WO1989003693A1

WO1989003693A1 - Method of using fluorocarbons in nuclear magnetic resonance imaging

Info

Publication number: WO1989003693A1
Application number: PCT/US1988/003830
Authority: WO
Inventors: David M. Long, Jr.
Original assignee: Fluoromed Pharmaceutical, Inc.
Priority date: 1987-10-27
Filing date: 1988-10-27
Publication date: 1989-05-05
Also published as: AU2803289A

Abstract

A fluorocarbon introduced into a selected animal body tissue or space defines a tissue or space within the body to be contrasted by a nuclear magnetic resonance imaging system. The introduced fluorocarbon may be passively imaged by its absence of hydrogen or other selected nuclei with a magnetic resonance imaging system adapted to image the densities of hydrogen nuclei or other selected nuclei. Fluorine nuclei in an introduced fluorocarbon emulsion may be actively imaged by scanning and detection with a magnetic resonance imaging system adapted for fluorine nuclei imaging. In the image developed or produced by the magnetic resonance imaging system, the fluorocarbon introduced into the animal body tissue or space is contrasted to the remaining body tissues or spaces to distinguish the fluorocarbon occupied tissue and spaces from other tissue and spaces.

Description

METHOD OF USING FLUOROCARBONS IN NUCLEAR MAGNETIC

RESONANCE IMAGING

Background of the Invention Field of the Invention The present invention relates to radiological imaging systems, and more particularly to use of a contrast enhancement agent in imaging of parts of an animal, to include human, body by exposure of the body to radiant energy in nuclear magnetic resonance imaging systems. Description of the Prior Art

In the past, nuclear magnetic resonance imaging

("MRI") systems useful in the practice of the present invention have been known. Such systems are offered commercially by manufacturers such as, for example, General Electric Company, and literature exists describing the theoretical and practical use of MRI systems for body imaging, including manufacturers' manuals. For a general reference on the background of the theoretical description of the MRI system, the publication entitled NMR Tomography by William G. Bradley (1982) is available from Diasonics,

Inc., Milpitas, California, which is attached hereto as an

Appendix and incorporated herein for convenience.

In the magnetic resonance imaging systems, advantage is taken of the fact that some atomic nuclei, such as, for example, hydrogen nuclei, have both nuclear spin and nuclear magnetic moment, and therefore can be manipulated by applied magnetic fields. In the customary type of MRI system, a magnetic field is established across a body to align the spin axes of the nuclei of a particular chemical element, usually hydrogen, with the direction of the magnetic field. The aligned, spinning nuclei execute precessional motions around the aligning direction of the magnetic field. For the aligned, spinning nuclei, the frequency at which they precess around the direction of the magnetic field is a function of the particular nucleus

SUBSTITUTE SHEET which is involved and the magnetic field strength. The selectivity of this precessional frequency with respect to the strength of the applied magnetic field is very sharp and this precessional frequency is considered a resonant frequency.

In a customary MRI system after alignment or polarization of the selected nuclei, a burst of radio frequency energy at the resonant frequency is radiated at the target body to produce a coherent deflection of the spin alignment of the selected nuclei. When the deflecting radio energy is terminated, the deflected or disturbed spin axes are reoriented or realigned, and in this process radiate a characteristic radio frequency signal which can be detected by an external coil and then discriminated in the MRI system to establish image contrast between different types of tissue in the body. MRI systems have a variety of different excitation and discrimination modes available, such as, for example, free induction decay ("FID") , spin echo, continuous wave, which are known in the art.

Spatial discrimination for obtaining a three- dimensional imaging is also a known feature of MRI systems and is customarily accomplished by establishing magnetic field gradients in three-dimensional orthogonal directions. The steep and sharp variation of spin resonance frequency with magnetic field strength allows selective imaging of points, lines or planes through the body being imaged.

Hydrogen has been usually selected as the basis for MRI scanning because of its abundance in the water content of the body and its prominent magnetic qualities. It is believed that investigations are being conducted to determine if sodium and phosphorous would also be satisfactory as the basis for magnetic resonance imaging.

MRI has been useful as a non-invasive imaging system for many body parts, for example some soft tissue of the body having high water concentrations. However, several

SUBSTITUTE SHEET body parts containing large amounts of water may be positioned together or closely proximate. In some instances, body parts are scarred together or, as in the case of intestines, are intertwined together within the body. Images developed from MRI often fail to show these body parts as distinct or distinguishable from surrounding structure having comparable hydrogen nuclei composition.

Similar difficulties and limitations are encountered in imaging such body parts as the liver, spleen and intestines which are not sufficiently contrasted from surrounding tissue, and tumors which are not sufficiently contrasted from their hosts.

It has been known to use brominated perfluorocarbonε as a contrast enhancement medium in radiological imaging, as shown in letters patent No. 3,975,512 to Long, the Applicant herein. Brominated and other fluorocarbons are known to be safe and biocompatible when used internally in body parts.

It is sought to provide a method of using safe, biocompatible contrast agents with MRI to contrast more clearly and more distinctly in MRI-produced images the several body parts which normally have substantially high water content and which are close or are intertwined together. Summary of the Invention

In brief, in accordance with one aspect of the present invention, fluorinated liquid compounds are inserted within body spaces within the body. Hereafter in this specification, the terms "space" and "body space" will be used and are intended to mean volumes which could be, among other things, cavities, lumens and areas such as, for examples, the pleural space, the bladder, urethra, ureters, fallopian tubes, ovaries and other parts of the genital urinary tract, eye chambers, ear, paranaεal sinus, stomach, lumens and spaces of the vascular system. The vascular system includes blood vessels of the arterial and venous

SUB_ST_ITUTESHEET systems as well as the lymphatic system. The term "non- vascular" is intended when used herein to denote tissue or spaces which are not within the arterial, venous or lymphatic systems, blood and lymph vessels, vessel walls, the heart and spaces within.

The fluoro-compounds in one embodiment may be neat and in the alternative embodiment will be in biocompatible emulsions. Hereafter in this specification, the term "neat" will be used to indicate a compound per se not in emulsion, mixture or dispersion.

The magnetic resonance imaging system, in another aspect, is arranged to produce images using fluorine as the basis, rather than hydrogen. Such an adaptation may consist primarily of insuring that the frequency of the radio frequency deflecting signals conforms to the spin resonance frequency of the fluorine with corresponding tuning of the detection system.

In one aspect of the present invention, the magnetic resonance imaging system can image hydrogen nuclei in the customary manner, and the fluorinated compound can be introduced neat to occupy certain body spaces or used to replace aqueous concentrations therein, The resultant MRI images, for which hydrogen was used as the basis, will have a signal void in the spaces filled with the fluorocarbon. These signal voids will more distinctly contrast with the hydrogen nuclei or water concentrations in adjacent spaces or body elements.

Other novel features which are believed to be characteristic of the invention, both as to organization and methods of operation, together with further objects and advantages thereof, will be better understood from the following description in which preferred embodiments of the invention are described by way of example.

Detailed Description of the Preferred Embodiment Magnetic resonance imaging is normally based upon hydrogen nuclei because of their abundance in the water

SUBSTITUTESHEET content of the animal, including the human, body, and the prominent magnetic qualities of water. This property of water, however, may be problematic in that some spaces within the body have several organs closely adjacent to each other or are intertwined so that an image based upon water content will not sufficiently distinguish between these contiguous and proximate organs. For example, the intestines of most bodies actually intertwine with themselves and are contiguous with, or close to, abdominal and retroperitoneal fat, pancreas, liver, adrenal glands, bladder, blood vessels and other normal or diseased structures, all of which have substantial water content. Images made by MRI using conventional hydrogen, i.e., proton imaging techniques for these abdominal spaces frequently have so many of these organs appearing with substantially the same signal intensity that they are not readily distinguished.

By means of the present invention, fluorocarbons, liquid at room temperature, are introduced into spaces within the animal, including the human, body..^' These liquid fluorocarbon compounds contain substantial amounts of fluorine nuclei, are substantially physiologically and chemically inert, are substantially non-toxic in human bodies and have good biological tolerance. The fluorocarbons, for the most part, are devoid of hydrogen atoms. Some fluorocarbons, such as F-44E (C4F9CH-CHC4F9) contain two hydrogen atoms per molecule, but the number of hydrogen nuclei is substantially low so that even these fluorocarbons are substantially, or sufficiently, free of hydrogen nuclei for nuclear magnetic resonance imaging purposes. The spaces filled with fluorocarbon therefore appear in a hydrogen-based MRI system as more distinct contrasting signal voids.

Fluorocarbons have the distinct characteristic of being immiscible in water or hydrophobic, and thus will

SUBSTITUTE SHEET exclude or displace water containing elements within the body spaces where the fluorocarbon exists or is positioned. In one embodiment, fluorocarbons not in emulsion, that is to say neat fluorocarbons, can be used to provide more clear and distinct imaging of various body parts, tissue and spaces which are contiguous and very near other body parts, tissue and spaces having comparable densities of water content, by using the MRI system in the ordinary way having hydrogen, i.e., proton, as the basis for imaging. Neat or substantially pure fluorocarbon can be inserted into certain non-vascular body parts, tissue or spaces, which can biologically tolerate neat, unemulsified fluorocarbon. Normally most spaces within the body, as well as body tissue, contain substantial densities of water and thus hydrogen nuclei or protons. Fluorocarbons, however, are immiscible in water and will have the tendency to replace water with fluorocarbon, or, as in the case of the gastrointestinal lumens, to fill up the space or replace the succus entericus with fluorocarbon to the exclusion of the succus entericus.

Without such introduction of fluorocarbon, many spaces when imaged using the proton based MRI system show upon the image as substantially the same body part. This result is believed to be due to the fact that water, and hence proton densities of these contiguous or closely proximate body spaces and body tissue, are comparable. Thus, from the MRI image, it is frequently difficult to distinguish between the lumen, the intestinal wall, the abdominal and retroperitoneal feat, pancreas, liver, ovaries, uterus, fallopian tubes, prostate glands, adrenal glands, kidney, bladder, ureters, blood vessels, lymphatic system and other normal or diseased structures in the surrounding volumes within the body. Indeed, the intestine itself is intertwined with itself and with other structure, so that it is frequently difficult to distinguish one loop from another lo >oopp.. TThhee wwaallll _po__£_t-^±feJ*yβ_" intestine, when it is empty,

is normally collapsed against itself except for succus entericus secretions within, so that in conventional MRI images, a continuous bright space is indicated for the water containing walls and the intestinal secretion, appearing to the image reader as a single structure.

The fluorocarbon can be inserted within one or more of selected body spaces to the substantial exclusion of proton containing water. When the conventional MRI image is produced by the MRI system, the body space, which normally contains water, will show in the image as a distinct dark area indicating the substantial absence of protons. The fluorocarbon can be inserted into he intestines by way of the mouth as, for example, by swallowing the fluorocarbon. After allowing for a suitable, but typically short time for the fluorocarbon liquid to reach the intestine, images of the gastrointestinal tract, abdominal area and peritoneal cavity can be made using the usual MRI system's images based upon proton densities. The peritoneal cavity normally and within this specification, is considered to be and includes every cavity and tissue from the diaphragm to the pelvis. The fluorocarbon will fill the gastrointestinal lumen even if nothing occupied the lumen before ingestion. In some instances, the fluorocarbon may replace water containing substances in the lumen. Filling the lumen with fluorocarbon separates the walls, and separates or replaces the succus entericus secretion of the intestine with non-hydrogen matter, so that the sides of the intestine walls are separate and distinct. Moreover, the intestines are more clearly distinguished from the other, non-fluorocarbon containing body tissue and spaces which heretofore have frequently been confused with the intestines.

Other body spaces which can be flooded with fluorocarbon orally through the mouth to the exclusion of water, at least sufficiently so as to improve the MRI images resulting from conventional proton based MRI

SUBSTITUTE SHEET scanning, include the stomach and trachea. It can be readily appreciated that other body spaces can be flooded by other ports of injection, such as the anterior and posterior eye spaces, the ear, the urinary bladder by way of the urethra and the intestines by way of the posterior opening. Additionally, fluorocarbon liquid can be inserted by syringe into the peritoneal cavities, ureter, urethra, renal pelvis, joint spaces of the bone, lymphatic vessels, the subarachnoid space, the ventricular cavities and the cerebral spinal space.

This embodiment of the present invention can be better understood by reference to the following illustrative examples. EXAMPLE I The gastrointestinal tract was imaged using MRI scans adapted for hydrogen imaging on a rat using PFOB, perfluoroctylbromide (C8F17Br) as a contrast enhancement agent. A Srague-Dawley rat weighing approximately 300 grams was sedated with ketamine (30 mg.) and acepromazine (0.6 mg) , and MRI scan images were produced of the abdomen. After full recovery from the sedation in approximately two to three hours, the rat was re-sedated with ether, and a nasogastric tube was used to insert 16 ml per kilogram of body weight, for a total of 5 milliliterε, of the fluorocarbon directly into the stomach in two boluses of 8 ml/kg each, one at 30 minutes and the other at 15 minutes before MRI scanning. Two control rats were administered no PFOB.

MRI scans were performed by using the head coil on a General Electric 1.5-T Signa system, having a spin-echo sequence of TR = 2 seconds and TE = 25 and 50 milliseconds with a 256 x 256 matrix, 5 millimeter thickness and a 20 centimeter field of view. The extent and degree of intestine filling as shown in the MRI images were subjectively evaluated and compared with an abdominal radiograph of the rat obtained immediately after the MRI

SUBSTITUTESHEET scan to ensure that the signal void resulted from the fluorocarbon and not from air.

The rat given the PFOB showed substantial filling of both the stomach and of the intestines. The image of the abdomen highlighted the boundaries of the intestine from the lumen clearly and distinctly. EXAMPLE II

A second and third Sprague-Dawley rats were treated in substantially the same procedure as the rat of the previous example, except that only 13 ml/kg of body weight was inserted for one of the rats, and both rats had 1-bromotridecafluorohexane (C6F13Br, or "PFHB") instead of PFOB inserted in one bolus at 30 minutes before scanning. The rat receiving 16 ml/kg showed a more complete filling of the intestine, but both rats showed an insignificant amount of the fluorocarbon remaining in the stomach. The intestine was clearly delineated from the surrounding body tissue and spaces not containing the PFHB. EXAMPLE III A human had MRI scans made of the coronal plane. The human then drank two boluses of perfluoroctylbromide (C8F17Br) , the first at 30 minutes before, and the second at 5 minutes before a second set of MRI scans. The first bolus was of 5 ml per kilogram of body weight, and the second bolus was of 2 ml per kilogram of body weight, for a cumulative total of 525 ml of the fluorocarbon. Both scans were performed in the coronal plane with a partial- saturation sequence TR = 600 milliseconds and TE = 25 milliseconds, followed by an axial spin-echo series with TR = 2 seconds and TE = 20 and 70 milliseconds. The scans obtained before and after ingestion of the fluorocarbon were subjectively compared by observation for bowel recognition and ability to delineate the margin or boundary of normal structures such as the pancreas. No difference in the images of the stomach was observed, but the small intestine appeared in the image as

SUBSTITUTE SHEET a distinct dark area, showing sharp contrast with the water containing intestinal wall or margin. Further, the margin or boundary of the pancreas was more sharply observed by virtue of the filling of the gastric antrum and duodenum. EXAMPLE IV

A human had MRI scans made of the coronal plane and then drank slowly 5 ml of perfluoroctylbromide (PFOB) per kilogram of body weight from 30 minutes to 15 minutes before MRI scanning for a total of 370 ml, followed by drinking a bolus of 2 ml per kilogram of body weight, comprising a total of 134 ml, 10 minutes before scanning. The MRI images were produced with a partial-saturation sequence TR = 600 milliseconds and a TE = 25 milliseconds, followed by an axial spin-echo series with TR = 2 seconds and TE = 20 and 70 milliseconds.

After ingestion of the PFOB, the human had significant amounts of PFOB in the stomach and distal small bowel, but little or not PFOB in the proximal small bowel. The gastric wall of the stomach was recognized after PFOB ingestion, but not before ingestion. The pancreatic margin was smooth and well defined in the images produced after PFOB ingestion, whereas the margin appeared nodular in the images produced before ingestion. This clarity was believed to be due to the filling of the gastric antrum and duodenum. After ingestion of the PFOB, the MRI images of the intestine int he mid-abdomen and pelvis were dark and easily recognized.

In another embodiment of the present invention, fluorine nuclei in a biocompatible fluorocarbon emulsion is inserted in body spaces, such as the body spaces identified hereinabove, and in other body spaces for which neat fluorocarbons would normally be considered unsafe, such as the vascular system. Fluorine nuclei of the fluorocarbon have a different resonant frequency and precession frequency than hydrogen nuclei when subjected to the same magnetic field. The signal emitted by fluorine nuclei when

SUBSTITUTE SHEET reorienting after a radio frequency disturbance differs from the reorienting signals emitted by protons. Because of these differences, an MRI system can have its decrimination system modified so as to image preferentially the fluorine nuclei emitted signals, rather than the usual hydrogen nuclei.

Fluorocarbons can therefore be used as a contrast enhancement medium in an MRI system which is modified or arranged to detect and image fluorine nuclei. The fluorocarbon can be placed in certain body spaces by simple means. The fluorocarbon can be placed within the stomach and the intestines simply by drinking the fluorocarbon by mouth. The fluorocarbon will settle initially in the stomach and will progress into the intestines. Alternatively, the fluorocarbon can be administered posteriorly through the posterior opening. The body space consisting of the urinary bladder can be imaged suitably by introducing the fluorocarbon through the urethra.

The fluorocarbon can be introduced into the interperitoneal and pleural cavities through the body walls, such as by hypodermic syringes. Similarly, the cerebral spinal cavity, the ventriculo-subarachnoid space and the ventricles of the brain can have the fluorocarbon introduced with syringes through the body walls. The anterior and posterior chambers of the eyes, sinuses, uterus and fallopian tubes can also have the fluorocarbon positioned or placed therein selectively.

Fluorocarbons whose emulsions are useful for such MRI imaging based upon fluorine nuclei would include F- octylbromide, sometimes also known as perfluoroctylbromide, brominated perfluorocarbon or 1-bromoseptadecafluorohexane (C7F17Br) . Fluorocarbons having some but inconsequential numbers of hydrogen atoms, such as C4F9CH-CHC4F9, also known as F-44E may also be used. Other fluorocarbons would include other mono-brominated perfluorocarbons, such as l- bromopentadecaf1uoroseptane (C7F15Br) , and

SUBSTITUTE SHEET 1-bromotridecafluorohexane (C6F13Br, sometimes known as perfluorohexylbromide or "PFHB") . Other Fluorocarbons are i-C3F7CH-CHC6F13 (sometimes designated "F-i36E") , and C6F13CH=CHC6F13 ("F-66E"), C10F18 ("F-declin") , F-adamantane ("FA"), F-methyladamantane ("FMA"), F- 1, 3-dimethyladamantane ("FDMA") , F-declin ("FDC") , F-4-methyloctahydroquinolidizine ("FMOQ") , F-4-methylde- cahydroquinoline ("FHQ"), F-4-cyclohexylpyrrolidine ("FCHP"), F-2-butyltetrahydrofuran ("FC-75") , (CF- 3)2CFO(CF2CF2) 20CF(CF3)2, (CF3) 2CFO(CF2CF2) 30CF(CF3)2, (CF3)2CFO(CF2CF2)2F, (CF3)2CFO(CF2CF2)3F, (C6F13)20 and F[CF(CF3)CF20]2CHFCF3.

This embodiment of the present invention can be better understood by reference to the following illustrative examples. EXAMPLE V

Seventeen C3H mice two to four weeks after inoculation with a radiation induced fibrosarcoma tumor received intravenously 10 grams per kilogram of bodyweight perfluoroctylbromide (PFOB) emulsion having a mean particle size of 0.2 microns or less. The PFOB emulsion was 100% weight per volume PFOB, 6% weight per volume of lecithin, 0.00284% weight per volume Na2HP04, 0.0006% weight per volume NaH2P04, 0.0731% weight per volume NaCl, 0.05% weight per volume alpha tocopherol acetate and water in a quantity sufficient. After anesthesia, the mice were scanned using a General Electric NMR CSI 2 Tesla NMR spectrometer/imaging system, the radio frequency coil tuned at separate times for separate scans for H+ and F19 scanning. Spin echo F19 projection images were acquired using Tr = 1000 milliseconds, and TE = 10 milliseconds. The imaging matrix was 128 X 128, 2 to 8 excitations were acquired, the field of view was 150 millimeters and the imaging time was approximately 4 to 16 minutes. The scans were performed from 30 minutes to eight hours after injection of the PFOB emulsion and observed by four

SUBSTITUTESHE observers. The acquisition times of from one to eight minutes are comparable to H+ MRI techniques. A selective spin-echo pulse sequence was used to excite only the most significant of the three peaks emanating from the PFOB molecule to eliminate chemical shift artifacts resulting from the excitation of all three peaks.

All observers reported seeing the tumor with the F19 imaging. Also, the liver and spleen were seen in all mice. It is believed that the tumors were observed because the PFOB emulsion leaked through the tumor vascular endothelium and collected selectively in the tumor extracellular space. Fluorine signal was detected from the interstitial space of the tumor. EXAMPLE VI Six mice were imaged in a process similar to that described for Example V except that a driven equilibrium chemical shift selective F19 pulse sequence was used. The scanning parameters were identical to those used in Example V except that the TR was reduced to 50 milliseconds, and the number of excitations was from 2 to 64. These six mice had previously been imaged using the process of Example V, but the fluorine signal, although seen in the region of the tumor, was not sufficiently distinguishable from the noise to be called a positive result by all observers. The acquisition times and doses of PFOB emulsion were the same as in Example V.

The quality of the images was significantly better as indicated by the observers, and all mice had easily demonstrable tumors using the driven equilibrium approach. Images were obtained from the mice that shown a concentration of the fluorine nuclei in the liver and spleen, and not in the surrounding organs except for those parts of the reticuloendothelial system, so that the liver was distinctly contrasted. The contrasts were clear and useful for defining the liver and spleen in relation to the body. It is believed that fluorocarbon concentrations in

SUBSTITUTE8HZET these body parts is due in part to microphage pick up of emulsion particles from the blood stream. The image would thus represent the normal concentration of microphages in the liver, spleen, reticuloendothelial system and tumor body parts.

The foregoing detailed description of my invention and of preferred embodiments thereof, as to products, compositions and processes, is illustrative of specific embodiments only. It is to be understood, however, that additional embodiments may be perceived by those skilled in the art. The embodiments described herein, together with those additional embodiments, are considered to be within the scope of the present invention.

SUBSTITUTE SHEET

Claims

I CLAIM:

1. A method for imaging a selected non-vascular body space of an animal body comprising the steps of: introducing a biocompatible fluorocarbon into the non-vascular body space to at least partially fill the space; and imaging the space and surrounding tissue with a magnetic resonance imaging system adapted for hydrogen nucleus imaging to contrast the fluorocarbon occupied space from surrounding space or tissue containing substantial concentrations of hydrogen nuclei.

2. The method of Claim 1, wherein the biocompatible fluorocarbon is a neat fluorocarbon compound.

3. The method of Claim 2, wherein the biocompatible fluorocarbon is a mono-brominated perfluorocarbon.

4. The method of Claim 2, wherein the biocompatible fluorocarbon is neat perfluorohexylbromide.

5. The method of Claim 1, wherein the selected non- vascular body space is at least some portion of the gastrointestinal tract.

6. The method of Claim 1, wherein the selected non- vascular body space is at least some portion of the cerebro-spinal space.

7. In a process for radiological magnetic resonance imaging of a part of the body of an animal, the improvement comprising: contacting said body part with an effective amount of a biocompatible fluorocarbon emulsion; and imaging the body part with a magnetic resonance imaging system adapted for fluorine nuclei imaging.

8. The process improvement of Claim 7, wherein the biocompatible fluorocarbon emulsion is injected intravenously into the animal body.

9. The process improvement of Claim 7, wherein the biocompatible fluorocarbon emulsion is a mono-brominated perfluorocarbon.

SUBSTITUTE SHEET

10. The process improvement of Claim 7, wherein the biocompatible fluorocarbon emulsion is a perfluorohexyl¬ bromide.

11. The process improvement of Claim 7, wherein the biocompatible fluorocarbon emulsion is injected into the animal body to be transported by the blood to the body tissue to be imaged.

12. The process improvement of Claim 7, wherein the biocompatible fluorocarbon emulsion is injected intravenously into the animal body to be transported by the blood in the vascular system and concentrated by macrophages into the body parts to be imaged.

13. The process improvement of Claim 12, wherein the transported fluorocarbon emulsion is concentrated in at least one of the body parts from the group consisting of the liver, the spleen, the reticuloendothelial body parts and solid tumor body parts.

14. A contrast enhancement agent for use in magnetic resonance imaging of an animal body part comprising a biocompatible fluorocarbon emulsion suitable for intravenous injection into the animal.

15. The contrast agent of Claim 14, wherein the emulsion comprises a brominated perfluorocarbon.

16. The contrast agent of Claim 15, wherein the emulsion comprises a perfluorohexylbromide.

17. A method for imaging a non-vascular body space within an animal body comprising the steps of: introducing a biocompatible fluorocarbon into said non-vascular body space to at least partially fill said space; and imaging the space and surround tissue and body spaces with a magnetic resonance imaging system adapted for fluorine nuclei imaging.

18. The method of Claim 17, wherein the magnetic resonance imaging system is adapted for hydrogen nuclei

SUBSTITUTE SHEET imaging to image the fluorocarbon with absence-of-hydrogen contrast imaging.

19. A method for imaging a non-vascular body space within an animal body, wherein said space normally contains some aqueous fluid, comprising the steps of: introducing a biocompatible perfluorocarbon into a defined first, non-vascular body space to prevent aqueous fluid from occupying the same space and to define a body space substantially free of aqueous fluid; and imaging the body space and surrounding tissue with a magnetic resonance imaging system adapted to image an atomic nucleus other than the nuclei of fluorine and carbon.

20. The method of Claim 19, wherein the biocompatible perfluorocarbon is a mono-brominated perfluorocarbon.

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