Use of cyclodextrin as a radiation stabilizer

Abstract

The present invention provides a radiopharmaceutical composition comprising the following four components: (i) a radiolabeled compound; (ii) ethanol; (iii) a stabilizer for the radiolabeled compound; and (iv) cyclodextrin. The present invention also provides a radiopharmaceutical composition comprising: (i) a radiolabeled compound; (ii) a stabilizer for the radiolabeled compound, wherein the stabilizer comprises: ascorbic acid, aspartic acid, cysteine, maleic acid, gentisic acid, glutathione, glutamic acid, mannitol, nicotinamide, calcium chloride, N-tert-butyl-α-phenylnitrone (PBN), tartaric acid, p-aminobenzoic acid (pABA), chloride ions or salts or combinations thereof; and (iii) cyclodextrin.

Description

Technical Field

[0001] The present invention generally relates to radiopharmaceutical compositions comprising a radiolabeled compound and stabilized with a stabilizer and a cyclodextrin as a co-stabilizer. The present invention also relates to the use of such radiopharmaceutical compositions in methods of imaging a subject using the radiopharmaceutical compositions. Methods and kits for preparing the radiopharmaceutical compositions are also described. Background Art

[0002] Stabilizers are required in radiopharmaceutical formulations to reduce the formation of radioactive impurities during their shelf life.

[0003] Conventional radiopharmaceuticals contain radiopharmaceuticals, gases, and preparations containing solvents and stabilizers. Commonly used stabilizers include ethanol, sodium ascorbate, ascorbic acid, maleic acid, gentisic acid, and calcium chloride.

[0004] Cyclodextrins have previously been used to improve the solubility of poorly water-soluble substances. Summary of the invention

[0005] In one aspect, the present invention provides a radiopharmaceutical composition comprising the following four components:

[0006] (i) a radiolabeled compound comprising 18 F-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (ii) ethanol; (iii) a stabilizer for the radiolabeled compound, wherein the stabilizer comprises ascorbic acid; and (iv) a co-stabilizer for the radiolabeled compound, wherein the co-stabilizer is cyclodextrin.

[0007] The following subject matter is provided in combination with the aspects provided above and the additional aspects provided below.

[0008] The term radiopharmaceutical has its conventional meaning and refers to a radioactive compound suitable for in vivo mammalian administration for diagnostic or therapeutic purposes.

[0009] The radiopharmaceutical compositions described herein may comprise components as described in US2013129623.

[0010] Radiolabeled compounds include 18 F-labeled radiopharmaceuticals or pharmaceutically acceptable salts thereof. 18 Examples of F-labeled radiopharmaceuticals include [ 18 F]FDG, 18 F]FMAU, 18 F]FMISO, 18 F]FHBG, 18 F]AV-45, 18F]AV-19, 18 F]AV-1, 18 F]Flutemetamol, [ 18 F] Flurpiridaz, [ 18 F]K5,[ 18 F]HX4, 18 F]W372, 18 F]VM4-037, 18 F]CP18, 18 F]ML-10, 18 F]T808, 18 F]T807, 2-[ 18 F] fluoromethyl-L-phenylalanine or a combination thereof. Preferably, the radiolabeled compound is not [ 18 F]FLT.

[0011] Radiolabeled compounds may include compounds of formula (I):

[0012]

[0013] Formula (I),

[0014] Where A is selected from N (R 7 )、S、O、C(=O)O、NHCH 2 CH 2 O, bond or C (=O) N (R 7 );

[0015] When present, B is selected from hydrogen, alkoxyalkyl, alkoxy, aryl, C optionally substituted with an imaging moiety 1 -C 6 Alkyl, heteroaryl, and imaging moieties;

[0016] When present, C is selected from hydrogen, alkoxyalkyl, alkoxy, aryl, C optionally substituted with an imaging moiety 1 -C 6 Alkyl, heteroaryl, and imaging moieties;

[0017] D is selected from hydrogen, alkoxyalkyl, alkoxy, aryl, C optionally substituted with an imaging moiety 1 -C 6 Alkyl, heteroaryl, and an imaging moiety; or

[0018] C and D together with the atoms to which they are attached form a three- or four-membered carbon ring;

[0019] G is halogen or halogenated alkyl;

[0020] n is 0, 1, 2, or 3;

[0021] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 independently selected from hydrogen, C optionally substituted with an imaging moiety 1 -C 6 an alkyl group and an imaging moiety;

[0022] R 8 It is C 1 -C 6 An alkyl group, optionally substituted with an imaging moiety; and

[0023] E is selected from a bond, carbon, and oxygen, provided that when E is a bond, B and C are absent and D is selected from aryl and heteroaryl, and provided that when E is oxygen, B and C are absent and D is selected from hydrogen, alkoxyalkyl, aryl, C optionally substituted with an imaging moiety 1 -C 6 Alkyl and heteroaryl groups;

[0024] Provided that the imaging portion comprises 18 F and at least one imaging moiety is present in formula (I).

[0025] The substituent A of formula (I) may be O. 8 It may be tert-butyl. G may be chlorine.

[0026] Compounds of formula (I) and how to obtain them can be found, for example, in WO2005079391A2, the content of which is incorporated herein by reference.

[0027] The radiolabeled compound may comprise flurpiridaz, which has the following structure:

[0028] .

[0029] The term "stabilizer" specifically refers to a radiostabilizer, which is a compound that inhibits degradation reactions (e.g., redox processes) by capturing highly reactive free radicals, such as oxygen-containing free radicals generated by the radiolysis of water. The stabilizers of the present invention protect the radiolabeled compound(s) from radiolysis and thus reduce / prevent the purity of the radiolabeled compound(s) from decreasing over its shelf life. The term "co-stabilizer" refers to a compound that enhances the desired effect of a stabilizer.

[0030] Radiochemical purity (RCP) is determined using radio-TLC or HPLC and can be defined as the ratio of the (radiolabeled) drug substance peak to the total (radiolabeled) peak in the chromatogram. If a radiopharmaceutical is manufactured with a high radioactivity concentration (RAC), the decrease in RCP during storage may be greater than that at a lower RAC due to more radiolysis. High radioactivity causes the drug substance to destroy itself (i.e. radiolysis). The most effective stabilizers can be prepared by preparing different radiopharmaceutical formulations at similar RACs and comparing the changes over time (for 18 F compounds can be identified by a decrease in RCP (typically 8-10 hours) during storage. Radiopharmaceutical preparations that have the smallest decrease in RCP during storage have the most effective stabilizer for that particular drug substance.

[0031] In some cases, ethanol can be considered a stabilizer. More stabilizers include ascorbic acid, aspartic acid, cysteine, maleic acid, gentisic acid, glutathione, glutamic acid, mannitol, nicotinamide, calcium chloride, N-tert-butyl-α-phenylnitrone (PBN), tartaric acid and p-aminobenzoic acid (pABA), chloride ions or salts or combinations thereof. The stabilizer of the present invention comprises ascorbic acid. Ethanol can be included in an aqueous solution at up to 10% (volume / volume) of ethanol. Preferably, pharmaceutical grade materials are used.

[0032] The cyclodextrin may comprise: α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, or a pharmaceutically acceptable derivative or combination thereof. The cyclodextrin may comprise β-cyclodextrin. The cyclodextrin may comprise hydroxypropyl-β-cyclodextrin (HPbCD). In the context of the present invention, the cyclodextrin is a co-stabilizer.

[0033] The radiopharmaceutical composition may comprise a biocompatible carrier. A biocompatible carrier is a fluid, especially a liquid, in which the radiopharmaceutical can be suspended or preferably dissolved, so that the composition is physiologically tolerable, i.e., can be administered to the mammalian body without toxicity or excessive discomfort. The biocompatible carrier is suitably an injectable carrier liquid, such as sterile, pyrogen-free water for injection; an aqueous solution, such as saline (which can be advantageously balanced so that the final product for injection is isotonic); an aqueous buffer solution containing a biocompatible buffer (e.g., phosphate buffer); an aqueous solution of one or more tonicity-adjusting substances (e.g., salts of plasma cations with biocompatible counterions), sugars (e.g., glucose or sucrose), sugar alcohols (e.g., sorbitol or mannitol), glycols (e.g., glycerol) or other non-ionic polyol materials (e.g., polyethylene glycol, propylene glycol, etc.). Preferably, the biocompatible carrier is pyrogen-free water for injection, isotonic saline or phosphate buffer.

[0034] The radiopharmaceutical composition can be in a form suitable for mammalian administration. The phrase "form suitable for mammalian administration" refers to a composition that is sterile, pyrogen-free, does not contain compounds that produce toxic or adverse effects, and is formulated with a biocompatible pH (for the reagent of the present invention, about pH 4.0 to 10.5, preferably 4.5 to 9.5, more preferably 4.5 to 7.5) and a physiologically compatible osmotic pressure. Such a composition lacks particles that may have the risk of causing embolism in vivo, and is formulated so that no precipitation occurs when in contact with a biological fluid (e.g., blood). Such a composition also contains only biocompatible excipients, and is preferably isotonic.

[0035] Preferably, the mammal is an intact mammalian body, more preferably a human subject. Preferably, the radiopharmaceutical can be administered to the mammalian body in a minimally invasive manner, i.e., without significant health risks to the mammalian subject, even when performed under professional medical expertise. Such minimally invasive administration is preferably intravenous administration into a peripheral vein of the subject, without the need for local or general anesthesia.

[0036] In a specific embodiment of the present invention, the stabilizer comprises ascorbic acid and ethanol, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin (HPbCD), and the radiolabeled compound comprises flurpiridaz. The amount of ascorbic acid can be about 1 to about 100 mg / mL, the amount of ethanol can be about 2 to about 10% (volume / volume), and the amount of HPbCD can be about 1 to about 100 mg / mL.

[0037] In one embodiment of the invention, ascorbic acid is present in an amount of 1 to about 100 mg / mL, such as about 30 to about 50 mg / mL.

[0038] In one embodiment of the invention, HPbCD is present in an amount of about 1 to about 100 mg / mL, or about 40 to about 50 mg / mL, such as about 40 to about 47 mg / mL.

[0039] In one embodiment of the invention, ethanol is present in an amount of about 2 to about 10% (v / v), or about 5 to about 10% (v / v), such as 7% (v / v).

[0040] In another aspect, the present invention provides the use of a cyclodextrin as a co-stabilizer in a radiopharmaceutical composition. The definitions of the cyclodextrin and radiopharmaceutical composition used in this aspect are the same as provided above.

[0041] The radiopharmaceutical composition may comprise a radiolabeled compound, wherein the radiolabeled compound is not [ 18 F]FLT.

[0042] The present invention also provides methods of imaging a subject using the above-described radiopharmaceutical compositions.

[0043] The present invention also provides the above radiopharmaceutical composition for use in positron emission tomography (PET) imaging.

[0044] In another aspect, the present invention provides a method for preparing a radiopharmaceutical composition comprising combining the following four components: (i) a radiolabeled compound comprising 18 F-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (ii) ethanol; (iii) a stabilizer for the radiolabeled compound, wherein the stabilizer comprises ascorbic acid; and (iv) a co-stabilizer for the radiolabeled compound, wherein the co-stabilizer is cyclodextrin.

[0045] In yet another aspect, the present invention provides a kit for preparing a radiopharmaceutical composition, comprising the following four components: (i) a precursor compound for producing a radiolabeled compound, the radiolabeled compound comprising 18 F-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (ii) ethanol; (iii) a stabilizer for the radiolabeled compound; and (iv) a co-stabilizer for the radiolabeled compound, wherein the co-stabilizer is a cyclodextrin.

[0046] "Precursor compounds" include non-radioactive derivatives of radiolabeled compounds that are designed so that chemical reaction with a convenient chemical form of an in vivo detectable label occurs site-specifically, can be performed in a minimum number of steps (ideally a single step), and does not require significant purification (ideally no further purification) to obtain the desired in vivo imaging agent. Such precursor compounds are synthetic and can be conveniently obtained in good chemical purity. In one embodiment, the precursor compound is 18 A non-radioactive derivative of a F-labeled radiopharmaceutical comprising a leaving group which is separated from a precursor compound and a suitable 18 F-fluoride source reacts 18 F substitution.

[0047] The term "leaving group" refers to an atom or group of atoms that is displaced as a stable species during a substitution or displacement radiofluorination reaction. Suitable leaving groups include halogens and sulfonate-containing leaving groups. Specific examples of suitable leaving groups include iodide, bromide, chloride, mesylate, triflate, tosylate, nosylate, or 1,2-cyclic sulfate.

[0048] The term "appropriate 18"F-fluoride source" refers to a compound suitable for displacing a leaving group in a nucleophilic substitution reaction to produce 18 The chemical form of the F-labeled radiopharmaceutical is F-8-fluoride. 18 F-fluoride is usually obtained as an aqueous solution from nuclear reactions 18 O(p,n) 18 F is obtained and made reactive by addition of a cationic counterion and subsequent removal of water. Suitable cationic counterions should possess sufficient solubility in the anhydrous reaction solvent to maintain 18 F solubility. Suitable counterions include large, soft metal ions such as rubidium or cesium, potassium complexed with a cryptand such as KryptofixTM 222 (K222), or tetraalkylammonium salts. A suitable tetraalkylammonium salt is tetrabutylammonium bicarbonate. The well-known 18 A detailed discussion of F labeling techniques can be found in Chapter 6 of "Handbook of Radiopharmaceuticals" (2003; John Wiley and Sons: MJ Welch and CS Redvanly, Eds.).

[0049] When 18 F-flurpiridaz composition 18 In the case of F-radiopharmaceuticals, the precursor compound may be any of the following:

[0050]

[0051] wherein LG is a leaving group as defined above. 18 Further details of F-flurpiridaz and suitable kits can be found in, for example, WO2019185932A1 and WO2011097649A2, the contents of which are incorporated herein by reference.

[0052] The radiopharmaceutical composition may contain additional optional excipients. For example, such additional optional excipients include antimicrobial preservatives, pH adjusters, fillers, solubilizers or osmotic pressure adjusters.

[0053] The term "antimicrobial preservative" refers to an agent that inhibits the growth of potentially harmful microorganisms such as bacteria, yeasts or molds. Depending on the dosage applied, the antimicrobial preservative may also exhibit some bactericidal properties. The main effect of the antimicrobial preservative of the present invention is to inhibit the growth of any such microorganisms in the pharmaceutical composition. However, the antimicrobial preservative may also be optionally used to inhibit the growth of potentially harmful microorganisms in one or more components of the kit used to prepare the composition before administration. Suitable antimicrobial preservatives include: parabens, i.e., methyl, ethyl, propyl or butyl parabens or mixtures thereof; benzyl alcohol; ethanol, phenol; cresol; cetrimide and thimerosal. Preferred antimicrobial preservatives are parabens or ethanol.

[0054] The term "pH adjusting agent" refers to a compound or mixture of compounds that can be used to ensure that the pH of the composition is within acceptable limits for administration to humans or mammals (approximately pH 4.0-10.5, preferably 4.5-9.5, more preferably 4.5-7.5 for the agents of the present invention). Suitable such pH adjusting agents include pharmaceutically acceptable buffers, such as tris(hydroxymethyl)methylglycine (tricine), phosphates, acetates or TRIS [i.e., tris(hydroxymethyl)aminomethane], and pharmaceutically acceptable bases, such as sodium carbonate, sodium bicarbonate, or mixtures thereof. When the composition is used in the form of a kit, the pH adjusting agent can optionally be provided in a separate vial or container so that the user of the kit can adjust the pH as part of a multi-step procedure.

[0055] The term "filler" refers to pharmaceutically acceptable bulking agents that facilitate material handling during production and lyophilization. Suitable fillers include inorganic salts such as sodium chloride, and water-soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.

[0056] The term "solubilizer" refers to an additive present in the composition that increases the solubility of the radiopharmaceutical in the solvent. Preferred such solvents are aqueous media, and thus the solubilizer preferably improves solubility in water. Suitable such solubilizers include: C 1-4 alcohol; glycerol; polyethylene glycol (PEG); propylene glycol; polyoxyethylene sorbitan monooleate; sorbitan monooleate; polysorbates (e.g., Tween™); poly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymers (Pluronics™); cyclodextrins (e.g., alpha, beta, or gamma cyclodextrin, hydroxypropyl-beta-cyclodextrin, or hydroxypropyl-gamma-cyclodextrin), and lecithin.

[0057] Preferred solubilizers are cyclodextrin, C 1-4 alcohols, polysorbates and Pluronics™, more preferably cyclodextrins and C 2-4Alcohol. When the solubilizing agent is an alcohol, it is preferably ethanol or propanol, more preferably ethanol. Ethanol has several potential roles because it can also act as a biocompatible carrier, a radioprotectant, or an antimicrobial preservative. When the solubilizing agent is a cyclodextrin, it is preferably gamma-cyclodextrin, more preferably hydroxypropyl-β-cyclodextrin (HPbCD). The concentration of the cyclodextrin can be about 0.1 to about 50 mg / ml, preferably about 5 to about 50 mg / ml, more preferably 25 to 50 mg / ml, and most preferably about 40 to about 50 mg / ml.

[0058] The present inventors have found that the use of cyclodextrins as co-stabilizers improves the stability of radiopharmaceuticals compared to the use of conventional stabilizers. By adding cyclodextrins to the radiopharmaceutical formulation, the added value of a more radiochemically stable product as well as a more physically stable product that is more compatible with plastic contact materials (tubing, sterilizing filters, syringes, etc.) is obtained. This is even more advantageous if the active substance is poorly water soluble.

[0059] Edetate calcium disodium may also be used as an additional optional excipient.

[0060] Figure 1 Results of radiochemical purity (RCP) testing of various radiopharmaceutical compositions are shown as a function of radioactivity concentration (RAC).

[0061] Figure 2 Shown are the results of radiochemical purity (RCP) testing of various radiopharmaceutical compositions as a function of ascorbic acid concentration.

[0062] like Figure 1 It was shown that when HPbCD was present in the ascorbic acid formulation, RCP was more stable over 10 hours than when HPbCD was absent.

[0063] When prepared with 30 mg / mL ascorbic acid and 40 mg / mL HPbCD, compared with when prepared with 50 mg / mL ascorbic acid but without HPbCD, [ 18 HPbCD also improves the aqueous solubility of flurpiridaz and reduces the risk of incompatibility with consumer materials (e.g., tubing, sterilizing filters, syringes, etc.).

[0064] like Figure 2 As shown, when formulated with 30-50 mg / mL ascorbic acid (pH ~6), with or without 40-47 mg / mL HPbCD [ 18When [F] flurpiridaz was added, a decrease in RCP was observed within 4-10 hours. All samples contained approximately 7% (v / v) ethanol and were maintained under 0-21% (v / v) oxygen headspace gas.

[0065] The invention is described with reference to the following non-limiting examples.

[0066] Example 1: Purification by SPE 18 Radiosynthesis of F]Flurpiridaz

[0067] The GE Medical Systems PETtrace cyclotron with a silver target was used [ 18 O](p,n)[ 18 F] nuclear reaction to produce [ 18 [F]fluoride (approximately 200 GBq). A total target volume of 3.2-4.8 mL was used. The radioactive fluoride was trapped on a Waters QMA column (preconditioned with carbonate) and eluted with a solution of tetrabutylammonium bicarbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). The solution was driven off the QMA column with nitrogen to the reaction vessel. 18 The [F]fluoride was dried under a steady stream of nitrogen and vacuum at 110-120 °C for about 15 min. The precursor (10.2 mg) in MeCN (1.7 mL) was added to the dried [ 18 F] fluoride, and the reaction mixture was heated at 110 ° C for 3 minutes. The crude product was then hydrolyzed with NaOH solution (2M, 2.3 mL). The hydrolyzed crude product was then loaded onto a tC18 SPE column (Waters, product number WAT036800) and purified using the method described below.

[0068] The SPE column was washed with ascorbic acid (21 mL) to remove acetonitrile, NaOH, and hydrophilic chemicals and radiochemical impurities. The SPE column was then washed with 40% acetonitrile in water (11.9 mL) to remove hydroxy impurities. After this, the first SPE column was connected in series to the second SPE column (Waters, product number WAT036800), and both were washed in series with 40% acetonitrile in water (22.2 mL) and then with a nitrogen stream to remove [ 18 F]Flurpiridaz was transferred to the second column, and the more lipophilic chemicals and radiochemical impurities were trapped on the first SPE column. The second SPE column was washed with 40% acetonitrile in water (5.1 mL) and then ascorbic acid (21 mL) to remove acetonitrile. The product was then eluted from the second SPE column with 45% ethanol solution (9 mL, the first 2 mL was not collected) to remove [ 18F] Flurpiridaz eluted into the product vial.

[0069] The first 45 mL product vial consisted of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg / mL), ascorbic acid (50 mg / mL), and sodium hydroxide (7.5 mg / mL). The second 45 mL product vial consisted of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg / mL), ascorbic acid (50 mg / mL), hydroxypropyl-β-cyclodextrin (45 mg / mL; HPbCD), and sodium hydroxide (7.5 mg / mL).

[0070] The non-decay-corrected yields were 41-44%, and products with RACs of approximately 1800 MBq / mL were obtained (Table 1). The RCPs of the final products were 96-98%.

[0071] After 2 hours, the RCP of the formulation vials without HPbCD decreased by 0.8-1.4%, while the RCP of the formulation vials containing HPbCD decreased by 0.3-0.4% (Table 1). After 4 hours, the RCP of the formulation vials without HPbCD decreased by 1.1-1.7%, while the RCP of the formulation vials containing HPbCD decreased by 0.6%. Since the specification for RCP at the end of shelf life (8-10 hours) was 95%, the batch failed when HPbCD was excluded from the formulation.

[0072] In addition, when HPbCD was used in the formulation, the initial activity could be increased to 350 GBq, and the product RAC was about 2500 MBq / mL. The RCP was 96-98%, and the RCP decreased by about 0.5-1.3% within 8-10 hours.

[0073] Table 1 - [ 18 F] Representative formulations of Flurpiridaz

[0074]

[0075] As indicated above, the present inventors have discovered that the use of cyclodextrin as a co-stabilizer improves the radiostability of a radiopharmaceutical composition compared to the use of conventional radiostabilizers such as ascorbic acid alone or the use of a radiostabilizing system such as ascorbic acid and ethanol.

Claims

1. A radiopharmaceutical composition comprising the following four components: (i) a radiolabeled compound comprising a 18F-labeled radiopharmaceutical or a pharmaceutically acceptable salt thereof; (ii) ethanol; (iii) a stabilizer for the radiolabeled compound, wherein the stabilizer comprises ascorbic acid; and (iv) a co-stabilizer for a radiolabeled compound, wherein the co-stabilizer is a cyclodextrin, wherein the cyclodextrin comprises hydroxypropyl-β-cyclodextrin (HPbCD); wherein the radiolabeled compound comprises flurpiridaz:

2. The radiopharmaceutical composition of claim 1, wherein the ethanol comprises up to 10% v / v ethanol in aqueous solution.

3. The radiopharmaceutical composition of claim 1, wherein the radiopharmaceutical composition comprises a biocompatible carrier.

4. The radiopharmaceutical composition of claim 1, wherein the radiopharmaceutical composition is in a form suitable for mammalian administration.

5. The radiopharmaceutical composition of claim 1, wherein the amount of ascorbic acid is 1 to 100 mg / mL, the amount of ethanol is 2 to 10% v / v, and the amount of HPbCD is 1 to 100 mg / mL.

6. The radiopharmaceutical composition of claim 5, wherein the amount of HPbCD is 5 to 50 mg / mL.

7. The radiopharmaceutical composition of claim 6, wherein the amount of HPbCD is 25 to 50 mg / mL.

8. The radiopharmaceutical composition of claim 7, wherein the amount of HPbCD is 40 to 50 mg / mL.

9. The radiopharmaceutical composition of claim 8, wherein the amount of HPbCD is 40 to 47 mg / mL.

10. The radiopharmaceutical composition of claim 1, wherein the amount of ascorbic acid is 30 to 50 mg / mL.

11. The radiopharmaceutical composition of claim 1, wherein the amount of ethanol is 5 to 10% v / v.

12. The radiopharmaceutical composition of claim 11, wherein the amount of ethanol is 7% v / v.

13. The radiopharmaceutical composition of claim 1, wherein the pH of the composition is 4.0-10.

5.

14. The radiopharmaceutical composition of claim 13, wherein the pH of the composition is 4. 5-9.5。 15. The radiopharmaceutical composition of claim 1, comprising: (i) a radiolabeled compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; (ii) ethanol in an amount of 5 to 10% v / v; (iii) a stabilizer for a radiolabeled compound, wherein the stabilizer comprises ascorbic acid in an amount of 30 to 50 mg / mL; and (iv) a co-stabilizer of the radiolabeled compound, wherein the co-stabilizer is hydroxypropyl-β-cyclodextrin (HPbCD) in an amount of 40 to 50 mg / mL.

16. Use of cyclodextrin as a co-stabilizer in a radiopharmaceutical composition according to claim 1, wherein the cyclodextrin is used to protect the radiopharmaceutical composition from radiolysis.

17. Use of a radiopharmaceutical composition according to any one of claims 1 to 15 in the manufacture of an imaging agent.

18. The radiopharmaceutical composition of any one of claims 1-15 for use in positron emission tomography (PET) imaging.

19. A method of preparing a radiopharmaceutical composition comprising combining the following four components: (i) a radiolabeled compound as defined in any one of the preceding claims; (ii) ethanol; (iii) a stabiliser for a radiolabelled compound as defined in any one of the preceding claims; and (iv) A cyclodextrin as defined in any one of the preceding claims.

20. A kit for preparing a radiopharmaceutical composition comprising the following four components: (i) a precursor compound for the production of a radiolabelled compound as defined in any one of the preceding claims; (ii) ethanol; (iii) a stabiliser for a radiolabelled compound as defined in any one of the preceding claims; and (iv) A cyclodextrin as defined in any one of the preceding claims.

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