HK1146710B - Radiopharmaceutical composition - Google Patents

Description

Radiopharmaceutical compositions

Technical Field

The present invention relates to radiopharmaceutical compositions comprising amyloid-binding compounds and processes for preparing the same. The radiopharmaceutical compositions find particular use in the diagnosis of disease conditions in which abnormal amyloid deposition is implicated. The radiopharmaceutical compositions are useful as in vivo (vivo) imaging agents for Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).

Description of the related Art

Common excipients included in pharmaceutical compositions include buffers, lyophilization aids, stabilization aids, solubilization aids, and bacteriostats. The inclusion of one or more optional components in the formulation can improve the stability and shelf life of the drug, as well as the ease of synthesis of the drug by the end user being practiced. Solubilizing aids typically used in the preparation of pharmaceutical compositions include ethanol, glycerol, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitol fatty acid esters (polysorbates for short), poly (ethylene oxide) poly (propylene oxide) -poly (ethylene oxide) block copolymers (pluronics) and lecithin.

The Powell et al review provides a comprehensive list of excipients in Pharmaceutical compositions for parenteral administration [1998 PDA Journal of Pharmaceutical Science and technology 52(5) pp238-311]. There are almost 40 pharmaceutical compositions listed therein, which comprise polysorbate 80 at a concentration in the range of 0.0005-12% w/v. Known radiopharmaceutical compositions containing polyoxyethylene sorbitol fatty acid esters are¹¹¹In-hydroxyquinoline solution. The radiopharmaceutical composition contains, inter alia, 100. mu.g of polysorbate 80 per ml (equivalent to 0.01% w/v) in order to be able to dissolve in water and prevent the complex, when in aqueous solution, from binding to glass and plastic surfaces (EP 0017355).

To be suitable for intravenous administration, the radiopharmaceutical composition must be sterile, pyrogen-free, and dissolved in a suitable biocompatible carrier medium. To obtain the desired sterile, pyrogen-free radiopharmaceutical composition, it is prepared under sterile manufacturing conditions. Alternatively, the preparation may be carried out under non-sterile conditions, followed by terminal sterilisation using, for example, gamma radiation, autoclave, dry heat, membrane filtration (sometimes referred to as sterile filtration) or chemical treatment (e.g. with ethylene oxide). Sterile filtration can be achieved by formulating a kit through which the radiopharmaceutical composition passes. Such a formulation kit must be sterile and typically includes a 0.2 μm pore filter, and a silicone tube that allows the radiopharmaceutical composition to pass through the filter and into a suitable sterile container such as a vial or syringe. There is no particular industry standard for such formulation kits, and thus in practice various filter types and tubing are used for different formulation kits.

Radiopharmaceuticals are typically prepared by reaction of a non-radioactive precursor compound with a suitable radioisotope tracer (radiolabel), wherein only a small portion of the precursor compound is radiolabeled to produce the radiopharmaceutical. Therefore, retention on the surface of the formulation kit (dispensing kit) can lead to the loss of a larger proportion of the radiopharmaceutical, rendering the resulting radiopharmaceutical composition unsuitable for use. Radiopharmaceutical compositions comprising thioflavin derivative compounds are known to be useful in the diagnosis of subjects suffering from diseases characterised by amyloid deposits, as described in WO2002/16333 and WO 2004/083195. The present inventors have found that when known radiopharmaceutical compositions comprising these thioflavin derivative compounds are passed through the formulation kit, the radiopharmaceutical is severely retained on a range of different 0.2 μm pore filters and silicone tubes. Solutions to this technical problem are therefore sought in order to reduce the loss of thioflavin derivative compounds on the components of the formulation kit.

Summary of the invention

The present invention relates to radiopharmaceuticals and in particular to radiopharmaceutical compositions comprising a thioflavin derivative compound and polysorbate as an excipient. The radiopharmaceutical compositions of the present invention overcome the problems encountered with prior art compositions comprising the same type of compound. Also provided by the invention are methods of preparation of the radiopharmaceutical compositions of the invention and specific uses of the radiopharmaceutical compositions.

Detailed description of the invention

In one aspect, the present invention relates to a radiopharmaceutical composition comprising:

(i) a compound of the general formula I:

wherein:

z is S, NR ', O, or C (R')₂Wherein each R' is independently H or C_1-6Alkyl, with the proviso that when Z is C (R')₂When the tautomeric form of the heterocycle is indole:

y is hydrogen, C_1-6Alkyl, halogen, OR ' OR SR ', wherein R ' is H OR C_1-6Alkyl, or Y is-NR¹R²；

R^1-10Each independently selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_4-6Cycloalkyl, hydroxy, C_1-6Hydroxyalkyl radical, C_2-6Hydroxyalkenyl group, C_2-6Hydroxyalkynyl, thiol, C_1-6Mercaptoalkyl radical, C_2-6Mercaptoalkenyl radical, C_2-6Mercaptoalkynyl, C_1-6Mercaptoalkoxy, halogen, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenoalkynyl, C_1-6Haloalkoxy, amino, C_1-6Aminoalkyl radical, C_2-6Aminoalkenyl, C_2-6Aminoalkynyl, C_1-6Aminoalkoxy, cyano, C_1-6Cyanoalkyl radical, C_2-6Cyanoalkenyl radical, C_2-6Cyanoalkynyl, and C_1-6A cyanoalkoxy group; nitro radical, C_1-6Nitroalkyl, C_2-6Nitroalkenyl, C_2-6Nitroalkynyl, and C_1-6A nitroalkoxy group; and the combination of (a) and (b),

wherein at least one atom of the compound of formula I is a radioisotope suitable for in vivo imaging;

(ii) a biocompatible carrier medium; and the combination of (a) and (b),

(iii) 0.05-5.0% w/v polysorbate;

at a pH of 4.0 to 10.5.

Unless otherwise specified, the term "alkyl", alone or in combination, refers to a straight or branched chain alkyl group containing preferably from 1 to 10 carbon atoms, more preferably from 1 to 5 carbon atoms, and most preferably from 1 to 3 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl.

The term "alkenyl" denotes an unsaturated straight or branched aliphatic hydrocarbon group containing one double bond. Examples are radicals such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

The term "alkynyl" denotes an unsaturated straight or branched aliphatic hydrocarbon group containing one triple bond. Examples include groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

Unless otherwise specified, the term "alkoxy", alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined above. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

Unless otherwise specified, the term "cycloalkyl", alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group in which each cyclic moiety preferably contains from 3 to 8 carbon atom ring members (ring members), more preferably from 3 to 7 carbon atom ring members, and most preferably from 4 to 6 carbon atom ring members, and which may optionally be a benzo-fused ring system, which ring system is optionally substituted as defined herein for aryl. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2, 3-dihydro-1H-indenyl, adamantyl.

The term "hydroxy" refers to an-OH group. The terms "hydroxyalkyl," "hydroxyalkenyl," and "hydroxyalkynyl" as used herein, refer to at least one hydroxyl group attached to the parent molecular moiety through an alkyl, alkenyl, alkynyl, or alkoxy group, respectively.

The term "halogen" refers to a substituent selected from fluorine, chlorine, bromine or iodine. The terms "haloalkyl", "haloalkenyl", "haloalkynyl", "haloalkoxy", as used herein, refer to at least one halogen group attached to the parent molecular moiety through an alkyl, alkenyl, alkynyl or alkoxy group, respectively. Preferred halogen substituents are fluorine and iodine.

The term "thiol" refers to the-SH group. The terms "mercaptoalkyl", "mercaptoalkenyl", "mercaptoalkynyl", "mercaptoalkoxy", as used herein, refer to at least one thiol group attached to the parent molecular moiety through an alkyl, alkenyl, alkynyl or alkoxy group, respectively.

The term "cyano" as used herein refers to the group-CN. The terms "cyanoalkyl", "cyanoalkenyl", "cyanoalkynyl", "cyanoalkoxy", as used herein, refer to at least one cyano group attached to the parent molecular moiety through an alkyl, alkenyl, alkynyl or alkoxy group, respectively. Representative examples of cyanoalkyl groups include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term "nitro" means-NO₂A group. The terms "nitroalkyl", "nitroalkenyl", "nitroalkynyl", "nitroalkoxy", as used herein, refer to at least one nitro group attached to the parent molecular moiety through an alkyl, alkenyl, alkynyl or alkoxy group, respectively.

The term "compound of formula I" as used herein refers to the free compound or a pharmaceutically acceptable salt, prodrug (e.g., ester), or solvate thereof. Suitable salts, prodrugs, and solvates are those described in WO2004/083195 and WO 02/16333.

Preferred for formula I:

z is S, NR' or O; and the combination of (a) and (b),

y is-NR¹R²(ii) a And the combination of (a) and (b),

R^1-10each independently selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy, C_1-6Hydroxyalkyl, halogen, C_1-6Haloalkyl, and C_1-6A haloalkoxy group.

Most preferred for formula I:

z is S;

y is-NR¹R²(ii) a And the combination of (a) and (b),

R^1-10each independently selected from hydrogen, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy, hydroxy, C_1-3Hydroxyalkyl, halogen, C_1-3Haloalkyl, and C_1-3A haloalkoxy group.

In a particularly preferred embodiment, the compound of formula I is a compound of formula Ia:

wherein:

R¹¹and R¹²Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, nitro, amino, C_1-6Aminoalkyl, halogen or C_1-6A haloalkyl group;

R¹³is hydrogen, hydroxy, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl, C_1-6Haloalkenyl, -COOR', -OCH₂OR ', wherein R' is as defined for formula I; and the combination of (a) and (b),

Y^ais hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy or halogen, or-NR as defined above for formula I¹R²。

Preferably, for compounds of formula Ia:

R¹¹and R¹²Independently selected from hydrogen, C_1-6Alkyl or halogen;

R¹³is hydroxy, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or halogen;

Y^ais halogen or-NR as defined above for formula I¹R²。

Most preferably, for compounds of formula Ia:

R¹¹and R¹²Independently selected from hydrogen or halogen;

R¹³is hydroxy or C_1-6An alkoxy group;

Y^ais-NR¹R²Wherein R is¹Is hydrogen and R²Is hydrogen, C_1-6Alkyl or C_1-6A haloalkyl group.

A "radioisotope suitable for in vivo imaging" is a radioisotope that can be externally detected in a non-invasive (non-invasive) manner after in vivo administration. Examples of such radioactive isotopes include gamma-emitting radioactive halogens and positron-emitting radioactive non-metals, particularly those suitable for imaging using single photon emission tomography (SPECT) or Positron Emission Tomography (PET). Suitably, the radioisotope is selected from¹¹C，¹²³I，¹²⁴I，¹²⁵I，¹³¹I，⁷⁵Br，⁷⁶Br，⁷⁷Br, and¹⁸f, optimum use¹¹C，¹²³I, and¹⁸F。

in a particularly preferred embodiment, the radiopharmaceutical composition of the invention is a compound of formula Ia, wherein R is¹¹To R¹³One or Y of^aIs or includes radioactive carbon or radioactive halogen. Preferably, the radioactive carbon is¹¹C, and the radioactive halogen is preferably selected from¹²³I，¹²⁴I，¹²⁵I，¹³¹I，⁷⁵Br，⁷⁶Br，⁷⁷Br，¹⁷F and¹⁸F. most preferably, the radioactive halogen is¹²³I or¹⁸F. When formula Ia includes a radioactive carbon, it is preferably at Y^aMost preferably when Y^ais-NR¹R²Then (c) is performed. When formula Ia includes a radioactive halogen, it is preferably at R¹¹Or Y^aOr when Y is^ais-NR¹R²Wherein R is¹Is hydrogen and R²Is C_1-6Haloalkyl or C_2-6When haloalkenyl is present, it is preferably at Y^aOf (2) is used.

Non-limiting examples of particularly preferred compounds of formula Ia are the following:

compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

The "biocompatible carrier medium" is a fluid, especially a liquid, in which the radiopharmaceutical is suspended or dissolved to give a radiopharmaceutical composition which is physiologically tolerable, i.e. capable of administration to the mammalian body without toxicity or excessive discomfort. Typical biocompatible carrier media are, for example, pyrogen-free water for injection, isotonic saline and aqueous ethanol. For the radiopharmaceutical compositions of the invention, aqueous ethanol is preferred, with 5-10% (v/v) ethanol being particularly suitable for the compositions of the invention. Preferably, the biocompatible carrier medium is an aqueous ethanol solution comprising 6-8% (v/v) ethanol, most preferably 6.5-7.5% (v/v) ethanol, with 7% (v/v) being especially preferred.

The radiopharmaceutical composition may optionally further comprise additional components such as pH adjusting agents, pharmaceutically acceptable stabilizers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid), antimicrobial preservatives or fillers.

The term "pH-adjusting agent" refers to a compound or mixture of compounds used to ensure that the pH of the radiopharmaceutical composition is maintained within acceptable limits for mammalian administration (about pH 4.0 to 10.5). Suitable such pH-adjusting agents include pharmaceutically acceptable buffers such as tricine, phosphate or TRIS [ i.e. TRIS (hydroxymethyl) aminomethane ], and pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof. Preferably, the pH is maintained in the range 6.0 to 8.5, suitably 6.0 to 8.0 and most preferably in the range 5.8 to 7.2, with a pH in the range 7.0 to 7.2 being especially preferred. Preferred buffering agents for the radiopharmaceutical compositions of the invention are phosphate buffers, preferably from 0.005 to 0.1M, most preferably from 0.01M to 0.1M, and especially preferably from 0.01 to 0.05M and most especially preferably from 0.01 to 0.02M.

The term "antimicrobial preservative" refers to an agent that inhibits the growth of potentially harmful microorganisms such as bacteria, yeast, or mold. Antimicrobial preservatives may also exhibit some bactericidal properties depending on the dosage. The primary effect of the antimicrobial preservative of the present invention is to inhibit the growth of any such microorganisms in the radiopharmaceutical composition. Suitable antimicrobial preservatives include: parabens, i.e. methyl, ethyl, propyl or butyl parabens or mixtures thereof; benzyl alcohol; phenol; cresol; cetyltrimethylammonium bromide (cetrimide) and thimerosal (thiomersal). Preferred antimicrobial preservatives are parabens.

The term "filler" refers to a pharmaceutically acceptable extender that can facilitate material handling during product manufacture. Suitable fillers include inorganic salts such as sodium chloride, and water-soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.

Generally for radiopharmaceutical compositions, it is the goal to have the lowest possible amount of excipient to produce a pharmaceutically effective and physiologically tolerable composition.

The radiopharmaceutical compositions of the invention are suitable for use in containers having a seal suitable for single or multiple punctures with a hypodermic needle (e.g., a crimped-on septum seal closure) while maintaining sterile integrity. Such containers may contain single or multiple patient doses. A typical dose container comprises a bulk vial (bulk visual) (suitably 5-50 cm) containing a single or multiple patient doses³E.g. 10-30cm³Volume) from which patient doses can be drawn into clinical grade syringes at various time intervals during the effective life of the formulation to accommodate clinical situations. Prefilled syringes are designed to contain a single patient dose and are therefore preferably disposable or other syringes suitable for clinical use. The pre-filled syringe may be fitted with a radiopharmaceutical syringe shield (shield) to protect the operator from the radiation dose. Suitable such radiopharmaceutical syringe shields are known in the art and preferably comprise lead or tungsten. Typically, the radiopharmaceutical composition of the invention has a radioactive concentration of from 50 to 100MBq/ml, suitably from 70 to 85MBq/ml, more suitably 80 MBq/ml. Individual patient doses typically contain 50-400MBq, more typically 80-370MBq, and have a volume of 1-10ml, preferably around 5ml, when administered.

"Polysorbate" is polyoxyethylene sorbitan ester. A review of polysorbates can be found in "Noninic Surfactants", M.J. Schick, Ed. (Dekker, New York, 1967) pp 247-299. Examples of polysorbates include polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, which are given their trade namesSuch as Tween 20, Tween 40, Tween 60 and Tween 80 from SSigma-Aldrich was purchased commercially. The numbers following "polysorbate" relate to the type of fatty acid associated with the polyoxyethylene sorbitan portion of the molecule. Monolaurate is represented by 20, monopalmitate by 40, monostearate by 60 and monooleate by 80. The concentration of polysorbate is suitably sufficient to eliminate substantially all binding of the compound of formula I to many filter types. Preferably, the loss of the compound of formula I on the filter during formulation is in the range 0-10%, most preferably 0-5.0%, particularly preferably 0-1.0%, and most particularly preferably 0%. In a preferred embodiment, the polysorbate of the radiopharmaceutical formulation is selected from polysorbate 20 or polysorbate 80, with polysorbate 80 being particularly preferred. Preferably, the concentration of polysorbate present in the radiopharmaceutical formulation is in the range 0.25-2.5% w/v, most preferably between 0.5 and 1.0% w/v, and especially preferably 0.5% w/v.

The compounds of formula I may be prepared from commercially available starting materials or by using the starting materials described in WO2002/16333, WO2004/083195 and WO2007/020400, or by standard methods of organic chemistry.

The compounds of formula I comprising a radiotracer such as radioactive carbon or radioactive halogen may suitably be prepared by reaction of a precursor compound with a suitable source of radioactive carbon or radioactive halogen.

"precursor compounds" include derivatives of the radioisotope labeled compounds of formula I that are designed such that a chemical reaction between site-specific and the appropriate chemical form of the radioisotope tracer occurs, that the reaction can be carried out in a minimal number of steps (ideally a single step) and without significant purification (ideally without further purification) to give the desired radioisotope labeled compound of formula I. Such precursor compounds are synthetic and can suitably be obtained in good chemical purity. The precursor compound may optionally include protecting groups for certain functional groups of the precursor compound.

The term "protecting group" refers to a group that prevents or inhibits an undesired chemical reaction, but which is designed to be sufficiently reactive to allow the group to be cleaved from the functional group under sufficiently mild conditions that the remainder of the molecule is not altered. After deprotection, the desired radioisotope labelled compound of general formula I is obtained. Protecting groups are well known to those skilled in the art and are suitably selected from, for amine groups: boc (where Boc is t-butyloxycarbonyl), Fmoc (where Fmoc is fluorenylmethoxycarbonyl), trifluoroacetyl, allyloxycarbonyl, Dde [ i.e., 1- (4, 4-dimethyl-2, 6-dioxocyclohexylidene) ethyl ] or Npys (i.e., 3-nitro-2-pyridinesulfinyl); and for carboxyl groups: methyl, tert-butyl or benzyl esters. For the hydroxyl group, suitable protecting groups are: methyl, ethyl or tert-butyl; an alkoxymethyl or ethyl group; a benzyl group; acetyl; a benzoyl group; trityl (trityl) (Trt) or trialkylsilyl groups such as tetrabutyldimethylsilyl. For thiol groups, suitable protecting groups are: trityl and 4-methoxybenzyl. The use of other protecting Groups has been described in 'Protective Groups in organic Synthesis', Theoroda W.Greene and Peter G.M.Wuts, (third edition, John Wiley & Sons, 1999).

Compounds of formula I labelled with a radioactive halogen or a radioactive carbon are preferred in the radiopharmaceutical compositions of the invention. Methods for obtaining radioiodinated, radiofluorinated and radiocarbonylated compounds of formula I via suitable precursor compounds will now be described.

Radioiodination

When the compounds of formula I are labelled with radioactive iodine, suitable precursor compounds are those which comprise derivatives which undergo electrophilic or nucleophilic iodination or undergo condensation with a labelled aldehyde or ketone. An example of the first category is:

(a) organometallic derivatives such as trialkylstannanes (e.g. trimethylstannyl or tributylstannyl), or trialkylsilanes (e.g. trimethylsilyl) or organoboron compounds (e.g. boronateesters or organotrifluoroborates);

(b) non-radioactive alkyl bromides for halogen exchange or alkyl tosylates, alkyl mesylates or alkyl triflates for nucleophilic iodination;

(c) aromatic rings activated for electrophilic iodination (e.g. phenols, phenylamines) and aromatic rings activated for nucleophilic iodination (e.g. aryldiazonium salts aryldiazonium, aryltrialkylammonium salts or nitroaryl derivatives).

The precursor compound for radioiodination preferably comprises: non-radioactive halogen atoms such as aryl iodides or bromides (to allow radioiodine exchange); an activated aryl ring (e.g., phenol or phenyl amine); organometallic substituents (e.g., trialkyltin, trialkylsilyl, or organoboron compounds); or an organic substituent such as triazene (triazene) or a good leaving group for nucleophilic substitution such as iodonium salt. Preferably for radioiodination, the precursor compound comprises an activated aryl ring or an organometallic substituent, most preferably a trialkyltin.

Precursor compounds and methods for introducing radioiodine into organic molecules have been described by Bolton [ j.lab.comp.radiopharm.,45，485-528(2002)]. Suitable organoboronate organoboron compounds and methods for their preparation have been described by Kabalaka et al [ nuclear.29，841-843(2002)and 30，369-373(2003)]. Suitable organic trifluoroborates and their preparation have been described by Kabalaka et al [ nuclear.31，935-938(2004)]。

Examples of aryl groups to which radioactive iodine can be attached are given below:

wherein in this case alkyl is preferably methyl or butyl. These groups contain substituents that allow easy substitution of the radioiodine onto the aromatic ring. Other substituents containing radioactive iodine can be synthesized by direct iodination via radioactive halogen exchange, e.g.

The radioactive iodine atom is preferably attached to an aromatic ring such as a benzene ring, or to a vinyl group via a direct covalent bond, because it is well known that iodine atoms bonded to saturated aliphatic systems are susceptible to in vivo metabolism and thus to radioactive iodine loss.

The source of radioactive iodine is selected from iodide or iodonium (I)⁺). Most preferably, the chemical form is iodide, which is typically converted to an electrophilic species by an oxidant during radiosynthesis.

Further details relating to certain methods of radioiodination of compounds of formula I are provided in WO2002/16333 and WO 2004/083195.

Radiofluorination

When the compounds of formula I are labelled with a radioisotope of fluorine, the radioactive fluorine atom may form part of a fluoroalkyl or fluoroalkoxy group, since alkyl fluorides are metabolically resistant in the body. The fluoroalkylation can be carried out by reaction of precursor compounds containing reactive groups, such as phenols, thiols and amides, with fluoroalkyl groups.

Alternatively, the radioactive fluorine atom may be attached to an aromatic ring such as a benzene ring via a direct covalent bond. For such aryl systems, the aryl group is selected from aryl diazonium salts, aryl groupsOn nitro compounds or aryl quaternary ammonium salts¹⁸Nucleophilic displacement of F-fluoride to give aryl-¹⁸Suitable routes for F derivatives.

The radiofluorination may be by using¹⁸The reaction of F-fluoride with a suitable chemical group in a precursor compound with a good leaving group, such as alkyl bromide, alkyl methanesulfonate or alkyl p-toluenesulfonate, is carried out via direct labeling.

Because of the fact that¹⁸The half-life of F is only 109.8 minutes, important is the intermediate¹⁸The F moiety has a high specific activity and is therefore produced by using a reaction process which is as rapid as possible.

Further details relating to certain methods of radiofluorination of compounds of general formula I are provided in WO2002/16333, WO2004/083195 and WO 2007/020400.

To obtain¹⁸More details of the synthetic pathway for F-labeled derivatives have been described by Bolton, j.lab.comp.radiopharm,45，485-528(2002)。

radioactive carbonylation

When the compounds of the formula I are used¹¹When labeled C, one labeling pathway is the reaction of a precursor compound belonging to the demethylated variant of the methylated compound of formula I with [ alpha ]¹¹C]Methyl iodide is reacted. It is also possible to react the desired labeled compound of the formula I with a Grignard reagent having a specific hydrocarbon chain¹¹C]CO₂Carrying out a reaction to introduce¹¹C。¹¹C can also be introduced as methyl on the aromatic ring, in which case the precursor compound comprises a trialkyltin group or B (OH)₂A group.

Because of the fact that¹¹The half-life of C is only 20.4 minutes, important is the intermediate¹¹The C moiety has a high specific radioactivity and is therefore produced by using a reaction process which is as rapid as possible.

Further details regarding certain methods of the radiocarbonylation of compounds of formula I are provided in WO2002/16333 and WO 2004/083195.

Such as¹¹A comprehensive overview of C-labelling technology can be found in Antoni et al, "assays on the Synthesis of¹¹C-Labelled Compounds”in Handbook ofRadiopharmaceuticals，Ed.M.J.Welch and C.S.Redvanly(2003，JohnWiley and Sons)。

When the compound of formula I is radiolabeled, the precursor compound may suitably be provided as part of a kit, for example for use in radiopharmaceuticals. Such kits may contain a cartridge (cartridge) that can be inserted (plug intos) into an adapted automated synthesizer. In addition to the precursor, the cartridge may contain a column (column) to remove any unwanted radioactive ions, and a suitable container attached to allow the reaction mixture to evaporate and the product to be formulated as desired. Reagents and solvents and other consumables required for synthesis can also be included with the compact disc carrying software that allows the synthesizer to operate in a manner that meets the customer's requirements for radioactive concentration, volume, lead time, etc. Suitably, all components of the kit are disposable in order to minimise the possibility of contamination between runs and may be sterile and quality assured.

After synthesis, the compound of formula I may require purification, which may be performed using standard methods, for example using High Performance Liquid Chromatography (HPLC), ion exchange chromatography, and/or flow through a solvent exchange cartridge.

High Performance Liquid Chromatography (HPLC) is a commonly used method in the preparation of radiopharmaceuticals and can be used to remove any chemical impurities present in the crude reaction mixture after synthesis of the compound of formula I. The HPLC method needs to be optimized for any particular compound. The normal phase or reverse phase column can be used with one of various organic solvents (e.g., methanol, acetonitrile, ethanol, 2-propanol) at neutral, acidic or basic pH. Preferably, a reverse phase column is used together with neutral pH conditions to achieve the most advantageous separation of the compounds of formula I.

Purification using a solvent exchange cartridge involves loading the compound of formula I into a column, followed by elution of the column with a suitable solvent, ethanol and aqueous ethanol being preferred solvents for the compound of formula I. Suitable solvent exchange cartridges include SEP-Pak^TMCartridges (Waters Corp.), such as C8, C18 or C30.

In an additional aspect, the present invention relates to a method of preparing the radiopharmaceutical composition of the invention, which comprises the steps of:

(i) admixing a compound of formula I, a biocompatible carrier medium, and 0.05-5.0% w/v polysorbate;

(ii) the pH of the resulting mixture is adjusted to 4.0 to 10.5, if necessary.

After step (ii), the composition may be sterilized. Sterilization can be carried out by standard methods of the prior art, such as gamma irradiation; sterilizing in an autoclave; dry heating; membrane filtration (sometimes referred to as sterile filtration); or chemically treated (e.g., with ethylene oxide). Sterile filtration can be performed through a formulation kit through which the radiopharmaceutical composition flows. Such formulation kits must be sterile and typically include a 0.2 μm pore filter, as well as a silicone tube that allows the radiopharmaceutical composition to flow through the filter and into a suitable sterile container such as a vial or syringe.

There is therefore further provided a process for the preparation of a radiopharmaceutical composition of the invention as described above, which further comprises the steps of:

(iii) (iii) sterilization of the compound obtained from step (ii), preferably by sterile filtration.

Step (I) may suitably be carried out by loading the compound of formula I into a solvent exchange cartridge as described above, followed by elution with a solvent or solvent mixture contained in a biocompatible carrier medium (e.g. water and ethanol). The eluate may be collected in a collection container, such as a vial, which has been pre-filled with polysorbate and any other excipients such as fillers (e.g. sodium chloride) and pH adjusting agents (e.g. pharmaceutically acceptable buffers such as phosphate buffer). In a preferred embodiment, the collection vessel is pre-filled according to the method and then stored at low temperature (reduced disposal) of-30 ℃ to-10 ℃, suitably-25 ℃ to-15 ℃, more suitably-20 ℃, and then returned to ambient temperature shortly before use. It has been found that storage of polysorbate in this way increases its shelf life and allows the production of radiopharmaceutical compositions having higher radioactive concentrations (RAC).

In step (I), the compound of formula I, the biocompatible carrier medium and the polysorbate and preferred examples thereof are each as defined above. As mentioned above, the preferred biocompatible carrier medium is aqueous ethanol.

Step (ii) of the preparation process may be carried out during or after step (i). For example, as described above, the pH adjusting agent may be in a pre-filled collection vessel in step (i), or added to step (i) during or after it has been performed.

In a preferred embodiment of the method of preparation, one or more steps are automated, as described above.

Examples 1 to 4 illustrate the advantages of the compositions and methods of the present invention for reducing compound 1 residue on various formulation kit components during sterile filtration.

In yet another aspect, the present invention relates to a radiopharmaceutical composition of the invention for use in determining the presence, location and/or amount of one or more amyloid deposits in an organ or body region of a subject. Preferably, the amyloid deposits are deposits of amyloid β and the organ or body area of the subject is the brain. The radiopharmaceutical compositions of the invention are useful for in vivo imaging of one or more amyloid deposits in a subject suspected of having an amyloid disorder. An "amyloid disorder" is a disorder characterized by amyloid deposition, such as Alzheimer's Disease (AD), familial AD, Down's syndrome, amyloidosis (amyloidosis), type II diabetes, and homozygotes of the apolipoprotein E4 isotopologue. The method of the invention is preferred for in vivo imaging of AD. The term "in vivo imaging" refers to any method that allows for the detection of a compound of formula I after administration of a radiopharmaceutical composition of the invention to a subject. Preferred methods of in vivo imaging are Positron Emission Tomography (PET) and single photon emission tomography (SPECT), with PET being particularly preferred. A "subject" is a mammal, preferably a human. In alternative embodiments, the methods of the invention may be performed at two or more different time points, typically in response to amyloid disorder-specific treatment, as a means of monitoring the progression or remission of the amyloid disorder.

Accordingly, there is provided a method of determining the presence, location and/or amount of one or more amyloid deposits in an organ or body region of a subject, the method comprising the steps of:

(i) administering to the subject a detectable amount of a radiopharmaceutical composition of the invention;

(ii) allowing the compound of formula I to bind to any amyloid deposits in the subject; and

(iii) determining the presence, location and/or amount of one or more amyloid deposits in the subject by in vivo imaging.

The above steps (ii) and (iii) may also be understood as the independent use of the radiopharmaceutical composition of the invention for determining the presence, location and/or amount of one or more amyloid deposits in a subject previously administered the radiopharmaceutical composition.

By "detectable amount" is meant an amount of the radiopharmaceutical composition administered sufficient to enable detection of binding of the compound of formula I to amyloid in a subject. The active dose (activity) injected is typically 50 to 400MBq, more typically 80 to 370MBq and has a volume of 1 to 10ml, preferably around 5 ml.

This aspect of the invention also includes the use of a compound of formula I in the manufacture of a radiopharmaceutical composition of the invention for determining the presence, location and/or amount of one or more amyloid deposits in an organ or body region of a subject.

Brief description of the embodiments

Example 1 describes experiments conducted to compare the values of [ 2 ] with PEG 400, propylene glycol or polysorbate 20¹⁹F]Formulations of compound 1.

Example 2 describes experiments conducted to compare the values of [ 2 ] with polysorbate 20 or polysorbate 80¹⁹F]Formulations of compound 1.

Example 3 describes experiments conducted to compare the values of [ 2 ], [ 80 ] with polysorbate¹⁹F]Adhesion of the formulation of compound 1 on two different filter types.

Example 4 describes experiments conducted to compare the polysorbate 80-containing [ poly (sorbitol) ], [¹⁹F]Adhesion of the formulation of compound 1 on three different silicone tube types.

Example 5 describes [ 2 ]¹⁸F]Automated synthesis of compound 1 and methods of its formulation into compositions of the invention.

Examples

Example 1: sterile formulation of Compound 1 formulation with PEG 400 and propylene glycol

A solution containing 7% v/v ethanol, 75 μ g of Compound 1, and either (i) 12% v/v Propylene Glycol (PG) or (ii) 10% v/v polyethylene glycol 400(PEG 400) in 0.01M sodium phosphate buffer, pH 7.4, was prepared. The percent loss of compound 1 on the various components of the formulation kit was evaluated by High Performance Liquid Chromatography (HPLC) in the following experiments:

for both excipients, the amount lost in the syringe and hard tube was small. The main losses were found to be in the filter and for propylene glycol (main losses) also in the silicone tube. These results indicate that even in the presence of 12% PG or 10% PEG 400, significant loss of compound 1 was observed on the surface of the formulation kit, most notably on the filter.

Example 2: compound 1 composition with polysorbate 20 and polysorbate 80 Comparison of sterile filtration of

A solution was prepared containing 7% v/v ethanol formed in 0.01M sodium phosphate buffer at pH 7.4, 75 μ g of compound 1, and selected v/v% amounts of polysorbate 20 and polysorbate 80. 4 filtration experiments were performed as follows:

experiment of	Polysorbate 20 v/v%	Polysorbate 80 v/v%
			1	0.1	0

2	5.0	0
			3	0	0.1
4	0	5.0

Each solution was drawn into a 10ml syringe to a volume of about 9.5 ml. The volume in the syringe was adjusted down to 9 ml; the residue was used as a sample for analysis before filtration (untreated reference).

Through Pall S-200DLL 25 Rebel with 25mm diameter^TMStripe filter "Hydrophilic polyethersulfone and hydrophobic strip Rebel membranes, 0.20 μm pores and 2.80cm "(Pall Filter) were used for filtration. 1ml of solution per fraction is forced through the filter. In the first 1mlIn fractions, only about 0.4ml passed (dead volume close to 0.6 ml). The remaining fraction was then 1ml except for the last fraction, which was close to 1.9ml, and air was also forced through to collect the entire volume of solution. The volume of these fractions was measured by the use of an automatic pipette.

The Tween (Tween) -containing solutions are slightly frothy, so these solutions have to be carefully pressurized through the filter (average time to filter 9ml is about 1 minute 20 seconds).

The recovery after filtration was as follows:

the overall recovery after filtration was 92% for 0.1% polysorbate 20 and 80, and 100% for 5.0% polysorbate 20 and 80. These results show that even at low concentrations, the presence of polysorbate 20 or polysorbate 80 in the formulation of compound I results in significantly reduced loss of compound I on the filter.

Example 3: comparison of sterile filtration of Compound 1 compositions on various Filter types

A solution was prepared containing 7% v/v ethanol formed in 10mM sodium phosphate buffer, pH 7.4, 75 μ g of Compound 1, and a selected amount of polysorbate 80 at v/v%. By using Pall filters and havingMillipore of membranesGV 33mm filtration unit 0,22 μm (Millex filter), and various v/v% amounts of polysorbate 80 10 filtration experiments were performed as follows:

experiment of	Filter	Polysorbate 80 (v/v%)
			1	Pall	0.03
2	Pall	0.1
			3	Pall	0.3
4	Pall	1.0
			5	Pall	5.0
6	Millex	0.03
			7	Millex	0.1
8	Millex	0.3
			9	Millex	1.0
10	Millex	5.0

Each solution was drawn into a 10ml syringe to a volume of about 9.5 ml. The volume in the syringe was adjusted down to 9 ml; the residue was used as a sample for analysis before filtration (untreated reference).

Each solution was pressurized once (taking about 16 seconds) through the filter as described above. The% recovery after filtration, calculated on the area of compound 1, was as follows:

polysorbate 80 v/v%	Pall	Millex
			0.03	72	101
0.1	92	100
			0.3	95	101
1.0	95	104
			5.0	100	101

These results clearly show that the presence of polysorbate 80 at a concentration of at least 0.3% v/v is sufficient to reduce the loss of compound 1 even on the filter, with significant losses on the filter previously observed.

Example 4: comparison of adsorption of Compound 1 onto various polysiloxane tubes

A solution was prepared containing 7% v/v ethanol formed in 10mM sodium phosphate buffer, pH 7.4, 75 μ g of Compound 1, and a selected amount of polysorbate 80 at v/v%. Various silicone tube types were tested as follows:

experiment of	Polysiloxane pipe	Polysorbate 80 v/v%
			1	0.8 x4.0Pt-curing*	0
2	1.6 x4.8Pt-Cure**	0
			3	1.6x4.8Perox curing***	0
4	0.8 x4.0Pt-curing*	1
			5	1.6 x4.8Pt-Cure**	1
6	1.6x4.8Perox curing***	1
			7	0.8 x4.0Pt-curing*	5
8	1.6 x4.8Pt-Cure**	5
			9	1.6x4.8Perox curing***	5

Silikoslange platinum cure, 0.8mm ID

^**Advantapure Silikonlange platinum cure, 1.6mm ID

^***Mediline (Angleur, Belgium) silicone tubing, peroxide cured, 1.6mm ID

The percent loss of compound 1 on the tube was calculated in each experiment. Fluorine analysis before and after passage through the tube resulted in the following:

experiment of	Time of treatment	Volume treated (μ l)	% loss of Compound 1
				1	2min 0sec	350	63
2	2min 7sec	1400	41
				3	2min 6sec	1400	45
4	2min 3sec	350	0
				5	2min 10sec	1400	1

6	2min 4sec	1400	0
				7	2min 2sec	350	0
8	2min 4sec	1400	1
				9	2min 1sec	1400	1

These results indicate that significant loss of compound 1 on each tube type has been reduced or even eliminated for the inclusion of at least 1.0% v/v polysorbate in the formulation.

Example 5: 2- [3- [ ¹⁸ F]Fluoro-4- (methylamino) phenyl]-6-hydroxy-benzothiazole (Compound) 1) Automated synthesis of

FASTlab^TM(GE Healthcare) the single-use fluid paths of the automated synthesizer apparatus were loaded with the following reagents and mounted on the FASTlab platform:

I. 150mM tetrabutylammonium bicarbonate in 80: 20 acetonitrile: water (0.8ml)

Final intermediate solution: 75mM 2- [ 3-nitro-4 (methylcarbonylamino) phenyl ] -6-ethoxymethoxy-benzothiazole in dimethylsulfoxide (1.37ml)

III.4M hydrochloric acid (4ml)

Ethanol (2X 4ml)

V. Water (100ml)

In addition, a product collection vial containing the following excipients was placed adjacent to the FASTlab platform:

0.67% (w/v) polysorbate 80, 1.21% (w/v) sodium chloride, 18.82mM phosphate buffer, pH 7; (Total volume 37.2 ml).

When 2¹⁸F]The fluoride is rich in¹⁸O]Is loaded into the start-up position of the synthesizer, the operator initiates the sequence causing the following sequence of events to occur:

the fluoride solution flows through a QMA (quaternized methyl ammonium) cartridge, trapping the fluoride and sending the enriched water to waste. The QMA cartridge was then eluted with 350. mu.l of a 150mM tetrabutylammonium bicarbonate solution to recover fluoride, and the resulting solution was passed into the reaction vessel.

The reactor was heated at 120 ℃ and held under vacuum for 5 minutes while passing a stream of nitrogen over the solution. A stream of nitrogen was then passed directly through the remaining solution under the same heating and vacuum conditions for 4 minutes to dry the contents of the reactor. The final intermediate solution (1ml) was added to the reaction vessel and the temperature was increased to 130 ℃ over 15 minutes. This step realizes the operation of¹⁸F]Introduction of fluoride into the final intermediate. The solution was cooled to 95 ℃ after which 0.25ml of hydrochloric acid solution was added. The mixture is heated to 125 ℃ for 5 minutes to effect deprotection of the benzothiazole derivative to form 2- [3- ] [ 2- ] [¹⁸F]Fluoro-4- (methylamino) phenyl]-6-hydroxy-benzothiazole in crude solution. The reaction vessel was diluted with 1ml ethanol: water (1: 1 vol) and injected into a C30HPLC column (250X 10mm, 5 μm) located adjacent to the FASTlab platform. The column was eluted with 0.8% triethylamine: acetonitrile (53: 47 vol) at 5 ml/min. The desired product was confirmed by radioactive detection and turned back to FASTlab. Purified 2- [3-, [ 2 ], [ 2- ]¹⁸F]Fluoro-4- (methylamino) phenyl]The solution of-6-hydroxy-benzothiazole was passed directly through two C30 solid phase extraction cartridges (extraction cartridge) (preconditioned with 1ml ethanol and 15ml water) so that the product remained on the cartridge. The cartridge was rinsed with water to wash any remaining HPLC eluting solvent to wasteTo (3). The product was then eluted from the C30 cartridge with 3.5ml ethanol and then 9.3ml water into a pre-filled product collection vial to give a final product volume of 50ml (0.5% (w/v) polysorbate 80, 7% (v/v) ethanol, 0.9% (w/v) sodium chloride, 14mM phosphate buffer, pH 7).

Claims (26)

1. A radiopharmaceutical composition which comprises:

(i) a compound of the general formula I:

wherein:

z is S, NR ', O, or C (R')₂Wherein each R' is independently H or C_1-6Alkyl, with the proviso that when Z is C (R')₂When the heterocyclic ring is mutually boundThe isomeric forms are indoles:

y is hydrogen, C_1-6Alkyl, halogen, OR ' OR SR ', wherein R ' is H OR C_1-6Alkyl, or Y is-NR¹R²；

R^1-10Each independently selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_4-6Cycloalkyl, hydroxy, C_1-6Hydroxyalkyl radical, C_2-6Hydroxyalkenyl group, C_2-6Hydroxyalkynyl, thiol, C_1-6Mercaptoalkyl radical, C_2-6Mercaptoalkenyl radical, C_2-6Mercaptoalkynyl, C_1-6Mercaptoalkoxy, halogen, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenoalkynyl, C_1-6Haloalkoxy, amino, C_1-6Aminoalkyl radical, C_2-6Aminoalkenyl, C_2-6Aminoalkynyl, C_1-6Aminoalkoxy, cyano, C_1-6Cyanoalkyl radical, C_2-6Cyanoalkenyl radical, C_2-6Cyanoalkynyl, and C_1-6A cyanoalkoxy group; nitro radical, C_1-6Nitroalkyl, C_2-6Nitroalkenyl, C_2-6Nitroalkynyl, and C_1-6A nitroalkoxy group; and the combination of (a) and (b),

wherein at least one atom of the compound of formula I is a radioisotope suitable for in vivo imaging;

(ii) a biocompatible carrier medium; and the combination of (a) and (b),

(iii) 0.05-5.0% w/v polysorbate;

the composition is at a pH of 4.0 to 10.5.

2. The radiopharmaceutical composition of claim 1, where in the compound of formula I:

z is S, NR' or O; and the combination of (a) and (b),

R^1-10each independently selected from hydrogen，C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy, C_1-6Hydroxyalkyl, halogen, C_1-6Haloalkyl, and C_1-6A haloalkoxy group.

3. The radiopharmaceutical composition of claim 1 or 2, where in the compound of formula I:

z is S;

y is-NR¹R²(ii) a And the combination of (a) and (b),

R^1-10each independently selected from hydrogen, C_1-3Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy, hydroxy, C_1-3Hydroxyalkyl, halogen, C_1-3Haloalkyl, and C_1-3A haloalkoxy group.

4. A radiopharmaceutical composition which comprises a compound of formula Ia:

wherein:

R¹¹and R¹²Independently selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, nitro, amino, C_1-6Aminoalkyl, halogen and C_1-6A haloalkyl group;

R¹³is hydrogen, hydroxy, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, halogen, C_1-6Haloalkyl, C_1-6Haloalkenyl, -COOR, -OCH₂OR, wherein R is hydrogen OR C_1-6An alkyl group; and the combination of (a) and (b),

Y^ais hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, or-NR¹R²，

R¹And R²Each independently selected from hydrogen, C_1-6An alkyl group, a carboxyl group,C_2-6alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, hydroxy, C_1-6Hydroxyalkyl, halogen, C_1-6Haloalkyl, and C_1-6A haloalkoxy group;

wherein at least one atom of the compound of formula Ia is a radioisotope suitable for in vivo imaging;

(ii) a biocompatible carrier medium; and the combination of (a) and (b),

(iii) 0.05-5.0% w/v polysorbate;

the composition is at a pH of 4.0 to 10.5.

5. The radiopharmaceutical composition of claim 4, where in the compound of formula Ia:

R¹¹and R¹²Independently selected from hydrogen, C_1-6Alkyl or halogen;

R¹³is hydroxy, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy or halogen;

Y^ais halogen or-NR¹R²Wherein R is¹And R²As defined in claim 2.

6. The radiopharmaceutical composition of claim 5, wherein:

R¹¹and R¹²Independently selected from hydrogen or halogen;

R¹³is hydroxy or C_1-6An alkoxy group;

Y^ais-NR¹R²Wherein R is¹Is hydrogen and R²Is hydrogen, C_1-6Alkyl or C_1-6A haloalkyl group.

7. The radiopharmaceutical composition of any one of claims 1 to 6, where the radioisotope suitable for in vivo imaging in the compound of general formula I or Ia is selected from¹¹C，¹²³I，¹²⁴I，¹²⁵I，¹³¹I，⁷⁵Br，⁷⁶Br，⁷⁷Br, and¹⁸F。

8. the radiopharmaceutical composition of claim 7, where the radioisotope suitable for in vivo imaging in the compound of formula I or Ia is¹⁸F。

9. The radiopharmaceutical composition of any one of claims 1 to 7, where the compound of general formula I or Ia is selected from:

compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6.

10. The radiopharmaceutical composition of any one of claims 1 to 9, where the compound of general formula I or Ia is:

compound 1.

11. A radiopharmaceutical composition according to any one of claims 1 to 10 which comprises 0.25-2.5% w/v polysorbate.

12. A radiopharmaceutical composition of claim 11 which comprises 0.5-1.0% w/v polysorbate.

13. A radiopharmaceutical composition according to any one of claims 1 to 12 wherein the polysorbate is polysorbate 80.

14. The radiopharmaceutical composition of any one of claims 1 to 13, where the biocompatible carrier medium is aqueous ethanol.

15. The radiopharmaceutical composition of any one of claims 1 to 13, where the biocompatible carrier medium is 5-10% (v/v) ethanol.

16. The radiopharmaceutical composition of any one of claims 1 to 13, where the biocompatible carrier medium is 6-8% (v/v) ethanol.

17. The radiopharmaceutical composition of any one of claims 1 to 13, where the biocompatible carrier medium is 6.5-7.5% (v/v) ethanol.

18. The radiopharmaceutical composition of any one of claims 1 to 13, where the biocompatible carrier medium is 7% (v/v) ethanol.

19. A process for the preparation of a radiopharmaceutical composition of any one of claims 1 to 18, which comprises the steps of:

(i) admixing a compound of formula I or Ia, a biocompatible carrier medium and 0.05-5.0% w/v polysorbate, wherein the compound of formula I or Ia, biocompatible carrier medium, and polysorbate are as defined in any one of claims 1 to 18;

(ii) optionally, the pH of the resulting mixture is adjusted to 4.0 to 10.5.

20. The method of claim 19, further comprising the steps of:

(iii) (iii) sterilization of the compound obtained from step (ii).

21. The method of claim 20, wherein the sterilization is by sterile filtration.

22. Use of a radiopharmaceutical composition of any one of claims 1 to 18 in the manufacture of a medicament for determining the presence, location and/or amount of one or more amyloid deposits in an organ or body region of a subject.

23. Use of a detectable amount of a radiopharmaceutical composition of any one of claims 1-18 in the manufacture of a medicament for determining the presence, location and/or amount of one or more amyloid deposits in an organ or body region of a subject, wherein:

allowing the compound of formula I or Ia to bind to any amyloid deposits in the subject; and

determining the presence, location and/or amount of one or more amyloid deposits in a subject by in vivo imaging.

24. The use of claim 23, wherein the amyloid deposits are deposits of amyloid β and the organ or body area of the subject is the brain.

25. The use of claim 23 or 24, wherein the in vivo imaging is performed by PET or SPECT.

26. Use according to any one of claims 23 to 24, which is carried out at two or more different time points, for monitoring the progression or remission of an amyloid disorder in response to an amyloid disorder-specific treatment.