PHARMACEUTICAL COMPOSITION COMPRISING FLUORINE-18 LABELLED GASES

Abstract

There is provided a process for the preparation of a pharmaceutical composition comprising an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled sulphur hexafluoride ([.sup.18F]SF.sub.6) and .sup.18F-labelled carbon tetrafluoride ([.sup.18F]CF.sub.4), comprising the steps: a) Filling a target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulphur hexafluoride (SF.sub.6) and carbon tetrafluoride (CF.sub.4); b) Irradiating the gas mixture of step a) with protons with energies from 0.1 to 50 MeV. The pharmaceutical composition obtainable by the process and its uses in diagnosis, prognosis and lung function studies based on positron emission tomography (PET) are also claimed.

Claims

1. A process for the preparation of a pharmaceutical composition comprising an .sup.18F-labeled gas selected from the group consisting of .sup.18F-labeled sulfur hexafluoride (SF.sub.6) and .sup.18F-labeled carbon tetrafluoride (CF.sub.4), comprising the steps: a) Filling a target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulfur hexafluoride (SF.sub.6) and carbon tetrafluoride (CF.sub.4); b) Irradiating the gas mixture of step a) with protons with energies from 0.1 to 50 MeV.

2. The process according to claim 1, comprising a previous step comprising: filling the target with a gas mixture comprising .sup.18O-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 2 to 18 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target.

3. The process according to claim 1, further comprising the steps: c) Purifying either the mixture of .sup.18F-labeled plus unlabeled sulfur hexafluoride (SF.sub.6) or the mixture of .sup.18F-labeled plus unlabeled carbon tetrafluoride (CF.sub.4); d) Formulating either the .sup.18F-labeled plus unlabeled SF.sub.6 or the .sup.18F-labeled plus unlabeled CF.sub.4 with a pharmaceutically acceptable carrier.

4. The process according to claim 1, wherein the target is made of aluminium, nickel, niobium, silver, quartz, graphite, glass, gold, titanium, chromium, iron or a combination thereof.

5. The process according to claim 1, wherein the gas mixture of step a) comprises air, molecular fluorine (F.sub.2), nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulfur fluoride, a carbon fluoride, an optionally halogenated low molecular weight hydrocarbon, or combinations thereof.

6. The process according to claim 3, wherein in step c) the purification of .sup.18F-labeled plus unlabeled sulfur hexafluoride (SF.sub.6) or the purification of .sup.18F-labeled plus unlabeled carbon tetrafluoride (CF.sub.4) is carried out by solid phase extraction and the purified gas is trapped in a cold cryogenic trap.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of an .sup.18F-labeled gas selected from the group consisting of .sup.18F-labeled sulfur hexafluoride (SF.sub.6) and .sup.18F-labeled carbon tetrafluoride (CF.sub.4), and at least one pharmaceutically acceptable carrier; wherein the concentration of either .sup.18F-labeled plus unlabeled SF.sub.6 or .sup.18F-labeled plus unlabeled CF.sub.4 is from 810.sup.6% to 80%, expressed in volume, at P=1 bar and T=298K.

8. The pharmaceutical composition accordindly to claim 7 wherein the .sup.18F-labeled gas is .sup.18F-labeled SF.sub.6 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulfur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

9. The pharmaceutical composition accordingly to claim 7 wherein the .sup.18F-labeled gas is .sup.18F-labeled CF.sub.4 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulfur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

10. The pharmaceutical composition according to claim 7, wherein the concentration of radioactivity due to .sup.18F-labeled SF.sub.6 or .sup.18F-labeled CF.sub.4 is from 0.3 MBq/L to 37000 MBq/L, measured at P=1 bar and T=298K.

11. The pharmaceutical composition according to claim 10, wherein the concentration of radioactivity due to .sup.18F-labeled SF.sub.6 or .sup.18F-labeled CF.sub.4 is from 0.3 MBq/L to 247 MBq/L, measured at P=1 bar and T=298K.

12. The pharmaceutical composition according to claim 7 obtainable by the process comprising the steps: a) Filling a target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulfur hexafluoride (SF6) and carbon tetrafluoride (CF.sub.4); b) Irradiating the gas mixture of step a) with protons with energies from 0.1 to 50 MeV.

13. The pharmaceutical composition according to claim 7, wherein the total amount of either .sup.18F-labeled plus unlabeled SF.sub.6 or .sup.18F-labeled plus unlabeled CF.sub.4 administered is from 0.1 ng to 5 g per kilogram of body weight.

14. (canceled)

15. (canceled)

16. A method for acquiring contrast images from a subject in need thereof, including a human, comprising administering to the subject an effective amount of an .sup.18F-labeled gas selected from the group consisting of .sup.18F-labeled sulfur hexafluoride (SF.sub.6) and .sup.18F-labeled carbon tetrafluoride (CF.sub.4) as defined in claim 7, and at least one pharmaceutically acceptable carrier.

17. The method of claim 16, wherein the images acquisition is carried out by Positron Emission Tomography (PET).

18. A method for the diagnosis, prognosis and stratification of pulmonary diseases comprising administering the pharmaceutical composition defined in claim 7 to a subject in need thereof, including a human.

19. The method of claim 18, wherein the respiratory disease is selected from the group consisting of asthma, cystic fibrosis, lung cancer, emphysema, chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary fibrosis, tuberculosis, chronic respiratory failure and acute respiratory distress syndrome.

20. The process according to claim 2, further comprising the steps: c) Purifying either the mixture of .sup.18F-labeled plus unlabeled sulfur hexafluoride (SF.sub.6) or the mixture of .sup.18F-labeled plus unlabeled carbon tetrafluoride (CF.sub.4); d) Formulating either the .sup.18F-labeled plus unlabeled SF.sub.6 or the .sup.18F-labeled plus unlabeled CF.sub.4 with a pharmaceutically acceptable carrier.

21. The process according to claim 2, wherein the gas mixture of step a) comprises air, molecular fluorine (F.sub.2), nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulfur fluoride, a carbon fluoride, an optionally halogenated low molecular weight hydrocarbon, or combinations thereof.

22. The pharmaceutical composition according to claim 7 obtainable by a process comprising the steps: i) filling the target with a gas mixture comprising .sup.18O-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 2 to 18 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target; ii) Filling the target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulfur hexafluoride (SF.sub.6) and carbon tetrafluoride (CEO; iii) Irradiating the gas mixture of step ii) with protons with energies from 0.1 to 50 MeV.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1. Configuration of the target used for the production of [.sup.18F]CF.sub.4 and [.sup.18F]SF.sub.6; (1) proton beam; (2) target chamber; (3) stainless steel-high pressure container and liquid nitrogen cooling bath; (4) Exhaust; (5) [.sup.18O]O.sub.2 gas bottle; (6) Neon gas bottle; (7) CF.sub.4 or SF.sub.6 gas bottle; (8) radiochemistry lab; V.sub.1-V.sub.6 are 2-way, normally-closed electro-valves.

[0016] FIG. 2. Configuration of the collection system placed into one of the hot cells of the radiochemistry lab: (9) stainless steel-high pressure container and liquid nitrogen cooling bath; (10) gas-tight syringe; (11) vacuum pump; V.sub.2 is the same valve as in FIG. 1; V.sub.7-V.sub.10 are 2-way, normally-closed electro-valves.

[0017] FIG. 3. Configuration of the administration system. The mixture [.sup.18F]CF.sub.4/CF.sub.4/Ne is introduced in a gas-tight syringe (B) placed in an automated syringe pump, and released at 10 mL/min into the main oxygen gas stream just after the isofluorane vaporizer (C). The oxygen is obtained from a gas bottle (A) at a flow of 1L/min. The animal, placed into the PET-CT camera (E) inhales the radioactive gas mixed with the oxygen (carrier) and the isofluorane. The exhaust gas is passed through an active charcoal filter.

[0018] FIG. 4. Chromatogram (radioactivity detector) corresponding to the analysis of cyclotron produced [.sup.18F]CF.sub.4 immediately after transfer of the activity to the radiochemistry lab. Two radioactive peaks, with retention times of 1.93 (4.1) and 2.53 min (4.2), respectively, corresponding to [.sup.18F]CF.sub.4 (4.1) and [.sup.11C]CO.sub.2 (4.2), are identified.

[0019] FIG. 5. Chromatogram (radioactivity detector) corresponding to the analysis of cyclotron produced [.sup.18F]CF.sub.4 120 minutes after transfer of the activity to the radiochemistry lab. Only one radioactive peak, with retention time of 1.93 min (5.1), corresponding to [.sup.18F]CF.sub.4 can be identified.

[0020] FIG. 6. Chromatogram (MS detector) corresponding to the analysis of cyclotron produced [.sup.18F]CF.sub.4 after transfer of the activity to the radiochemistry lab. Five major species with retention times=1.45, 1.65, 2.25, 2.70 and 3.92, that were identified with the mass spectra as N.sub.2 (6.3), CF.sub.4 (6.1), CO.sub.2 (6.2), C.sub.2F.sub.6 (6.4), and C.sub.2F.sub.6O.sub.3 (6.5), respectively, were observed. One very minor peak appeared at RT=4.50 min, but the chemical structure could not be elucidated (6.6, insert).

[0021] FIG. 7. Chromatogram (MS detector) corresponding to the analysis of cyclotron produced [.sup.18F]SF.sub.6 after transfer of the activity to the radiochemistry lab. Four major species with retention times=1.45, 1.65, 1.70 and 2.95 were identified with the mass spectra as N.sub.2 (7.1), CF.sub.4 (7.2), F.sub.3N (7.3), and SF.sub.6 (7.4). One unidentified peak was found at RT=4.35 (7.5).

[0022] FIG. 8. PET-CT images showing the distribution of the radioactive gas in the lungs. Images are the result of summing all reconstructed frames: (A) 3D-volume render of the CT and the PET image, in sagital (left) and coronal (right) views; the lungs are marked as 8.1; (B) representative coronal slices; the lungs are marked as 8.2.

[0023] FIG. 9. Concentration of radioactivity in the lungs as a function of time, as calculated from PET-CT images. Results are meanstandard deviation, n=2.

DETAILED DESCRIPTION OF THE INVENTION

[0024] For the sake of understanding, the following definitions are included and expected to be applied throughout description, claims and drawings.

[0025] The term pharmaceutical composition refers to the mixture of .sup.18F-labelled gases together with other components such as a carrier gas or a mixture of carrier gases or a diluent. The pharmaceutical composition facilitates the administration of .sup.18F-labelled SF.sub.6 or .sup.18F-labelled CF.sub.4 to the organism so that it can be traced inside the body by different imaging techniques in a precise and safe manner. Throughout this description, the terms pharmaceutical composition and diagnostic composition are considered equivalent and are used interchangeably. The administration of the pharmaceutical composition can be carried out for diagnostic, prognostic, patient stratification, response to treatment and other purposes. The pharmaceutical composition can be used in a diseased subject or in a normal subject, the subject being an animal including, but not limited to, a human. Thus, the pharmaceutical composition can also be a veterinary composition when given to a subject other than a human. Because the pharmaceutical composition in the context of the present invention comprises a radiolabelled gas, it could also be termed a radiopharmaceutical composition.

[0026] The term pharmaceutically effective amount as used herein, refers to an amount of a compound (in this case .sup.18F-labelled SF.sub.6 or CF.sub.4) which, when administered, is enough to enable imaging in an efficient, precise, reliable and yet safe manner, so that the image can aid in determining a diagnosis, prognosis, evolution of disease, patient stratification, lung function analyses, etc. It is to be noted that when administered via inhalation, any of the two gases (SF.sub.6 or CF.sub.4) are given as a mixture of .sup.18F-labelled and .sup.18F-unlabelled gas. The particular dose of gas administered according to the invention will be set obviously by the circumstances associated with each case, including the administered gas, the route of administration, the disease being diagnosed, the imaging technology used to interpret the emitted radiation, and similar considerations.

[0027] The term pharmaceutically acceptable carrier as used herein refers to pharmaceutically acceptable materials, compositions or excipients. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable risk/benefit ratio. In the present invention, the pharmaceutically acceptable carrier used for administering the .sup.18F-labelled CF.sub.4 or SF.sub.6 can comprise air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, an optionally halogenated low molecular weight hydrocarbon, or a combination thereof.

[0028] For the purposes of the invention, the term optionally halogenated low molecular weight hydrocarbon encompasses C1-C8 hydrocarbon and C1-C8 halogenated hydrocarbon.

[0029] The term .sup.18O-isotopically enriched oxygen as used herein refers to molecular oxygen that is enriched with the Oxygen-18 isotope, one of the natural isotopes of oxygen. Naturally occurring oxygen is composed of three stable isotopes, Oxygen-16, Oxygen-17 and Oxygen-18, .sup.16Obeing the most abundant (99.762%).

[0030] The term target as used herein refers to a physical object that contains the material to be irradiated with protons, and that is coupled to the cyclotron chamber where protons are accelerated. For instance, the target can be integrated by different parts, mainly: (i) a collimator to focus the proton beam; (ii) a spacer that physically separates the cyclotron main chamber from the material to be irradiated; (iii) the target body, that is directly in contact with the material to be irradiated.

[0031] The term cryogenic retrieval as used herein refers to a process to recover a material by cooling. For example, when irradiation of the gas in the target finishes, the pressure in the target body can be ca. 20 bar. The target body can be connected via a stainless steel tube and a valve to a stainless steel container. The stainless steel container can be cooled with liquid nitrogen and the valve can be opened. As a result, the pressure in the stainless steel container decreases. This decrease in the pressure can suck the irradiated gas from the target body to the stainless steel container.

[0032] The term solid phase extraction as used herein refers to a sample preparation process by which compounds that are in a gas mixture are separated from other compounds in the mixture according to their physical and chemical properties, using a solid trap (e.g. powder).

[0033] The term cold cryogenic trap as used herein refers to a container immersed in a cold bath, in the case of the present invention, liquid nitrogen, although any cooling agent could be used.

[0034] As mentioned above, the first aspect of the present invention is a process for the preparation of a pharmaceutical composition comprising an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled sulphur hexafluoride (SF.sub.6) and .sup.18F-labelled carbon tetrafluoride (CF.sub.4), comprising the steps: a) Filling a target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulphur hexafluoride (SF.sub.6) and carbon tetrafluoride (CF.sub.4); b) Irradiating the gas mixture of step a) with protons with energies from 0.1 to 50 MeV;

[0035] In a particular embodiment of the first aspect of the invention, in step b) the irradiation of the gas mixture of step a) is with protons with energies from 1 to 50 MeV.

[0036] In a particular embodiment of the first aspect of the invention, in step b) the irradiation of the gas mixture of step a) is with protons with energies from 10 to 50 MeV.

[0037] In a particular embodiment of the first aspect of the invention, in step b) the irradiation of the gas mixture of step a) is with protons with energies from 10 to 40 MeV.

[0038] In a particular embodiment of the first aspect of the invention, in step b) the irradiation of the gas mixture of step a) is with protons with energies from 10 to 30 MeV.

[0039] In a particular embodiment of the first aspect of the invention, in step b) the irradiation of the gas mixture of step a) is with protons with energies from 10 to 20 MeV.

[0040] In a particular embodiment of the first aspect of the invention, the process for the preparation of the pharmaceutical composition comprises a previous step comprising: filling the target with a gas mixture comprising .sup.18O-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 2 to 18 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target.

[0041] In a particular embodiment of the first aspect of the invention, the process for the preparation of the pharmaceutical composition comprises a previous step comprising: filling the target with a gas mixture comprising .sup.18O-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 3 to 10 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target.

[0042] In a particular embodiment of the first aspect of the invention, the process for the preparation of the pharmaceutical composition comprises a previous step comprising: filling the target with a gas mixture comprising .sup.18O-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 4 to 8 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target.

[0043] In a particular embodiment of the first aspect of the invention, the process further comprises the steps: c) Purifying either the mixture of .sup.18F-labelled plus unlabelled sulphur hexafluoride (SF.sub.6) or the mixture of .sup.18F-labelled plus unlabelled carbon tetrafluoride (CF.sub.4); d) Formulating either the .sup.18F-labelled plus unlabelled SF.sub.6 or the .sup.18F-labelled plus unlabelled CF.sub.4 with a pharmaceutically acceptable carrier.

[0044] In a particular embodiment of the first aspect of the invention, the target is made of aluminium, nickel, niobium, silver, quartz, graphite, glass, gold, titanium, chromium, iron or a combination thereof.

[0045] In a particular embodiment of the first aspect of the invention, the gas mixture of step a) or the pharmaceutically acceptable carrier of step d) comprise air, molecular fluorine (F.sub.2), nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a carbon fluoride, an optionally halogenated low molecular weight hydrocarbon, or combinations thereof.

[0046] In a particular embodiment of the first aspect of the invention in step c) the purification of .sup.18F-labelled plus unlabelled sulphur hexafluoride (SF.sub.6) or the purification of .sup.18F-labelled plus unlabelled carbon tetrafluoride (CF.sub.4) is carried out by solid phase extraction and the purified gas is trapped in a cold cryogenic trap.

[0047] As it has been stated above, a second aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled sulphur hexafluoride (SF.sub.6) and .sup.18F-labelled carbon tetrafluoride (CF.sub.4), and at least one pharmaceutically acceptable carrier.

[0048] The pharmaceutical composition which is the second aspect of the invention will typically be produced in a facility endowed with a cyclotron or any other technology suitable to produce the labelled gas and will have to be transported to the site of use (typically a hospital). In order to do so, the labelled gas will have to be handled in a container suitable for the transportation of radioactive gases.

[0049] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled SF.sub.6 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

[0050] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled CF.sub.4 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

[0051] In a particular embodiment of the second aspect of the invention, the inert gas is selected from the group consisting of helium (He), argon (Ar), neon (Ne), krypton (Kr), xenon (Xe), and radon (Rn), N2, CO2, halogenated hydrocarbons and combinations thereof.

[0052] In a particular embodiment of the second aspect of the invention, the concentration of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 is from 810.sup.6% to 80%, expressed in volume, at P=1 bar and T=298K.

[0053] In a particular embodiment of the second aspect of the invention, the concentration of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 is from 810.sup.3% to 80%, expressed in volume, at P=1 bar and T=298K.

[0054] In a particular embodiment of the second aspect of the invention, the concentration of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 is from 810.sup.1% 80%, expressed in volume, at P=1 bar and T=298K.

[0055] In a particular embodiment of the second aspect of the invention, the concentration of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 is from 8% to 80%, expressed in volume, at P=1 bar and T=298K.

[0056] In a particular embodiment of the second aspect of the invention, the concentration of radioactivity due to .sup.18F-labelled SF.sub.6 or .sup.18F-labelled CF.sub.4 is from 0.3 MBq/L to 37000 MBq/L, measured at P=1 bar and T=298K.

[0057] In a particular embodiment of the second aspect of the invention, the concentration of radioactivity due to .sup.18F-labelled SF.sub.6 or .sup.18F-labelled CF.sub.4 is from 0.3 MBq/L to 247 MBq/L, measured at P=1 bar and T=298K.

[0058] In a particular embodiment of the second aspect of the invention, the total amount of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 0.1 ng to 5 g per kilogram of body weight.

[0059] In a particular embodiment of the second aspect of the invention, the total amount of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 0.1 ng to 100 mg per kilogram of body weight.

[0060] In a particular embodiment of the second aspect of the invention, the total amount of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 0.5 ng to 50 mg per kilogram of body weight.

[0061] In a particular embodiment of the second aspect of the invention, the total amount of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 0.8 ng to 20 mg per kilogram of body weight.

[0062] In a particular embodiment of the second aspect of the invention, the total amount of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 1 ng to 10 mg per kilogram of body weight.

[0063] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled SF.sub.6, the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, and optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the total amount of .sup.18F-labelled plus unlabelled SF.sub.6 administered is from 0.1 ng to 100 mg per kilogram of body weight.

[0064] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled CF.sub.4, and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, an optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the total amount of .sup.18F-labelled plus unlabelled CF.sub.4 administered is from 0.1 ng to 100 mg per kilogram of body weight

[0065] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled SF.sub.6, the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, and optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the concentration of .sup.18F-labelled plus unlabelled SF.sub.6 is from 810.sup.6% to 80%, expressed in volume, at P=1 bar and T=298K.

[0066] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled CF.sub.4, and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, an optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the concentration of .sup.18F-labelled plus unlabelled CF.sub.4 is from 810.sup.6% to 80%, expressed in volume, at P=1 bar and T=298K.

[0067] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled SF.sub.6, the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, and optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the concentration of radioactivity due to .sup.18F-labelled SF.sub.6 is from 0.3 MBq/L to 37000 MBq/L, measured at P=1 bar and T=298K.

[0068] In a particular embodiment of the second aspect of the invention, the .sup.18F-labelled gas is .sup.18F-labelled CF.sub.4, and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, an optionally halogenated low molecular weight hydrocarbon and combinations thereof, and the the concentration of radioactivity due to .sup.18F-labelled CF.sub.4 is from 0.3 MBq/L to 37000 MBq/L, measured at P=1 bar and T=298K.

[0069] It also forms part of the invention a pharmaceutical composition according to the second aspect of the invention obtainable by the process of the first aspect of the invention.

[0070] As it has been stated above, a third aspect of the invention is the pharmaceutical composition according to the second aspect of the invention for use as an image contrast agent. This third aspect can be also formulated as a pharmaceutical composition according to the second aspect of the invention for use in the assessment of lung function, and additionally as a pharmaceutical composition according to the second aspect of the invention for use in diagnosis, prognosis and stratification of pulmonary disease.

[0071] The third aspect of the invention can also be formulated as the use of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled SF.sub.6 and .sup.18F-labelled CF.sub.4 for the preparation of a pharmaceutical composition for the assessment of lung function. The third aspect of the invention can also be formulated as the use of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled SF.sub.6 and .sup.18F-labelled CF.sub.4 for the preparation of a pharmaceutical composition for the diagnosis, prognosis and stratification of respiratory disease.

[0072] The third aspect can also be formulated as a method for the assessment of lung function which comprises administering a pharmaceutically effective amount of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled SF.sub.6 and .sup.18F-labelled CF.sub.4 to a subject in need thereof, including a human. The third aspect can also be formulated as a method of diagnosis, prognosis and stratification of respiratory disease which comprises administering a pharmaceutically effective amount of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled SF.sub.6 and .sup.18F-labelled CF.sub.4 to a subject in need thereof, including a human.

[0073] In a particular embodiment of the third aspect of the invention, the use as an image contrast agent is in the study of respiratory disease, wherein the respiratory disease is selected from the group consisting of asthma, cystic fibrosis, lung cancer, emphysema, chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary fibrosis, tuberculosis, chronic respiratory failure and acute respiratory distress syndrome.

[0074] In a particular embodiment of the third aspect of the invention, the imaging is carried out by Positron Emission Tomography (PET).

[0075] In a particular embodiment of the third aspect of the invention, the respiratory disease is selected from the group consisting of asthma, cystic fibrosis, lung cancer, emphysema, chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary fibrosis, tuberculosis, chronic respiratory failure and acute respiratory distress syndrome, and the imaging is carried out by Positron Emission Tomography (PET).

[0076] It is understood herein that a respiratory disease is a disease that impairs proper lung function, either by having its origin in the respiratory tract or because the disease has its origin in another system or organ but affects the respiratory tract as a side-effect.

[0077] Throughout the description and claims the word comprise and variations of the word, are not intended to exclude other technical features, additives, components, or steps.

[0078] Furthermore, the word comprise and its variations encompasses the term consisting of. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

EXAMPLES

A) Material and Methods

[0079] Production of [.sup.18F]CF.sub.4 and [.sup.18F]SF.sub.6

[0080] Target Configuration:

[0081] The strategy for the production of [.sup.18F]CF.sub.4 and [.sup.18F]SF.sub.6 is based in the double shoot method using the target provided by IBA (http://www.iba-radiopharmasolutions.com)for the production of [.sup.18F]F.sub.2 (see FIG. 1 for scheme).

[0082] The target consists of an aluminum target body (internal volume around 50 mL) physically isolated from the cyclotron main chamber by two metallic disks (made of aluminum and titanium) both cooled with helium gas. The target body and the collimator are water cooled. The target chamber (2 in FIG. 1) contains the gas that is irradiated with the protons (1 in FIG. 1). The target chamber has two inlet/outlet ports connected via stainless steel tubing to remotely-controlled electro-valves (V.sub.1-V.sub.6 in FIG. 1). V.sub.1 is connected to a stainless steel-high pressure container (3 in FIG. 1) which can be introduced in a liquid nitrogen cooling bath. V.sub.2 is connected to the radiochemistry lab (outside the cyclotron vault, 8 in FIG. 1). V.sub.3 is an exhaust (4 in FIG. 1). V.sub.4 is connected to the [.sup.18O]O.sub.2 gas bottle (5 in FIG. 1). V.sub.5 and V.sub.6 are connected to the Neon and CF.sub.4/SF.sub.6 bottles, respectively, both of them placed out of the cyclotron vault (6 and 7 in FIG. 1, respectively).

[0083] Production Process A:

[0084] Step 1: The target was filled with [.sup.18O]O.sub.2 by opening V.sub.4 to a final pressure P.sub.1. After reaching the appropriate pressure, V.sub.4 was closed.

[0085] Step 2: The target was irradiated with protons (nominal energy of the cyclotron=18 MeV) at a proton intensity of 15 pA measured in the target and an integrated current of C.sub.1 Ah.

[0086] Step 3: After irradiation, the stainless steel-high pressure container was introduced in the liquid nitrogen bath, V.sub.1 was opened and the gas content of the target was recovered in the container. When the pressure in the target was below 0.2 bar (absolute pressure), V.sub.1 was closed.

[0087] Step 4: V.sub.6 was opened and the target chamber was filled with CF.sub.4 or SF.sub.6 gas (for the production of [.sup.18]CF.sub.4or [.sup.18F]SF.sub.6, respectively) to a pressure P.sub.2. After reaching the appropriate pressure, V.sub.6 was closed.

[0088] Step 5: V.sub.5 was opened and the target chamber was topped with Neon gas to a final pressure P.sub.3. After reaching the appropriate pressure, V.sub.5 was closed.

[0089] Step 6: The target was irradiated with protons at a proton intensity of 15 pA measured in the target and an integrated current of C.sub.2 pAh.

[0090] Step 7: After the end of the second irradiation, V.sub.2, V.sub.7, and V.sub.8 were opened and the target gas was unloaded to one of the hot cells in the radiochemistry lab into a stainless steel-high pressure container immersed in a liquid nitrogen cooling bath (9 in FIG. 2). NOTE: Previous to the transfer of the activity to the radiochemistry lab, the stainless steel-high pressure container was emptied under vacuum by opening V.sub.8 and V.sub.9 (FIG. 2).

[0091] Step 8: After complete transfer (pressure in the target<1 bar above atmospheric pressure) V.sub.2, V.sub.7, and V.sub.8 were closed and after 120 minutes, the activity present in the stainless steel-high pressure container was measured in a dose calibrator.

[0092] Step 9: A fraction of the gas was collected in a gas-tight syringe (10 in FIG. 2) by opening V.sub.8 and V.sub.10, and the sample was analyzed as explained below.

[0093] Production Process B:

[0094] Because .sup.19F is known to undergo the .sup.19F(p, pn).sup.18F nuclear reaction, we explored the formation of [.sup.18F]CF.sub.4 and [.sup.18F]SF.sub.6 by direct irradiation of mixtures of CF.sub.4/Neon or SF.sub.6/Neon, respectively, in a single shot method. The process was as follows:

[0095] Step 1: V.sub.6 in FIG. 1 was opened and the target chamber was filled with CF.sub.4 or SF.sub.6 gas to a pressure P.sub.2. After reaching the appropriate pressure, V.sub.6 was closed.

[0096] Step 2: V.sub.5 in FIG. 1 was opened and the target chamber was topped with Neon gas to a final pressure P.sub.3. After reaching the appropriate pressure, V.sub.5 was closed.

[0097] Step 3: The target was irradiated with protons at a proton intensity of 15 A measured in the target and an integrated current of C.sub.2 Ah.

[0098] Step 4: After the end of the irradiation, V.sub.2, V.sub.7, and V.sub.8 were opened and the target gas was unloaded to one of the hot cells in the radiochemistry lab into a stainless steel-high pressure container immersed in a liquid nitrogen cooling bath (9 in FIG. 2). NOTE:

[0099] Previous to the transfer of the activity to the radiochemistry lab, the stainless steel-high pressure container was emptied under vacuum by opening V.sub.8 and V.sub.9 (FIG. 2).

[0100] Analysis of the Trapped Gas (for both Methods):

[0101] A fraction of the trapped gas was analysed by gas-chromatography-Mass spectrometry, immediately after transfer and at t=120 minutes. Analyses were performed on an Agilent 7820A network GC connected to an Agilent 5975c inert XL MSD with Triple axis detector and a radioactivity detector. A J&W PoraPlot column (length: 27.5 m, internal diameter: 0.32 mm) was used as stationary phase. The inlet conditions were 150 C., 6.8 psi and a flow rate of 2.5 ml/min. Helium (99.9999%) was used as the carrier gas. The oven temperature was set to 36 C. The analyses were made in scan mode.

[0102] Imaging Studies

[0103] Imaging studies were conducted with [.sup.18F]CF.sub.4.

[0104] Animals:

[0105] Male rats (n=2) weighing 35014 g (Sprague-Dawley, Harlan, Udine, Italy) were used to perform PET studies. The animals were cared for and handled in accordance with the Guidelines for Accommodation and Care of Animals (European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes) and internal guidelines, and experimental procedures were approved by the Ethical Committee and local authorities.

[0106] Administration of the Labelled Compounds:

[0107] The radioactive gas was administered by inhalation, by mixing the mixture [.sup.18F]CF.sub.4/CF.sub.4/Ne obtained at the end of the production process (process A) with the oxygen carrier gas. With that aim, the system depicted in FIG. 3 was implemented.

[0108] PET-CT System:

[0109] PET studies were performed using an eXploreVista-CT small animal PET-CT system (GE Healthcare).

[0110] Image Acquisition:

[0111] The procedure was as follows:

[0112] Step 1: Rats were anesthetized in an induction chamber using a mixture of 3-4% isoflurane in O.sub.2.

[0113] Step 2: Animals were rapidly moved into the PET-CT camera, were anaesthesia was maintained with a mixture of 1.5-2.0% isofluorane in O.sub.2. During the stay into the PET-CT camera, animals were kept normothermic using a heating blanket (Homeothermic Blanket Control Unit; Bruker). Regular breathing (frequency of 5010 breaths/minute) was maintained by adjustment of anaesthetic conditions. Respiration and body temperature of the animals were monitored throughout the scan.

[0114] Step 3: At t=0 min, with the animal under anaesthesia, acquisition of PET images was started in list mode.

[0115] Step 4: At t=1 minute, the syringe pump was started and the radioactive gas ([.sup.18F]CF.sub.4, diluted with Neon and non-radioactive CF.sub.4, 74 MBq, 2 mCi) was introduced in the main stream of oxygen and consequently administered to the animal.

[0116] Step 5: At t=2 minutes, the syringe pump was stopped, and image acquisition was continued until t=10 minutes.

[0117] Step 6: After finalising the PET image acquisition, a whole body CT scan was performed, providing anatomical information as well as the attenuation map, for the later image reconstruction.

[0118] Image Reconstruction and Analysis:

[0119] Images were reconstructed (decay and CT-based attenuation corrected) with OSEM-2D. Twenty nine frames (320s, 1010s, 420s and 1230s) were defined to gain information about the spatiotemporal distribution of the radioactivity. PET images were analysed using PMOD image analysis software (PMOD Technologies Ltd, Zurich, Switzerland). Volumes of interest (VOIs) were manually drawn in the lungs on the CT images. VOIs were then transferred to the PET images and the concentration of radioactivity was obtained for each organ and time frame as cps/cm.sup.3. All frames were finally summed and re-processed to get more accurate images of the distribution of radioactivity within the lungs.

[0120] B) Results

[0121] Production of f.sup.18F1CF.sub.4

[0122] Production Process A: Identification of the Radioactive and Non-Radioactive Gases:

[0123] Initial experiments were performed by fixing the following experimental conditions: P.sub.1=20 bar; C.sub.1=1 pAh; P.sub.2=4 bar; P.sub.3=20 bar; C.sub.2=1 pAh. These experiments were conducted to identify the radioactive and non radioactive gases present in the final gas collected in the radiochemistry lab.

[0124] GC-MS analysis performed just after irradiation confirmed the presence of two radioactive gases, with retention times (RTs) of 1.93 and 2.53 min, corresponding to [.sup.18F]CF.sub.4 and [.sup.11C]CO.sub.2 by co-elution with reference standards (FIG. 4). Analysis of the same sample after 120 min confirmed the complete disappearance of the peak corresponding to [.sup.11C]CO.sub.2 (FIG. 5). MS analysis confirmed the presence of 5 major species with RTs=1.45, 1.65, 2.25, 2.70 and 3.92, that were identified with the mass spectra as N.sub.2, CF.sub.4, CO.sub.2, C.sub.2F.sub.6, and C.sub.2F.sub.6O.sub.3, respectively (FIG. 6). One very minor peak appeared at RT=4.50 min, but the chemical structure could not be elucidated (FIG. 6, insert).

[0125] Production Process A: Formation of [.sup.18F]CF.sub.4:

[0126] After identification of the radioactive and non radioactive gases present in the final mixture, experiments were performed by fixing the following experimental conditions: P.sub.1=20 bar; C.sub.1=1 or 4 pAh; P.sub.2=4 bar; P.sub.3=20 bar; C.sub.2=1, 2 or 4 Ah. After the second irradiation and trapping of the irradiated gas in the stainless steel-high pressure container, V.sub.8 was closed. After 120 minutes, the amount of activity was measured in a dose calibrator and the gas was analyzed using the same analytical system as described above. The results expressed as amount of radioactivity, decay corrected to the end of the irradiation process, are shown in Table 1.

TABLE-US-00001 TABLE 1 Amount of activity, decay corrected to the end of irradiation, obtained under different experimental conditions for production process A. Entry C.sub.1 (Ah) C.sub.2 (Ah) Mean (GBq) SDEV (GBq) 1 1 1 2.30 0.08 2 1 2 2.47 0.08 3 1 4 2.75 0.13 4 4 4 8.43 0.59

[0127] As it can be seen in the table, the amount of activity generated was quite independent of C.sub.2 value, suggesting that the isotopic exchange reaction is relatively fast. Increasing the integrated current C.sub.1 resulted in a significant increase in the final amount of radioactivity, as shown in entry 4.

[0128] Production Process B: Identification of the Radioactive and Non-Radioactive Gases

[0129] Chromatographic profiles equivalent to those obtained when method A was used were obtained.

[0130] Production Process B: Formation of [.sup.18F]CF.sub.4:

[0131] Experiments were performed by fixing the following experimental conditions: P.sub.2=2 or 4 bar; P.sub.3=20 bar; C.sub.2=4 or 8 pAh. After the irradiation and trapping of the irradiated gas in the stainless steel-high pressure container, V.sub.8 was closed. After 120 minutes, the amount of activity was measured in a dose calibrator and the gas was analyzed using the same analytical system as described above. The results expressed as amount of radioactivity, decay corrected to the end of the irradiation process, are shown in Table 2.

TABLE-US-00002 TABLE 2 Amount of activity, decay corrected to the end of irradiation, obtained under different experimental conditions for production process B. Entry P.sub.2 (bar) C.sub.2 (Ah) Mean (GBq) SDEV (GBq) 1 2 4 0.27 0.03 2 2 8 0.49 0.04 3 4 4 0.58 0.04 4 4 8 0.80 0.06

[0132] As it can be seen, despite the presence of [.sup.18F]CF.sub.4 could be detected, the production yield was much lower than that obtained using the double shot method. For equivalent experimental conditions (P.sub.2=4 bar; C.sub.2=4 pAh, entries 4 in Table 1 and 3 in Table 2), values of 8.430.59 and 0.580.04 were obtained for methods A and B, respectively.

[0133] Production of [.sup.18F]SF.sub.6

[0134] Production Process A: Identification of the Radioactive and Non-Radioactive Gases

[0135] For the production of this radioactive species, only optimal experimental conditions were assayed: P.sub.1=20 bar; C.sub.1=4 pAh; P.sub.2=4 bar; P.sub.3=20 bar; C.sub.2=4 pAh. The analysis of the radioactive gas by radio GC-MS confirmed, after 120 min of decay, the presence of only one radioactive species with RT=3.35 min, which was identified as [.sup.18F]SF.sub.6. MS analysis confirmed the presence of 5 species with RTs =1.45, 1.65, 1.70, 2.95 and 4.35, that were identified with the mass spectra as N.sub.2, CF.sub.4, F.sub.3N, SF.sub.6, and one unidentified compound (FIG. 7).

[0136] Production process A: Formation of E.sup.8F1SF.sub.6:

[0137] The results expressed as amount of radioactivity, decay corrected to the end of the irradiation process, are shown in Table 3.

TABLE-US-00003 TABLE 3 Amount of activity, decay corrected to the end of irradiation, obtained for production process A. Entry C.sub.1 (Ah) C.sub.2 (Ah) Mean (GBq) SDEV (GBq) 1 4 4 6.77 0.21

[0138] Production Process B: Identification of the Radioactive and Non-Radioactive Gases

[0139] Chromatographic profiles equivalent to those obtained when method A was used were obtained.

[0140] Production Process B: Formation of E.sup.8F1SF.sub.6:

[0141] Experiments were performed by fixing the following experimental conditions: P.sub.2=4 bar; P.sub.3=20 bar; C.sub.2=4 pAh. After the irradiation and trapping of the irradiated gas in the stainless steel-high pressure container, V.sub.8 was closed. After 120 minutes, the amount of activity was measured in a dose calibrator and the gas was analyzed using the same analytical system as described above. The results expressed as amount of radioactivity, decay corrected to the end of the irradiation process, are shown in Table 4.

TABLE-US-00004 TABLE 4 Amount of activity, decay corrected to the end of irradiation, obtained for production process B. Entry P.sub.2 (bar) C.sub.2 (Ah) Mean (GBq) SDEV (GBq) 1 4 4 0.36 0.05

[0142] As it can be seen, despite the presence of [.sup.18F]SF.sub.6 could be detected, the production yield was much lower than that obtained using the double shot method.

[0143] Imaging Studies

[0144] Summed images clearly show a uniform distribution of the radioactive gas in the lungs (FIG. 8). Dynamic images showed immediate distribution of the radioactive gas in the lungs. The time-activity curve (FIG. 9) corresponding to a VOI drawn in the whole lungs shows a plateau, which is reached immediately after the onset of contrast agent administration. When the delivery of the radioactive gas is discontinued, almost complete elimination of the radioactivity is achieved in a few seconds.

REFERENCES CITED IN THE APPLICATION

[0145] Banister S., et al., Fluorine-18 chemistry for PET: A concise Introduction, Current Radiopharmaceuticals 2010, vol. 3, pp. 68-80

[0146] Murata K., et al. Ventilation imaging with positron emission tomography and Nitrogen-13 Radiology 1986, vol. 158, pp. 303-307

[0147] Yu J, et al. 19F: A versatile reporter for non-invasive physiology and pharmacology using magnetic resonance Current Medicinal Chemistry 2005, vol. 12, pp. 819-848

[0148] Gens T. A. et al. The exchange of F18 between metallic fluorides and gaseous fluorine compounds J. Am. Chem. Soc. 1957, vol. 79, pp. 1001-1002

[0149] Rogers M. T., Katz J. Fluorine Exchange reactions between hydrogen fluoride and the halogen fluorides J. Am. Chem. Soc. 1952, vol. 74, pp. 1375-1377

[0150] Boggs et al: Non-exchange of F18 between HF and Fluorinated Methanes, J. Am. Chem. Soc., 1955, 77 (24), pp 6505-6506

[0151] Cramer et al: Gas phase fluorination of benzene, fluorobenzene, m-difluorobenzene, and trifluoromethylbenzene by reactions of thermal fluorine-18 atoms, J. Am. Chem. Soc., 1974, 96 (21), pp 6579-6584

[0152] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0153] Clause 1. A process for the preparation of a pharmaceutical composition comprising an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled sulphur hexafluoride (SF.sub.6) and .sup.18F-labelled carbon tetrafluoride (CF.sub.4), comprising the steps:

[0154] a) Filling a target with a gas mixture comprising a fluorinated gas selected from the group consisting of sulphur hexafluoride (SF.sub.6) and carbon tetrafluoride (CF.sub.4);

[0155] b) Irradiating the gas mixture of step a) with protons with energies from 0.1 to 50 MeV.

[0156] Clause 2. The process for the preparation of the pharmaceutical composition of clause 1, comprising a previous step comprising: filling the target with a gas mixture comprising .sup.18F-isotopically enriched Oxygen, irradiating the gas mixture with protons with energies in the range from 2 to 18 MeV and subsequently removing the mixture of irradiated gas comprising .sup.18O-isotopically enriched Oxygen from the target.

[0157] Clause 3. The process of any one of clauses 1-2, further comprising the steps:

[0158] c) Purifying either the mixture of .sup.18F-labelled plus unlabelled sulphur hexafluoride (SF.sub.6) or the mixture of .sup.18F-labelled plus unlabelled carbon tetrafluoride (CF.sub.4);

[0159] d) Formulating either the .sup.18F-labelled plus unlabelled SF.sub.6 or the .sup.18F-labelled plus unlabelled CF.sub.4 with a pharmaceutically acceptable carrier.

[0160] Clause 4. The process of any one of clauses 1-3, wherein the target is made of aluminium, nickel, niobium, silver, quartz, graphite, glass, gold, titanium, chromium, iron or a combination thereof.

[0161] Clause 5. The process for the preparation of the pharmaceutical composition of any one of clauses 1-4, wherein the gas mixture of step a) or the pharmaceutically acceptable carrier of step d) comprise air, molecular fluorine (F.sub.2), nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a carbon fluoride, an optionally halogenated low molecular weight hydrocarbon, or combinations thereof.

[0162] Clause 6. The process for the preparation of the pharmaceutical composition according to any one of clauses 1-5, wherein in step c) the purification of .sup.18F-labelled plus unlabelled sulphur hexafluoride (SF.sub.6) or the purification of .sup.18F-labelled plus unlabelled carbon tetrafluoride (CF.sub.4) is carried out by solid phase extraction and the purified gas is trapped in a cold cryogenic trap.

[0163] Clause 7. A pharmaceutical composition comprising a pharmaceutically effective amount of an .sup.18F-labelled gas selected from the group consisting of .sup.18F-labelled sulphur hexafluoride (SF.sub.6) and .sup.18F-labelled carbon tetrafluoride (CF.sub.4), and at least one pharmaceutically acceptable carrier.

[0164] 8. The pharmaceutical composition of clause 7 wherein the .sup.18F-labelled gas is .sup.18F-labelled SF.sub.6 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

[0165] Clause 9. The pharmaceutical composition of clause 7 wherein the .sup.18F-labelled gas is .sup.18F-labelled CF.sub.4 and the pharmaceutically acceptable carrier is selected from the group consisting of air, water, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, a C1-C8 hydrocarbon, a C1-C8 halogenated hydrocarbon and combinations thereof.

[0166] Clause 10. The pharmaceutical composition of any one of clauses 7-9, wherein the concentration of either .sup.18F-labelled plus unlabelled SF.sub.6 or .sup.18F-labelled plus unlabelled CF.sub.4 is from 810.sup.6% to 80%, expressed in volume, at P=1 bar and T=298K.

[0167] Clause 11. The pharmaceutical composition of any one of clauses 7-10, wherein the concentration of radioactivity due to .sup.18F-labelled SF.sub.6 or .sup.18F-labelled CF.sub.4 is from 0.3 MBq/L to 37000 MBq/L, measured at P=1 bar and T=298K.

[0168] Clause 12. The pharmaceutical composition of clause 11, wherein the concentration of radioactivity due to .sup.18F-labelled SF.sub.6 or .sup.18F-labelled CF.sub.4 is from 0.3 MBq/L to 247 MBq/L, measured at P=1 bar and T=298K.

[0169] Clause 13. The pharmaceutical composition according to any one of clauses 7-12 obtainable by the process as defined in any one of clauses 1-6.

[0170] Clause 14. A pharmaceutical composition as defined in any one of clauses 7-12 for use as an image contrast agent.

[0171] Clause 15. The pharmaceutical composition for use according to clause 14, wherein the imaging is carried out by Positron Emission Tomography (PET).