WO2009027452A2 - Radiopharmaceutical composition - Google Patents
Radiopharmaceutical composition Download PDFInfo
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- WO2009027452A2 WO2009027452A2 PCT/EP2008/061275 EP2008061275W WO2009027452A2 WO 2009027452 A2 WO2009027452 A2 WO 2009027452A2 EP 2008061275 W EP2008061275 W EP 2008061275W WO 2009027452 A2 WO2009027452 A2 WO 2009027452A2
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- radiopharmaceutical composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a radiopharmaceutical composition
- a radiopharmaceutical composition comprising an amyloid-binding compound and methods for preparing the same.
- the radiopharmaceutical composition finds use inter alia in the diagnosis of disease states in which abnormal amyloid deposition is involved.
- the radiopharmaceutical composition may be useful as an in vivo imaging agent for use in Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT).
- PET Positron Emission Tomography
- SPECT Single Photon Emission Computed Tomography
- Common excipients included in pharmaceutical compositions include buffers, lyophilisation aids, stabilization aids, solubilisation aids and bacteriostats.
- the inclusion of one or more optional components in the formulation can improve the stability and shelf-life of the pharmaceutical, as well as the ease of synthesis of the pharmaceutical by the practising end user.
- Solubilisation aids typically used in the preparation of pharmaceutical compositions include ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooloeate, polysorbates, poly(oxyethylene) poly(oxypropylene)- poly(oxyethylene) block copolymers (Pluronics) and lecithin.
- a review by Powell et al provides a comprehensive list of excipients used in pharmaceutical compositions intended for parenteral administration [1998 PDA Journal of Pharmaceutical Science and Technology 52(5) pp238-31 1].
- pharmaceutical compositions listed therein that comprise polysorbate 80, in concentrations ranging from 0.0005 to 12 %w/v.
- a known radiopharmaceutical composition containing a polysorbate is 111 ln-oxyquinoline solution.
- the radiopharmaceutical composition contains, amongst other things, 10O ⁇ g of polysorbate 80 per millilitre (equivalent to 0.01 %w/v) in order to enable dissolution in water and to prevent binding of the complex when in aqueous solution to glass and plastic surfaces (EP0017355).
- radiopharmaceutical compositions In order to be suitable for intravenous administration, radiopharmaceutical compositions must be sterile, non-pyrogenic, and dissolved in a suitable biocompatible carrier medium.
- preparation may be under aseptic manufacture conditions.
- preparation may be under non-sterile conditions, followed by terminal sterilisation using e.g. gamma-irradiation; autoclaving; dry heat; membrane filtration (sometimes called sterile filtration); or chemical treatment (e.g. with ethylene oxide).
- Sterile filtration can be achieved by means of a dispensing kit through which the radiopharmaceutical composition is passed.
- Such a dispensing kit must be sterile and typically comprises a 0.2 ⁇ m pore filter, along with silicone tubing which permits the radiopharmaceutical composition to pass through the filter and into a suitable sterile receptacle such as a vial or syringe.
- a suitable sterile receptacle such as a vial or syringe.
- Radiopharmaceuticals are typically prepared by reaction of a non-radioactive precursor compound with a suitable radiolabel, with only a tiny fraction of the precursor compound being radiolabeled to produce the radiopharmaceutical. As a consequence, retention to the surfaces of a dispensing kit can result in the loss of a relatively large proportion of the radiopharmaceutical to the extent that the resulting radiopharmaceutical composition is not fit for use.
- Radiopharmaceutical compositions comprising thioflavin derivative compounds are known to be useful in the diagnosis of patients having diseases characterised by amyloid deposits, as described in WO2002/16333 and WO2004/083195.
- the present inventors have found that, when known radiopharmaceutical compositions comprising these thioflavin derivative compounds are passed through dispensing kits, the radiopharmaceutical is strongly retained on a range of different 0.2 ⁇ m pore filters and silicone tubings. A solution was therefore sought in order to reduce loss of thioflavin derivative compounds to dispensing kit components.
- the present invention relates to radiopharmaceuticals and in particular to a radiopharmaceutical composition comprising a thioflavin derivative compound with polysorbate as an excipient.
- the radiopharmaceutical composition of the invention overcomes problems encountered with prior art compositions comprising the same class of compounds. Also provided by the invention is a method for the preparation of the radiopharmaceutical composition of the invention as well as particular uses of the radiopharmaceutical composition.
- the present invention relates to a radiopharmaceutical composition
- a radiopharmaceutical composition comprising:
- Z is S, NR , O, or C(R ) 2 wherein each R is independently H or C- ⁇ - 6 alkyl, such that the tautomeric form of the heterocyclic ring when Z is C(R ) 2 is an indole:
- Y is hydrogen, Ci -6 alkyl, halo, OR or SR , wherein R is H or Ci_ 6 alkyl, or Y is -NR 1 R 2 ;
- R 1"10 are each independently selected from the group consisting of hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, Ci_ 6 alkoxy, C 4-6 cycloalkyl, hydroxyl, Ci -6 hydroxyalkyl, C 2 -6 hydroxyalkenyl, C 2-6 hydroxyalkynyl, thiol, Ci -6 thioalkyl, C 2 _ 6 thioalkenyl, C2- 6 thioalkynyl, C- ⁇ -6 thioalkoxy, halo, Ci_6 haloalkyl, C 2 - 6 haloalkenyl, C 2 - 6 haloalky ⁇ yl, Ci -6 haloalkoxy, amino, Ci_ 6 aminoalkyl, C 2 - 6 aminoalkenyl, C 2 - 6 aminoalkynyl, Ci -6 aminoalkoxy, cyano, Ci_ 6 cyanoalkyl, C 2-6
- alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably from 1 to 10 carbon atoms, more preferably from 1 to 5 carbon atoms, most preferably 1 to 3 carbon atoms.
- examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl.
- alkenyl denotes an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one double bond. Examples groups such as vinyl (ethenyl), 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-pentenyl, 4-methyl-3-pentenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, A- hexenyl and 5-hexenyl.
- alkynyl denotes an unsaturated straight-chain 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.
- alkoxy means an alkyl ether radical wherein the term alkyl is as defined above.
- suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy.
- cycloalkyl alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains preferably from 3 to 8 carbon atom ring members, more preferably from 3 to 7 carbon atom ring members, most preferably from 4 to 6 carbon atom ring members, and which may optionally be a benzo fused ring system which is optionally substituted as defined herein with respect to the definition of aryl.
- cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1 H-indenyl, adamantyl.
- hydroxyl refers to a -OH group.
- hydroxyalkyl refers to at least one hydroxy group appended to the parent molecular moiety through an alkyl, alkenyl, alkynyl, or alkoxy, respectively.
- halo means a substituent selected from fluorine, chlorine, bromine or iodine.
- haloalkyl haloalkenyl
- haloalkynyl haloalkoxy
- Preferred halo substituents are fluoro and iodo.
- thiol means an -SH group.
- thioalkyl means an alkenyl, thioalkynyl, “thioalkoxy” as used herein, refer to at least one thiol group appended to the parent molecular moiety through an alkyl, alkenyl, alkynyl, or alkoxy, respectively.
- cyano refers to a -CN group.
- cyanoalkyl refers to at least one cyano group appended to the parent molecular moiety through an alkyl, alkenyl, alkynyl, or alkoxy, respectively.
- Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
- nitro means an -NO 2 group.
- nitroalkyl refers to at least one nitro group appended to the parent molecular moiety through an alkyl, alkenyl, alkynyl, or alkoxy, respectively.
- compound of Formula I means the free compound or alternatively a pharmaceutically acceptable salt, prodrug (such as an ester), or solvate thereof. Suitable salts, prodrugs, and solvates are as described in WO 2004/083195 and WO 02/16333.
- Z is S, NR' or O
- Y is -NR 1 R 2 ;
- R 1'10 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Ci_ 6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, halo, Ci -6 haloalkyl, and C 1-6 haloalkoxy.
- Y is -NR 1 R 2 ;
- R 1"10 are each independently selected from the group consisting of hydrogen, Ci -3 alkyl, C 2 - 4 alkenyl, C 2-4 alkynyl, Ci -3 alkoxy, hydroxyl, Ci_ 3 hydroxyalkyl, halo, C 1-3 haloalkyl, and Ci -3 haloalkoxy.
- said compound of Formula I is a compound of Formula Ia:
- R 11 and R 12 are independently selected from hydrogen, d_ 6 alkyl, Ci -6 alkoxy, nitro, amino, Ci -6 aminoalkyl, halo or Ci -6 haloalkyl;
- R 13 is hydrogen, hydroxy, nitro, cyano, Ci_6 alkyl, C 2-6 alkenyl, C-2- 6 alkynyl, Ci_ 6 alkoxy, halo, Ci_ 6 haloalkyl, Ci_ 6 haloalkenyl, -COOR , -OCH 2 OR , wherein R is as defined for Formula I; and,
- Y a is hydrogen, hydroxyl, Ci -6 alkyl, Ci -6 alkoxy or halo, or is -NR 1 R 2 as defined above for Formula I.
- R 11 and R 12 are independently selected from hydrogen, Ci_ 6 alkyl or halo;
- R 13 is hydroxy, Ci -6 alkyl, C 2-6 alkenyl, C2 -6 alkynyl, Ci -6 alkoxy or halo;
- Y a is halo or -NR 1 R 2 as defined above for Formula I.
- R 11 and R 12 are independently selected from hydrogen or halo
- R 13 is hydroxy or Ci_ 6 alkoxy
- Y a is -NR 1 R 2 wherein R 1 is hydrogen and R 2 is hydrogen, Ci -6 alkyl or Ci -6 haloalkyl.
- a “radioactive isotope suitable for in vivo imaging” is a radioactive isotope which can be detected externally in a non-invasive manner following administration in vivo.
- 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).
- SPECT single-photon emission tomography
- PET positron emission tomography
- the radioactive isotope is selected from 1 1 C, 123 I, 124 1, 125 I, 131 I 1 75 Br, 76 Br, 77 Br, and 18 F , most suitably 11 C, 123 I, and 18 F
- the radiopharmaceutical composition of the 5 invention is a compound of Formula Ia wherein one of R 11 to R 13 or Y a is, or comprises, radioactive carbon or a radioactive halogen.
- said radioactive carbon is 11 C
- said radioactive halogen is preferably selected from 1 23 I, 124 1, 125 I, 131 I, 75 Br, 76 Br, 77 Br, 17 F, and 18 F.
- said radioactive halogen is 123 I or 18 F.
- Formula Ia comprises a radioactive carbon, it is i o preferably an atom in Y a , most preferably when Y a is -NR 1 R 2 .
- Formula Ia comprises a radioactive halogen, it is preferably one of R 11 or Y a , or an atom in Y a when Y a is-NR 1 R 2 with R 1 being hydrogen and R 2 being Ci_ 6 haloalkyl or C 2 -e haloalkenyl.
- Non-limiting examples of the especially preferred compounds of Formula Ia are as 15 follows:
- the "biocompatible carrier medium” is a fluid, especially a liquid, in which the radiopharmaceutical is suspended or dissolved, resulting in a radiopharmaceutical composition that is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort.
- Typical biocompatible carrier media are, e.g. pyrogen-free water for injection, isotonic saline and aqueous ethanol solution.
- an aqueous ethanol solution is preferred, with 5-10% (v/v) ethanol being particularly suitable for the composition of the present invention.
- 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 a pH-adjusting agent, pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid), an antimicrobial preservative or filler.
- additional components such as a pH-adjusting agent, pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid), an antimicrobial preservative or filler.
- pH-adjusting agent means a compound or mixture of compounds useful to ensure that the pH of the radiopharmaceutical composition is maintained within the acceptable limits for mammalian administration (approximately pH 4.0 to
- Suitable such pH-adjusting agents include pharmaceutically acceptable buffers, such as tricine, phosphate or TRIS [i.e. fr7s(hydroxymethyl)aminomethane], and pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof.
- the pH is maintained in the range 6.0 to 8.5 , suitably 6.0 to 8.0 and most preferably in the 5 range 5.8 to 7.2, with a pH in the range 7.0 to 7.2 being especially preferred.
- a preferred buffer for the radiopharmaceutical compositions of the invention is phosphate buffer, preferably 0.005-0.1 M, most preferably 0.01 M-0.1 M, and especially preferably 0.01-0.05M and most especially preferably 0.01-0.02M.
- antimicrobial preservative an agent which inhibits the o growth of potentially harmful micro-organisms such as bacteria, yeasts or moulds.
- the antimicrobial preservative may also exhibit some bactericidal properties, depending on the dose.
- the main role of the antimicrobial preservative(s) of the present invention is to inhibit the growth of any such micro-organism in the radiopharmaceutical composition.
- Suitable antimicrobial preservative(s) include:5 the parabens, ie. methyl, ethyl, propyl or butyl paraben or mixtures thereof; benzyl alcohol; phenol; cresol; cetrimide and thiomersal.
- Preferred antimicrobial preservative(s) are the parabens.
- filler is meant a pharmaceutically acceptable bulking agent which may facilitate material handling during product production.
- suitable fillers include0 inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.
- the aim is to have the lowest quantities of excipients possible that produce a pharmaceutically effective as well as physiologically tolerable composition.
- the radiopharmaceutical composition of the invention is suitably supplied for use in a container provided with a seal which is suitable for single or multiple puncturing with a hypodermic needle (e.g. a crimped-on septum seal closure) whilst maintaining sterile integrity.
- a hypodermic needle e.g. a crimped-on septum seal closure
- Such containers may contain single or multiple patient doses.
- Typical dose containers comprise a bulk vial (suitably 5 to 50cm 3 , o for example 10 to 30 cm 3 volume) which contains single or multiple patient doses, whereby a patient dose or doses can thus be withdrawn into clinical grade syringes at various time intervals during the viable lifetime of the preparation to suit the clinical situation.
- Pre-filled syringes are designed to contain a single patient dose, and are therefore preferably a disposable or other syringe suitable for clinical use.
- the pre-filled syringe may be provided with a radiopharmaceutical syringe shield to protect the operator from radioactive dose. Suitable such radiopharmaceutical syringe shields are known in the art and preferably comprise either lead or tungsten.
- the radiopharmaceutical composition of the invention has a radioactive concentration of 50 to 100MBq/ml, suitably 70 to 85MBq/ml, more suitably 8OM Bq/ml.
- a single patient dose will typically contain 50 to 400MBq, more typically 80 to 370MBq at the time of administration and will have a volume of 1 to 10ml, preferably around 5ml.
- polysorbate is a polyoxyethylene sorbitan ester.
- a comprehensive description of polysorbates can be found in "Nonionic Surfactants", M. J. Schick, Ed. (Dekker, New York, 1967) pp247-299.
- Examples of polysorbates include polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80, which are commercially available under the trade name Tween ® as Tween 20, Tween 40, Tween 60 and Tween 80, respectively, from Sigma-Aldrich.
- the numberfollowing "polysorbate” is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule.
- Monolaurate is indicated by 20
- monopalmitate is indicated by 40
- monostearate by 60
- monooleate by 80.
- the concentration of polysorbate is suitably sufficient to eliminate substantially all binding of the compound of Formula I to a range of filter types.
- the loss of compound of Formula I to the filter during dispensing is in the range 0-10%, most preferably 0-5.0%, especially preferably 0-1.0%, and most especially preferably 0%.
- the polysorbate of said radiopharmaceutical formulation is selected from polysorbate 20 or polysorbate 80, with polysorbate 80 being particularly preferred.
- 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.
- Compounds of Formula I may be prepared from commercially available starting materials or using starting materials as described in WO2002/16333, WO2004/083195 and WO2007/020400, or by standard methods of organic chemistry.
- Compounds of Formula I comprising a radiolabel such as radioactive carbon or a radioactive halogen may be conveniently prepared by reaction of a precursor compound with a suitable source of the radioactive carbon or radioactive halogen.
- a "precursor compound” comprises a derivative of a radiolabeled compound of Formula I, designed so that chemical reaction with a convenient chemical form of the radiolabel occurs site-specifically; can be conducted in the minimum number of steps (ideally a single step); and without the need for significant purification (ideally no further purification), to give the desired radiolabeled compound of Formula I.
- Such precursor compounds are synthetic and can conveniently be obtained in good chemical purity.
- the precursor compound may optionally comprise a protecting group for certain functional groups of the precursor compound.
- protecting group is meant a group which inhibits or suppresses undesirable chemical reactions, but which is designed to be sufficiently reactive that it may be cleaved from the functional group in question under mild enough conditions that do not modify the rest of the molecule. After deprotection the desired radiolabeled compound of Formula I is obtained.
- Protecting groups are well known to those skilled in the art and are suitably chosen from, for amine groups: Boc (where Boc is ferf-butyloxycarbonyl), Fmoc (where Fmoc is fluorenylmethoxycarbonyl), trifluoroacetyl, allyloxycarbonyl, Dde [i.e.
- Suitable protecting groups are: methyl, ethyl or te/t-butyl; alkoxymethyl or alkoxyethyl; benzyl; acetyl; benzoyl; trityl (Trt) or trialkylsilyl such as tetrabutyldimethylsilyl.
- suitable protecting groups are: trityl and 4-methoxybenzyl.
- further protecting groups are described in 'Protective Groups in Organic Synthesis', Theorodora W. Greene and Peter G. M. Wuts, (Third Edition, John Wiley & Sons, 1999).
- suitable precursor compounds are those which comprise a derivative which either undergoes electrophilic or nucleophilic iodination or undergoes condensation with a labelled aldehyde or ketone. Examples of the first category are:
- organometallic derivatives such as a trialkylstannane (eg. trimethylstannyl or tributylstannyl), or a trialkylsilane (eg. trimethylsilyl) or an organoboron compound (eg. boronate esters or organotrifluoroborates);
- a trialkylstannane eg. trimethylstannyl or tributylstannyl
- a trialkylsilane eg. trimethylsilyl
- organoboron compound eg. boronate esters or organotrifluoroborates
- aromatic rings activated towards electrophilic iodination e.g. phenols, phenylamines
- aromatic rings activated towards nucleophilic iodination e.g. aryl iodonium salt aryl diazonium, aryl trialkylammonium salts or nitroaryl derivatives.
- the precursor compound for radioiodination preferably comprises: a nonradioactive halogen atom such as an aryl iodide or bromide (to permit radioiodine exchange); an activated aryl ring (e.g. a phenol or phenylamine); an organometallic substituent (e.g. trialkyltin, trialkylsilyl or organoboron compound); or an organic substituent such as triazenes or a good leaving group for nucleophilic substitution such as an iodonium salt.
- the precursor compound comprises an activated aryl ring or an organometallic substituent, said organometallic substituent most preferably being trialkyltin.
- alkyl in this case is preferably methyl or butyl.
- These groups contain substituents which permit facile radioiodine substitution onto the aromatic ring.
- Alternative substituents containing radioactive iodine can be synthesised by direct iodination via radiohalogen exchange, e.g.
- the radioiodine atom is preferably attached via a direct covalent bond to an aromatic ring such as a benzene ring, or a vinyl group since it is known that iodine atoms bound to saturated aliphatic systems are prone to in vivo metabolism and hence loss of the radioiodine.
- the source of the radioiodine is chosen from iodide ion or the iodonium ion (I + ). Most preferably, the chemical form is iodide ion, which is typically converted to an electrophilic species by an oxidant during radiosynthesis.
- Ra diofluorination When the compound of Formula I is labelled with a radioactive isotope of fluorine the radiofluorine atom may form part of a fluoroalkyl or fluoroalkoxy group, since alkyl fluorides are resistant to in vivo metabolism. Fluoroalkylation may be carried out by reaction of a precursor compound containing a reactive group such as phenol, thiol and amide with a fluoroalkyl group.
- the radiofluorine atom may be attached via a direct covalent bond to an aromatic ring such as a benzene ring.
- an aromatic ring such as a benzene ring.
- 18 F-fluoride nucleophilic displacement from an aryl diazonium salt, aryl nitro compound or an aryl quaternary ammonium salt are suitable routes to aryl- 18 F derivatives.
- Radiofluorination may be carried out via direct labelling using the reaction of 18 F- fluoride with a suitable chemical group in the precursor compound having a good leaving group, such as an alkyl bromide, alkyl mesylate or alkyl tosylate.
- a suitable chemical group in the precursor compound having a good leaving group such as an alkyl bromide, alkyl mesylate or alkyl tosylate.
- one approach to labelling is to react a precursor compound which is the desmethylated version of a methylated compound of Formula I with [ 11 C]methyl iodide. It is also possible to incorporate 11 C by reacting Grignard reagent of the particular hydrocarbon chain of the desired labelled compound of Formula I with [ 11 C]CC> 2 . 11 C could also be introduced as a methyl group on an aromatic ring, in which case the precursor compound would include a trialkyltin group or a B(OH) 2 group. As the half-life of 11 C is only 20.4 minutes, it is important that the intermediate 11 C moieties have high specific activity and, consequently, are produced using a reaction process which is as rapid as possible.
- the precursor compound may be conveniently provided as part of a kit, for example for use in a radiopharmacy.
- a kit may contain a cartridge which can be plugged into a suitably adapted automated synthesiser.
- the cartridge may contain, apart from the precursor, a column to remove any unwanted radioactive ion, and an appropriate vessel connected so as to allow the reaction mixture to be evaporated and allow the product to be formulated as required.
- the reagents and solvents and other consumables required for the synthesis may also be included together with a compact disc carrying the software which allows the synthesiser to be operated in a way so as to meet the customers' requirements for radioactive concentration, volumes, time of delivery, etc.
- all components of the kits are disposable to minimise the possibility of contamination between runs and may be sterile and quality assured.
- the compound of Formula I may require purification which may be effected using standard methods, for example using high-performance liquid chromatography (HPLC), ion-exchange chromatography, and/or passing through a solvent exchange cartridge.
- HPLC high-performance liquid chromatography
- ion-exchange chromatography ion-exchange chromatography
- HPLC High performance liquid chromatography
- a normal phase or reverse phase column can be used with one of a variety of organic solvents, e.g. methanol, acetonitrile, ethanol, 2-propanol at neutral, acidic or basic pH.
- a reverse phase column is used with neutral pH conditions to achieve the most favourable separation of a compound of Formula I.
- Suitable solvent exchange cartridges include SEP-Pak TM cartridges (Waters), such as C8, C18 or C30.
- the present invention relates to a method for preparation of the radiopharmaceutical composition of the invention comprising the following steps:
- the composition may be sterilised.
- Sterilisation may be effected by standard methods of the art, for example gamma-irradiation; autoclaving; dry heat; membrane filtration (sometimes called sterile filtration); or chemical treatment (e.g. with ethylene oxide).
- Sterile filtration can be achieved by means of a dispensing kit through which the radiopharmaceutical composition is passed.
- a dispensing kit must be sterile and typically comprises a 0.2 ⁇ m pore filter, along with silicone tubing which permits the radiopharmaceutical composition to pass through the filter and into a suitable sterile receptacle such as a vial or syringe.
- step (iii) sterilisation of the composition resulting from step (ii), preferably by sterile filtration.
- Step (i) may conveniently be effected by loading the compound of Formula I onto a solvent exchange cartridge as described above, and then eluting with a solvent or mixture of solvents comprised in the biocompatible carrier medium (for example, water and ethanol).
- the eluate may be collected in a collection container such as a vial, pre-filled with the polysorbate and any other excipients such as a filler (for example, sodium chloride) and pH-adjusting agent (for example a pharmaceutically acceptable buffer, such as phosphate buffer).
- a filler for example, sodium chloride
- pH-adjusting agent for example a pharmaceutically acceptable buffer, such as phosphate buffer
- the collection container is pre-filled as described and then stored at reduced temperature of -30 0 C to -10 0 C, suitably -25°C to -15°C, more suitably at -20 0 C and then brought to ambient temperature shortly before use. It has been found that storage of the polysorbate in this way increases its shelf-life and enables production of a radiopharmaceutical composition having higher radioactive concentration (RAC).
- RAC radioactive concentration
- step (i) the compound of Formula I, the biocompatible carrier medium and the polysorbate and preferred embodiments therefor are each as defined above.
- a preferred biocompatible carrier medium is aqueous ethanol.
- Step (ii) of the method of preparation may be performed during step (i) or thereafter.
- a pH adjusting agent may be in the pre-filled collection container during step (i) or may be added thereto during or after performance of step (i).
- one or more steps is automated, as described above.
- Examples 1 to 4 demonstrate the advantages of the compositions and methods of the invention in reducing the retention of Compound 1 to a range of dispensing kit components during sterile filtration.
- the present invention relates to the radiopharmaceutical composition of the invention for use in the determination of the presence, location and/or amount of one or more amyloid deposits in an organ or body area of a subject.
- the amyloid deposits are deposits of amyloid ⁇
- the organ or body area of the subject is the brain.
- the radiopharmaceutical composition of the invention is for in vivo imaging of one or more amyloid deposits in a subject suspected of having an amyloid condition.
- an "amyloid condition” is a disorder or 5 condition characterised by amyloid deposition, such as Alzheimer's disease (AD), familial AD, Down's syndrome, amyloidosis, type Il diabetes mellitus, and homozygotes for the apolipoprotein E4 allele.
- the method of the invention is preferably for in vivo imaging of AD.
- the term "in vivo imaging” refers to any method which permits the detection of a compound of Formula I following i o administration of the 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 especially preferred.
- PET positron emission tomography
- SPECT single-photon emission tomography
- a "subject” is a mammal, preferably a human. In an alternative embodiment, the method of the invention may be carried out at two or
- a method for determination of the presence, location, and/or amount of one or more amyloid deposits in an organ or body area 20 of a subject which comprises the steps:
- Steps (ii) and (iii) above can also be understood to be a standalone use of the radiopharmaceutical composition of the invention for the determination of the presence, location and/or amount of one or more amyloid deposits in a subject pre-administered with said radiopharmaceutical composition.
- a “detectable quantity” means that the amount of the radiopharmaceutical composition administered is sufficient to enable detection of binding of the compound of Formula I to amyloid in a subject. Injected activities are typically 50 to 400MBq, more typically 80 to 370MBq and will have a volume of 1 to 10ml, preferably around 5ml.
- This aspect of the invention also encompasses use of a compound of Formula I in the manufacture of the 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 area of a subject.
- Example 1 describes experiments carried out to compare formulations of [ 19 F]Compound 1 having PEG 400, propylene glycol or polysorbate 20.
- Example 2 describes experiments carried out to compare formulations of [ 19 F]Compound 1 having polysorbate 20 or polysorbate 80.
- Example 3 describes experiments carried out to compare sticking of formulations of [ 19 F]Compound 1 having polysorbate 80 onto two different filter types.
- Example 4 describes experiments carried out to compare sticking of formulations of [ 19 F]Compound 1 having polysorbate 80 onto three different silicone tubing types.
- Example 5 describes automated synthesis of [ 18 F]Compound 1 and its formulation into a composition of the invention.
- Example 1 Sterile Dispensing of Compound 1 Formulations with PEG 400 and Propylene Glycol Solutions were prepared containing 7% v/v ethanol in 0.01 M sodium phosphate buffer at pH 7 4, 75 ⁇ g of Compound 1 and either ( ⁇ ) 12% v/v propylene glycol (PG) or ( ⁇ ) 10% v/v polyethylene glycol 400 (PEG 400). Percentage loss of Compound 1 to various components of a dispensing kit was evaluated by High Performance Liquid Chromatography (HPLC) in the following experiments
- Example 2 Comparison of Sterile Filtration of Compound 1 Compositions with Polvsorbate 20 and Polysorbate 80
- a single-use fluid pathway for a FASTIab TM (GE Healthcare) automated synthesiser unit was loaded with following reagents and mounted onto the FASTIab platform:
- the fluoride solution passed through a QMA (quaternary methyl ammonium) cartridge, trapping the fluoride and sending the enriched waterto waste.
- the QMA cartridge was then eluted with 350 ⁇ l of the 150 mM tetrabutylammonium bicarbonate solution in orderto recoverthe fluoride and the resultant solution was 5 passed into the reactor vessel.
- the reactor vessel was heated at 120 0 C and held under vacuum for 5 minutes while a flow of nitrogen passed over the solution. The nitrogen flow was then passed directly through the remaining solution for 4 minutes under the same heating and vacuum conditions to dry the contents of the reactor.
- the final intermediate solution (1 ml) was added to the reactor vessel and the temperature was raised to 130 0 C for 15 minutes.
- the column was eluted with 0.8% triethylamine:acetonitrile (53:47 by volume) at 5 ml/min.
- the desired product was identified by radio-detection and diverted back onto the FASTIab.
- the resulting solution of purified 2-[3-[ 18 F]fluoro-4-(methylamino)phenyl]-6-hydroxy- benzothiazole was passed directly through two C30 solid phase extraction cartridges (pre-conditioned with 1 ml ethanol and 15 ml water) so that the product was retained on the cartridges.
- the cartridges were rinsed with water to wash any residual HPLC elution solvents to waste.
- the product was then eluted from the C30 cartridges and into the pre-filled product collection vial with 3.5 ml ethanol followed by 9.3 ml water to give a final product volume of 50 ml (0.5% (w/v) polysorbate 80, 7% (v/v) ethanol, 0.9% (w/v) sodium chloride, 14 mM phosphate buffer, pH 7).
Abstract
Description
Claims
Priority Applications (16)
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PL08803301T PL2182988T3 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
US12/673,602 US8916131B2 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
AU2008292201A AU2008292201B2 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
BRPI0815129A BRPI0815129B8 (en) | 2007-08-30 | 2008-08-28 | radiopharmaceutical composition, and, methods for preparing a radiopharmaceutical composition. |
MX2010002196A MX2010002196A (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition. |
CN2008801048119A CN101790387B (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
RU2010101935/15A RU2475267C2 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
NZ583616A NZ583616A (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
JP2010522366A JP5367708B2 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
CA2694084A CA2694084C (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
EP08803301.4A EP2182988B1 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
DK08803301.4T DK2182988T3 (en) | 2007-08-30 | 2008-08-28 | RADIO PHARMACEUTICAL PREPARATION |
ES08803301.4T ES2464715T3 (en) | 2007-08-30 | 2008-08-28 | Radiopharmaceutical composition |
IL203316A IL203316A (en) | 2007-08-30 | 2010-01-14 | Radiopharmaceutical composition comprising isotopically-labeled benzothiazole compound and a biocompatible carrier, a method for preparing the composition and a method of imaging using the same |
HK11100867.7A HK1146710A1 (en) | 2007-08-30 | 2011-01-27 | Radiopharmaceutical composition |
NO2015006C NO2015006I1 (en) | 2007-08-30 | 2015-02-18 | Fluoromethamol (18F) |
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US96890407P | 2007-08-30 | 2007-08-30 | |
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EP (1) | EP2182988B1 (en) |
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Cited By (6)
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WO2011044406A3 (en) * | 2009-10-08 | 2011-06-23 | Ge Healthcare Limited | Purification method |
WO2017071980A1 (en) | 2015-10-28 | 2017-05-04 | Ge Healthcare Limited | Method for producing flutemetamol |
WO2018158137A1 (en) | 2017-02-28 | 2018-09-07 | Ge Healthcare Limited | A process for producing flutemetamol |
US11389538B2 (en) | 2014-12-04 | 2022-07-19 | Ge Healthcare Limited | Method for removing acetaldehyde |
US11878081B1 (en) | 2022-12-23 | 2024-01-23 | Tap Pharmaceuticals Ag | Pharmaceutical formulations of tafamidis |
US11980685B1 (en) | 2022-12-23 | 2024-05-14 | Tap Pharmaceuticals, Ag | Liquid pharmaceutical formulations of tafamidis |
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AU2013263297B2 (en) * | 2012-04-10 | 2017-11-30 | Lantheus Medical Imaging, Inc. | Radiopharmaceutical synthesis methods |
CN109400615B (en) * | 2017-08-18 | 2021-07-16 | 上海交通大学医学院附属新华医院 | Beta-amyloid targeted coumarin compound and preparation and application thereof |
BR112022019360A2 (en) * | 2020-03-27 | 2022-12-27 | Jubilant Pharma Holdings Inc | RADIOPHARMACEUTICAL DISPENSING SYSTEM |
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EP0017355A2 (en) | 1979-03-21 | 1980-10-15 | AMERSHAM INTERNATIONAL plc | Indium-111 oxine complex composition |
WO2007064773A2 (en) | 2005-12-01 | 2007-06-07 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Isotopically-labeled benzothiazole compounds as imaging agents for amyloidogenic proteins |
Cited By (10)
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WO2011044406A3 (en) * | 2009-10-08 | 2011-06-23 | Ge Healthcare Limited | Purification method |
US8969580B2 (en) | 2009-10-08 | 2015-03-03 | Ge Healthcare Limited | Purification method |
US9346771B2 (en) | 2009-10-08 | 2016-05-24 | Ge Healthcare Limited | Purification method |
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US11389538B2 (en) | 2014-12-04 | 2022-07-19 | Ge Healthcare Limited | Method for removing acetaldehyde |
US11964020B2 (en) | 2014-12-04 | 2024-04-23 | Ge Healthcare Limited | Method for removing acetaldehyde |
WO2017071980A1 (en) | 2015-10-28 | 2017-05-04 | Ge Healthcare Limited | Method for producing flutemetamol |
WO2018158137A1 (en) | 2017-02-28 | 2018-09-07 | Ge Healthcare Limited | A process for producing flutemetamol |
US11878081B1 (en) | 2022-12-23 | 2024-01-23 | Tap Pharmaceuticals Ag | Pharmaceutical formulations of tafamidis |
US11980685B1 (en) | 2022-12-23 | 2024-05-14 | Tap Pharmaceuticals, Ag | Liquid pharmaceutical formulations of tafamidis |
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EP2182988B1 (en) | 2014-04-16 |
PT2182988E (en) | 2014-05-16 |
ZA201000718B (en) | 2010-10-27 |
RU2010101935A (en) | 2011-10-10 |
KR101571572B1 (en) | 2015-11-24 |
BRPI0815129B8 (en) | 2021-05-25 |
KR20100055440A (en) | 2010-05-26 |
US20110008254A1 (en) | 2011-01-13 |
PL2182988T3 (en) | 2015-02-27 |
CA2694084A1 (en) | 2009-03-05 |
WO2009027452A3 (en) | 2009-09-03 |
ES2464715T3 (en) | 2014-06-03 |
NO2015006I1 (en) | 2015-03-02 |
JP5367708B2 (en) | 2013-12-11 |
NZ583616A (en) | 2012-06-29 |
EP2182988A2 (en) | 2010-05-12 |
NO2015006I2 (en) | 2015-02-18 |
RU2475267C2 (en) | 2013-02-20 |
JP2010536931A (en) | 2010-12-02 |
AU2008292201B2 (en) | 2014-09-04 |
BRPI0815129B1 (en) | 2021-01-12 |
MX2010002196A (en) | 2010-03-18 |
HUS1500007I1 (en) | 2021-05-07 |
US8916131B2 (en) | 2014-12-23 |
IL203316A (en) | 2015-02-26 |
DK2182988T3 (en) | 2014-05-26 |
AU2008292201A1 (en) | 2009-03-05 |
BRPI0815129A2 (en) | 2015-02-03 |
CN101790387B (en) | 2013-03-20 |
CN101790387A (en) | 2010-07-28 |
HK1146710A1 (en) | 2011-07-08 |
CA2694084C (en) | 2015-07-07 |
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