIG. 9 is a diagram illustrating a halftone image of D gradient echo, TR = 10 ms, TE = 6 ms, flip = 40 degrees).

FIG. 6 is a diagram showing a halftone image of a difference image (TE = 6 ms, FIG. 5) obtained by subtracting the first echo image from the second echo image.

FIG. 7 shows MR images of a model including a blood sample (sample 0 is a control blood sample, and samples 1 to 6 (inner rings) are 0.48, 0.57, 0.69, 0.96, and 0.13 mM). Fully oxygenated blood containing SPI0 of Example 1 with Fe, with similar Fe concentrations, but with 0%, 25%, 50%, and 75% oxygenation on the outer and middle rings. FIG.

FIG. 8 is a graph showing the correlation between Fe concentration and R2 ^* as a function of blood oxygenation.

FIG. 9 is a graph showing the correlation between R2 ^* and blood oxygenation as a function of Fe concentration.

FIG. 10 is a view showing a halftone image of an MR image of an abnormal region of a pig.

FIG. 11 is a graph showing NMR linewidth as a function of Fe concentration in oxygenated and deoxygenated blood.

FIG. 12 is a graph showing NMR linewidth as a function of gadolinium concentration in oxygenated and deoxygenated blood.

FIG. 13 is a graph showing the correlation between R2 ^* of human blood versus Gd concentration as a function of blood oxygenation.

FIG. 14 shows a halftone image of an MR image (clockwise increase) of a model containing oxygenated (inner ring) and deoxygenated blood at Gd concentrations from 0.5 to 9.4 mM.

FIG. 15 is a diagram showing a halftone image of a spoil gradient echo image of oxygenated, partial oxygenated, and deoxygenated blood in a model.

FIG. 16 is a diagram showing a halftone image of a non-spoiled gradient echo image of oxygenated, partial oxygenated, and deoxygenated blood in a model.

[Procedure amendment]

[Submission date] May 10, 2001 (2001.5.10)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Invention Keller, Kenneth Edmund, New Jersey, U.S.A. 08822 Flemington, Cobblestone Court 1504 (72) Inventor Briley-Saevo, Karen, Norway, N-4001 Oslo, Nikobeien 1-2, Nicomed Imaging AS ( 72) Inventor Johansson, Lars Sweden, S-752.63 Apsara, Benorzgatan 104 F term (reference) 4C085 HH07 JJ02 KB07 KB08 LL01 4C096 AA10 AA11 AB01 B A06 BA25 BA36 DC33 FC14

Claims (19)

[Claims] 1. A method of imaging by magnetic resonance oxygenation local blood, into the vascular network in a subject human or non-human animal by administering the T ₂ of blood pool contrast agent, the contrast agent There detecting magnetic resonance signals from at least a portion of the vascular network of the subject are distributed, the oxygen partial pressure in at least a portion of the vascular network by processing the signals (pO ₂₎
How to generate metrics for Wherein sought R ₁ of blood in the arteries, then method according to claim 1 for determining the hematocrit (percentage of blood cells occupied in the blood). 3. The method according to claim 1, wherein the hematocrit and R2 ^* of the blood in the artery are determined, and then the pO ₂ in the vein is determined. 4. The method according to claim 1, wherein the index is an image indicating pO ₂ . Wherein said contrast agent A method according to any one of claims 1 to 4 of the venous blood R2 ^* is administered as quantitatively smaller than R2 ^* arterial blood. 6. The method according to claim 1, wherein the contrast agent is administered quantitatively such that R2 of venous blood is smaller than R2 of arterial blood. 7. The method of claim 6, wherein the magnetic resonance images are generated using a non-spoiled gradient echo sequence. 8. A method for generating a magnetic resonance image using a spoiled gradient echo sequence, and subtracting an image based on a non-spoiled gradient echo sequence from an image based on a spoiled gradient echo sequence, to thereby reduce the distance between an artery and a vein. The method according to claim 7, wherein the method generates an image with enhanced signal differences. 9. A method of forming a magnetic resonance image of the subject human or non-human animals, the administration of T ₂ blood pool contrast agent into the subject blood vessel network within the at least one of the subject and at least two images in the section, to generate at least two images is large T ₂ stressed than the second image of the first image is the image of said image, the said first image A method of obtaining an image representing an index of local blood oxygenation in said subject by comparing with a second image. 10. A method of forming a magnetic resonance image of lung function in a subject non-human or human, wherein the administration of T ₂ blood pool contrast agent into the subject blood vessel networks in at least in the lungs of the subject generating a portion of the T ₂ weighted magnetic resonance image, a method for identifying a region of abnormal MR signal intensity within said lungs. A method of 11. imaged by magnetic resonance localized blood oxygenation, into the vascular network in a subject human or non-human animal by administering the T ₂ of blood pool contrast agent, the contrast agent A method of detecting a magnetic resonance signal from at least a portion of a distributed vascular network of the subject, and processing the signal to provide augmentation of arterial and venous differences. 12. The contrast agent according to claim 1, wherein the contrast agent is a superparamagnetic iron oxide contrast agent.
A method according to any one of the preceding claims. 13. The method of claim 12, wherein the contrast agent is administered in an amount sufficient to create a concentration of at least 0.5B mM Fe that is ubiquitous in the subject's blood pool. 14. The method of claim 12, wherein said contrast agent is administered to a human subject at a dose of 0.2 to 8 mg Fe / kg body weight. 15. The method of claim 1, wherein the contrast agent is a gadolinium chelate contrast agent.
12. The method according to any one of claims 11 to 11. 16. The method of claim 15, wherein the gadolinium chelate contrast agent is administered in an amount sufficient to create a concentration of 0.2-10 mM Gd that is ubiquitous in the blood pool of the subject. the method of. 17. A method of imaging by magnetic resonance mammalian subject, the T ₂ of blood pool superparamagnetic iron oxide contrast agent to the subject a vascular network within 0.2~8m
g Fe / kg was administered in the range of body weight, the method of generating at least a portion of the T ₂ weighted magnetic resonance imaging in a subject. 18. A method for producing a contrast agent comprising using a physiologically acceptable paramagnetic material, ferrimagnetic material, ferromagnetic material or superparamagnetic material in the method according to claim 1. Description: Use to use. 19. The method of claim 1 or a magnetic resonance contrast medium containing T ₂ blood pool contrast agents used in any image forming method according to one of 17.