WO2018229083A1 - Composés destinés à être utilisés en tant que radioligands - Google Patents

Composés destinés à être utilisés en tant que radioligands Download PDF

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WO2018229083A1
WO2018229083A1 PCT/EP2018/065562 EP2018065562W WO2018229083A1 WO 2018229083 A1 WO2018229083 A1 WO 2018229083A1 EP 2018065562 W EP2018065562 W EP 2018065562W WO 2018229083 A1 WO2018229083 A1 WO 2018229083A1
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formula
compound
pharmaceutically acceptable
solvate
acceptable salt
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Peter Johnström
Magnus SCHOU
Zsolt CSELÉNYI
Maria SÖRHEDE-WINZELL
Stanko Skrtic
Lars Olof Mikael JOHANSSON
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AstraZeneca AB
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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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to compounds which may be used as radioligands, in particular as GPR44 radioligands for visualizing pancreatic beta cells.
  • the invention also relates to a process for preparing the radioligands and use of the radioligands in in vitro, ex vivo and in vivo beta cell imaging (BMI) methods.
  • BMI beta cell imaging
  • Beta cell imaging is positron emission tomography (PET) using radioligands containing positron-emitting radioisotopes, for example 11 C or 8F.
  • PET positron emission tomography
  • Beta cell imaging may also be conducted using in vitro or ex vivo techniques, for example by autoradiography (ARG).
  • ARG autoradiography
  • tritium ( 3 H) containing radioligands, which emit beta particle radiation can be used to image samples in vitro or ex vivo, for example by ARG analysis.
  • PET Positron emission tomography
  • PET is a non-invasive molecular imaging (in vivo) technique which allows the localization of a molecule labeled with positron emitting nuclides, based on the detection of positron annihilation radiation and subsequently processing of raw data into an image.
  • PET is frequently used for early detection, characterization, and real time monitoring of diseases, as well as investigating the effectiveness of therapeutic drugs.
  • PET can provide insights on the molecular interactions between the tracer molecule and the biological target, e.g., a protein, transporter, enzyme function and inhibition, metabolism and general biochemical function.
  • PET has become a powerful functional imaging tool and finds particular application in oncology, neuroscience and cardiovascular diseases.
  • PET imaging Another major utility of PET imaging is to understand and facilitate drug action and development which can be investigated in different ways.
  • existing drugs or new drug candidates can be radiolabeled and their pharmacokinetic parameters such as absorption, distribution, metabolism and excretion (ADME) can be established by PET.
  • ADME absorption, distribution, metabolism and excretion
  • decisions can be made in the very early stages of drug development regarding the prospects of a drug candidate.
  • pharmacodynamics or dose finding studies can be evaluated through receptor occupancy using PET radioligands.
  • Efforts have been made to develop PET radioligands for visualizing beta cells in the pancreas. Of the four majority cell types of the Islets of Langerhans of the pancreas, only beta cells secrete insulin in response to elevated blood glucose levels.
  • beta cells are responsible for keeping normal glucose levels of the blood, an adequate number of functional pancreatic beta cells are required.
  • the collective beta-cell numbers, or beta cell mass (BCM) is reduced significantly in both type 1 (T1 D) and type 2 (T2D) diabetes patients, compared to non-diabetic individuals.
  • T1 D an autoimmune attack against pancreatic beta cells results in a rapid loss of endocrine BCM and in T2D, insulin resistance and beta cell dysfunction build up a progressive reduction of BCM.
  • Autoradiography is a well-known in vitro or ex vivo technique by which samples taken from a subject can be imaged.
  • ARG may be used to determine the tissue (or cell) localization of a radioligand, for example, introduced into a metabolic pathway, bound to a receptor or enzyme, or hybridized to a nucleic acid.
  • uptake of radioligands in the sample can be analysed and, for example, used to assess the potential of a radioligand as a PET biomarker.
  • G-protein coupled receptor 44 has been identified as one of the beta cell specific proteins by antibody-based proteomics. GPR44 is also designated as the prostaglandin D 2 receptor 2 (DP 2 ), chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), cluster of differentiation (CD294) is a human protein encoded by the PTGDR2 gene. GPR44 is highly expressed, exclusively in insulin producing beta cells and absent from remaining islet cells as well as exocrine cells confirmed by both immunohistochemical (human pancreatic tissues from nondiabetic, T D and T2D individuals) and immunofluorescence (human islets) staining. Therefore, GPR44 is an important target of interest for visualizing beta cells in native pancreas.
  • DP 2 prostaglandin D 2 receptor 2
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • CD294 cluster of differentiation
  • beta cell imaging faces several challenges, principally relating to the anatomical location of the pancreas and dispersion of the beta cells (only 1 -2% of pancreas volume) there through. It has been estimated that the uptake of a PET radioligand should be 1 ,000 times higher in beta cells than in other cell types (exocrine pancreas, duct cells, vascular space, etc.) in order for visualization to be effective.
  • the present invention is based on the surprising discovery of compounds that are particularly suitable for use as radioligands for in vivo, in vitro and ex vivo BCI and in diagnostic methods relating to diagnosis of beta cell-related disorders.
  • the present invention provides a compound according to formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof:
  • the present invention provides a precursor to a compound according to formula (I) or formula (II), corresponding to a compound according to formula (III), or a pharmaceutically acceptable salt or solvate thereof:
  • the present invention also provides an intermediate compound according to formula (IV), or a pharmaceutically acceptable salt or solvate thereof:
  • the present invention provides an intermediate compound according to formula (V), or a pharmaceutically acceptable salt or solvate thereof:
  • the compounds according to formula (I), (II), (III), (IV) and (V), or pharmaceutically acceptable salts or solvates thereof are in the form of the (S) enantiomers at the stereogenic carbon centre, as illustrated below:
  • a "pharmaceutically acceptable salt” of a compound this may refer, for example, to a basic or acidic additional salt thereof.
  • base addition salts include salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as calcium and magnesium; salts of post-transition metal salts such as zinc and aluminium; and salts derived from organic bases such as benzathine, chloroprocaine, choline, tert-butylamine, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine and procaine.
  • Preferred base addition salts are selected from salts of alkali metals, most preferably sodium.
  • Examples of specific pharmaceutically acceptable salts of compounds of formula (I) and (II) include base addition salts of formula (la) and (lla) respectively, comprising a salt of the propionic acid moiety:
  • M + is the countercation of the base, which is for example an alkali metal cation, preferably a sodium cation.
  • the pharmaceutically acceptable salt of a compound of formula (III) corresponds to a base addition salt comprising a salt of the sulfinic acid moiety and further comprising a salt of the propionic acid moiety, corresponding to a salt of formula (Ilia).
  • the pharmaceutically acceptable salt of a compound of formula (III) corresponds to a base addition salt comprising a salt of the sulfinic acid moiety, corresponding to a salt of formula (1Mb):
  • M + is the countercation of the base, which is for example an alkali metal cation, preferably a sodium cation.
  • the pharmaceutically acceptable salt of a compound of formula (III) is a disodium salt corresponding to the salt of formula (Ilia).
  • Compounds of formula (I) and (II), or pharmaceutically acceptable salts or solvates thereof, may be prepared by reaction of a compound of formula (III) with a radiolabeled methylating agent, as outlined in Scheme I below. It has been found that a soft methylating agent (i.e.
  • the present invention also provides a process for the preparation of a compound according to formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore, wherein said process comprises the step of reacting a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof:
  • Whether a compound of formula (I) or (II) is prepared depends on the nature of the radiolabeled methylating agent that is employed. Typically, the methylating agent will be trapped in a solvent or reaction mixture and retained in a reaction vessel where methylation of the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, may occur.
  • a preferred methylating agent for use in the preparation of a compound of formula (I) is [ 11 C]CH 3 I.
  • This methylating agent is particular well known and has been used for methylation on sulfur.
  • [ 11 C]CH 3 I may be produced by "wet” or “dry” methods as described, for instance, in Link JM, Krohn KA, Clark JC. Production of [ 11 C]CH 3 I by single pass reaction of [ 11 C]CH 4 with l 2 . Nucl Med Biol. Jan 1997; 24(1 ):93-97.
  • [ 11 C]methane ([ 11 C]CH 4 ) is produced in-target via a 4 N(p,a) 11 C reaction on nitrogen with 10% hydrogen, using, for example, 16.4 MeV protons using a GEMS PET trace cyclotron (GE, Uppsala, Sweden).
  • the target gas is irradiated for 20-30 minutes with a beam intensity of, for instance, 35 ⁇ .
  • [ 11 C]CH is then mixed with vapors from iodine crystals followed by a radical iodination reaction in a closed recirculation system to produce [ 11 C]CH 3 I.
  • a preferred methylating agent for use in the preparation of a compound of formula (II) is [ 3 H]CH 3 I, which is widely available (including, for example, from American Radiolabeled Chemicals, St. Louis, MO, USA). Methods for preparing [ 3 H]CH 3 I and similar tritium labelled methylating agents, are also known based on the use of a tritium gas reagent.
  • the process for preparing a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, from reaction of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof may be conducted at any suitable temperature at which an acceptable rate of reaction is achieved and which avoids thermal decomposition and significant unwanted side reactions.
  • the reaction of a compound of formula (III) is conducted at above room temperature and below 100 °C.
  • the reaction is conducted at a temperature of from 50 °C to 90 °C, more preferably from 60 °C to 80 °C, most preferably from 65 °C to 75 °C.
  • the reaction of a compound of formula (III) may be conducted for any suitable period of time which provides an acceptable yield and maximises radiochemical stability of the radiolabeled product and may for instance be 15 minutes or less, preferably 10 minutes or less, more preferably 5 minutes or less.
  • the reaction of a compound of formula (III) may be conducted for a time period of from 1 minute to 15 minutes, preferably from 1 to 10 minutes, more preferably from 1 to 5 minutes, for example from 3 to 5 minutes.
  • the reaction of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, with a compound selected from 11 CH 3 R or C( 3 H) x ( 1 H) y R may be conducted in the presence of a solvent.
  • a solvent is an aprotic solvent, such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile, acetone, tetrahydrofuran or combinations thereof.
  • the time for the complete radiosynthesis e.g. production of 1C-Mel from 11 CH 4 , 1 C-methylation, purification, formulation and quality control is less than about three times the half-life of the relevant radioisotope. In some embodiments, the time for the complete radiosynthesis is about 1 hour or less, preferably about 30 minutes or less.
  • the process for preparing a compound formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof further comprises a preceding step of preparing the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, by hydrolysing a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof:
  • Conversion of the compound of formula (III) to a compound formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof may be conducted using any suitable base, including a base which may provide a base addition salt as described hereinbefore.
  • the base may be an alkali metal hydroxide, preferably sodium hydroxide, so as to generate the alkali metal salt of the compound of formula (III).
  • the reaction may be carried out in a suitable solvent, preferably one which has a volatility to allow removal of the solvent after the reaction by evaporation under reduced pressure. Examples of preferred solvents include methanol, dichloromethane, dichloroethane and combinations thereof.
  • the process for preparing a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof further comprises a preceding step of preparing the compound of formula (IV) by oxidation of a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof:
  • Oxidation of a compound of formula (V) may be conducted using any oxidising agent suitable for converting aromatic-substituted sulphides to the corresponding sulphones, including, for example, magnesium 2-carboperoxybenzoate.
  • the reaction may be carried out in a suitable solvent, preferably one which has a volatility to allow removal of the solvent after the reaction by evaporation under reduced pressure.
  • suitable solvents include dichloromethane and dichloroethane.
  • Compounds of formula (V) may be prepared from the reaction of a sulfoxide compound of formula (VI) by means of the Pummerer rearrangement though which the sulfur is reduced and the adjacent alkyl carbon atom is oxidised.
  • compounds of formula (VI) may be prepared from oxidation of a sulphide of formula (VII), as shown in Scheme III below.
  • Conversion of the compound of (VI) may be conducted in the presence of acetic anhydride and optionally also in the presence of an alkali metal acetate, such as sodium acetate, and preferably under reflux conditions.
  • Oxidation of the compound according to formula (VII) may be conducted using any oxidising agent suitable for converting aromatic-substituted sulphides to the corresponding sulphoxide, including, for example, meta-chloroperoxybenzoic acid (mCPBA).
  • mCPBA meta-chloroperoxybenzoic acid
  • the reaction may be carried out in a suitable solvent, preferably one which has a volatility to allow removal of the solvent after the reaction by evaporation under reduced pressure. Examples of preferred solvents include dichloromethane and dichloroethane.
  • Conversion of compound of formula (VIII) may be achieved by a Mitsunobu reaction with methyl 2-hydroxypropanoate, typically in the presence of diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), as well as triphenyl phosphine.
  • the reaction may be carried out in a suitable solvent, preferably an aprotic solvent, such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile tetrahydrofuran, or combinations thereof.
  • the components of the reaction are mixed at a temperature of less than 5 C, for example 0 C, before the reaction is allowed to warm to room temperature.
  • the Mitsunobu reaction in this case proceeds with inversion of molecular symmetry. Therefore, stereogenic control in the resulting compound of formula (VII) may be achieved by selecting the appropriate enantiomer of methyl 2-hydroxypropanoate.
  • the compounds of formula (I) to (VII) are in the form of the (S) enantiomers at the stereogenic carbon centre. Therefore, in order to provide compounds having this preferred stereochemistry, (R)-methyl 2-hydroxypropanoate is used in the above Mitsunobu reaction.
  • Conversion of the aniline of formula (X) to the corresponding methyl sulphide of formula (IX) may be achieved by reaction with dimethyldisulfide following initial diazotization of the aniline with isoamyl nitrite.
  • the reaction may be carried out in a suitable nonaqueous solvent, preferred examples of which include dichloromethane, dichloroethane and combinations thereof, and preferably at elevated temperature, for example 60 C.
  • Reduction of the nitro compound of formula (XI) to the aniline of formula (X) may be achieved using any suitable reducing agent, including tin chloride and zinc as well through the use of catalytic hydrogenation using nickel, palladium or platinum catalysts.
  • the conversion is achieved using zinc in acetic acid, preferably at elevated temperature, for example 50 C.
  • the compound of formula (XII) may be reacted with 2-chloro-1 -fluoro-4-nitrobenzene in the presence of a non-nucleophilic, inorganic base, preferably potassium carbonate, at elevated temperature, for example 120 C.
  • a non-nucleophilic, inorganic base preferably potassium carbonate
  • the reaction may be carried out in an aprotic solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile, tetrahydrofuran or combinations thereof.
  • Conversion of the boronic acid of formula (XIII) to the compound of formula (XII) may be achieved using any suitable method for conversion of aryl boronic acids to phenols. Examples include the use of tert-butyl hydroperoxide, and promoted with potassium hydroxide, or preferably using hydrogen peroxide in ethanol under reflux conditions.
  • the present invention provides a method, or compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method, of in vivo diagnosing a pancreatic beta cell-related disorder comprising the steps of:
  • step iv diagnosing the subject as having, or being at risk of having, a beta cell- related disorder based on the comparison in step iv).
  • the present invention provides a method, or compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method, of in vivo monitoring a change in pancreatic beta cell mass comprising the steps of:
  • step (iv) re-examining the subject after a period of time according to steps (i) to (iii); v) comparing the beta cell mass obtained in step (iii) to the beta cell mass obtained in step (iv);
  • step (v) monitoring a change in beta cell mass to monitor the impact of a therapeutic intervention or to monitor a beta cell-related disorder, based on the comparison in step (v).
  • methods described herein may be used for following changes in beta cell mass over time in a healthy subject or in patients suffering from a beta cell- related disorder, for example monitoring of the progression of a beta cell-related disorder.
  • methods described here can, for example, be used for monitoring the impact of pharmaceutical interventions that directly aim to increase beta cell mass, or for monitoring pharmaceutical interventions as safety analysis to exclude negative effects on beta cell mass.
  • the present invention provides a method, or compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method, of in vivo monitoring a change in pancreatic beta cell mass comprising the steps of:
  • step (iv) re-examining the subject after a period of time according to steps (i) to (iii); v) comparing the beta cell mass obtained in step (iii) to the beta cell mass obtained in step (iv).
  • the radioligand of formula (I) may be introduced into a subject as part of a pharmaceutical preparation comprising the radioligand and a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in yet a further aspect, the invention also provides pharmaceutical preparation comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical preparation will typically comprise from 0.01 to 100 pg/ml of the radioligand, preferably from 0.01 to 20 pg/ml, more preferably from 0.01 to 10 pg/ml, most preferably from I 0.01 to 5 pg/ml, for example from 0.02 to 2 pg/ml.
  • the pharmaceutically acceptable adjuvant, diluent or carrier may in preferred embodiments be liquid-based for providing a pharmaceutical preparation which may be administered intravenously.
  • PET-CT positron emission tomography-computed tomography
  • PET-MRI positron emission tomography-magnetic resonance imaging
  • beta cell mass quantification may be achieved though analysis of PET data using models familiar to the skilled person. For instance, two-tissue compartment modelling, Logan's linear graphical analysis and wavelet-aided parametric imaging using plasma input (PWAPI) can be used to determine distribution volume (V T ). Other models including one-tissue compartment models, multilinear analysis models and simplified reference tissue models may also be used.
  • the results of beta cell mass quantification may in turn be used for comparing against known or standard reference beta cell mass data representative of a healthy subject in order to assist in diagnosing a patient with a beta cell-related disorder.
  • the beta cell-related disorder is selected from type 1 diabetes mellitus, type 2 diabetes mellitus, hyperinsulinemia or pancreatic cancer such as insulinomas.
  • An increase of the beta cell mass in the subject under investigation relative to the reference value may indicate hyperinsulinemia, while a reduction of the beta cell mass in the subject under investigation relative to the reference value may indicate diabetes mellitus of type 1 or 2.
  • the present invention also provides an in vitro or ex vivo method of visualizing pancreatic beta cells in a sample, said method comprising the steps of: a) introducing a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, to a sample comprising pancreatic cells; and
  • Beta cells in a sample may be incubated with compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, before being visualized.
  • Visualization may be, for instance, by autoradiography techniques familiar to the skilled person.
  • a sample may be exposed to phosphor-imager screens and scanned using a phosphor imager (for example, a Cyclone Plus Phosphor imager - Perkin Elmer, or a Fujifilm BAS-5000 phosphor imager - Fujifilm, Tokyo, Japan) before being analyzed using, for instance, ImageJ (NIH).
  • a phosphor imager for example, a Cyclone Plus Phosphor imager - Perkin Elmer, or a Fujifilm BAS-5000 phosphor imager - Fujifilm, Tokyo, Japan
  • NASH ImageJ
  • a compound of formula (II) may be introduced into a subject or animal, following which a sample comprising beta cells is removed from the subject and the beta cells in the sample can be visualized ex vivo.
  • a sample comprising beta cells is removed from the subject and the beta cells in the sample can be visualized ex vivo.
  • One such clinical utility might be visualization of complete resection of an insulinoma being either the primary tumor or its metastasis.
  • the invention also provides a kit for selectively imaging pancreatic beta cells, or for use in diagnosing a beta cell related disorder, said kit comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore.
  • the kit may include instructions for use of the compound of formula (I) or formula (II) in an in vitro, ex vivo or in vivo visualization method or method of diagnosis.
  • the kit may be adapted for immediate use rather than storage for any length of time.
  • the invention also provides a kit for preparing a compound for use in selectively imaging pancreatic beta cells comprising: a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore.
  • the kit may include instructions for use of the compound of formula (III), in the preparation of a compound of formula (I) or (II) for use in an in vitro or in vivo or ex vivo beta cell visualization method or method of diagnosis of a beta cell related disorder.
  • the kit may also comprise a compound selected from 11 CH 3 R or C( 3 H) x ( 1 H)yR, wherein R is Br, CI or I; and wherein i) and ii) are not in admixture in the kit.
  • the present invention also provides a use of a compound according to formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, as defined herein as a radioligand, preferably wherein the radioligand is a GPR44 radioligand.
  • the invention provides use of a compound according to formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein as a PET radioligand.
  • the PET radioligand is used to monitor a change in beta cell mass, for example to monitor the impact of a therapeutic intervention or to monitor a beta cell-related disorder
  • Figures 1 A to 1 E show the results of in vitro autoradiography (ARG) of binding of a compound of formula (I) in pancreas from human non-diabetic subjects ( Figure 1 A), human subjects with T2D (Figure 1 B) and rat pancreas (Figure 1 C), as well as the uptake in the whole pancreatic sections ( Figure 1 D) and enrichment in islet hotspots (Figure 1 E);
  • ARG in vitro autoradiography
  • Figure 2 shows the results of islet-to-exocrine specific binding ratio for a nanomolar concentration of radioligand of formula (I);
  • Figure 3a shows the results of a competition binding assay to determine the potency of antagonists at human GPR44 in vitro by quantifying the ability of unlabeled ligand, (2S)- 2-(4-chloro-2-(2-chloro-4-(methylsulfonyl)phenoxy)phenoxy)propanoic acid, to displace binding of [ 3 H]ProstaglandinD 2 (PGD 2 ) from membranes of HEK293 cells transfected with human recombinant GPR44 and Ga16;
  • Figure 3b shows the results of a competition binding assay to quantify the ability of the unlabelled ligand, (2S)-2-(4-chloro-2-(2-chloro-4-(methylsulfonyl)phenoxy)phenoxy)- propanoic acid, to displace a radioligand of formula (II);
  • Figure 4 shows the results of a dynamic mass redistribution (DMR) assay with unlabelled ligand, (2S)-2-(4-chloro-2-(2-chloro-4-(methylsulfonyl)phenoxy)phenoxy)- propanoic acid in displacing the effect of PGD 2 on human clonal beta cells (EndoC cells);
  • DMR dynamic mass redistribution
  • Figure 5a shows the results of a fluorescence-activated cell sorting (FACS) analysis of human islet cells demonstrating GPR44 positive cells to be insulin positive cells. An isotype control showed the GPR44 antibody to be specific.
  • Figure 5b shows the results of experiments to determine the levels of insulin (INS) mRNA expression in FACS sorted GPR44 positive cells and GPR44 negative cells;
  • FACS fluorescence-activated cell sorting
  • Figures 6a and 6b show the results of investigations into quantification of binding in pancreas for a radioligand of formula (I) using ⁇ 20 min PET data and the 2-tissue compartment model for baseline ( Figure 6a) and following pretreatment with a GPR44 specific compound (Figure 6b); and
  • Figure 7 shows the results of PET data analysis using the two-tissue compartment model, Logan's linear graphical analysis and wavelet-aided parametric imaging using plasma input (PWAPI) for deriving the distribution volume (V T ), for base line experiments with a radioligand of formula (I) and experiments where there has also been a pretreatment with a GPR44 specific compound.
  • PWAPI plasma input
  • [ 11 C]Methane [ 11 C]CH 4 ) was produced in -target via the 4 N(p,c/.) 11 C reaction on nitrogen with 10% hydrogen, with 16.4 MeV protons using a GEMS PET trace cyclotron (GE, Uppsala, Sweden). Typically the target gas was irradiated for 20-30 minutes with a beam intensity of 35 ⁇ .
  • [ 11 C]CH 4 was released from the target and isolated on a Porapak Q trap cooled with liquid nitrogen. Following collection [ 11 C]CH 4 was released by warming the trap with pressurized air.
  • [ 11 C]CH 4 was then mixed with vapors from iodine crystals followed by a radical iodination reaction in a closed recirculation system to produce [ 11 C]CH 3 I.
  • the formed [ 11 C]CH 3 I was collected on a Porapak Q trap.
  • [ 11 C]CH 3 I was released from the Porapak Q trap by heating the trap using a custom-made oven.
  • RP semi-preparative reverse phase
  • the reaction mixture was diluted with sterile water (500 ⁇ _) before injecting the mixture into a built-in high performance liquid chromatography (HPLC) system for the purification of the radiolabeled title compound.
  • HPLC high performance liquid chromatography
  • the product was eluted with a mobile phase of 35% acetonitrile (ACN) in ammonium formate (AF, 0.1 M) containing sodium-L- ascorbate (500 mg/L) with a flow rate of 4 mL/min which gave a radioactive fraction corresponding to pure (2S)-2-(4-chloro-2-(2-chloro-4-([ 11 C]methylsulfonyl)phenoxy)- phenoxy)propanoic acid.
  • ACN acetonitrile
  • AF ammonium formate
  • the radiochemical purity, radiochemical identity and stability of the title compound of Example 5 were determined using an analytical HPLC system which included an Eclips XDB RP column (Agilent, C18, 4.6 * 150 mm, 5 pm particle size), Merck-Hitatchi L-7100 Pump, L-7400 UV detector and GM-tube for radioactivity detection (VWR International).
  • a wavelength of 254 nm and a mobile phase system of 25% acetonitrile (ACN) in ammonium formate (AF) (0.1 M) at a flow rate of 3 mUmin was used for the analysis.
  • the radiochemical purity, radiochemical identity and the stability of the title compound of Example 6 were determined using analytical HPLC system which included an ACE RP column (C18, 4.6 * 150 mm, 5 ⁇ particle size), Merck-Hitatchi L-7100 Pump, L-7400 UV detector and GM-tube for radioactivity detection (VWR International).
  • a wavelength of 254 nm and a mobile phase system of 30% ACN in AF (0.1 M) at flow rate of 2 mL/min was used for the analysis.
  • Example 5 Each sample was analyzed two times and compared to a reference standard analyzed two times. The identity and the purity of the title compound of Example 5 was confirmed by co- injection with unlabeled reference standard, (2S)-2-(4-chloro-2-(2-chloro-4- (methylsulfonyl)phenoxy)phenoxy)-propanoic acid.
  • the unlabeled reference standard, (2S)-2-(4-chloro-2-(2-chloro-4-(methylsulfonyl)phenoxy)phenoxy)-propanoic acid may be produced by any suitable method, for example by the method described in WO 2005/018529, or by the method of Example 6 using unlabeled methyl iodide.
  • the stability of the title compound of Example 5 in the formulated solution of that example was tested at different time intervals; 30, 60, 90, 120 minutes after the synthesis using radio-HPLC.
  • the formulated title compound of Example 5 was found to be radiochemically stable for up to 2 h.
  • Example 6 The identity and the purity of title compound of Example 6 was confirmed by co-injection with unlabeled reference standard, (2S)-2-(4-chloro-2-(2-chloro-4- (methylsulfonyl)phenoxy)phenoxy)-propanoic acid.
  • the formulation from Example 6 was stored at -18°C with specific radioactivity of 2 GBq/pmol and the purity of the radioligand was >99.9% up to one week after radiosynthesis.
  • Example 8 Liquid chromatography-mass spectrometry (LC-MS/MS) analysis
  • Pancreatic biopsies were collected from deceased human donors of healthy subjects, subjects with type 2 diabetes (T2D), as well as from Sprague Dawley rats. The biopsies were frozen to -80°C and processed into 20 pm slices. The rat pancreas was used as a negative control, since rat pancreatic islets does not express GPR44. The use of human tissue was approved by the Uppsala Ethical Review Board (Dnr 2015-401 ; #201 1/473, #Ups 02-577) and tissues obtained from Uppsala Biobank.
  • the sections were dried and exposed to phosphor-imager screen for 40 minutes in case of the radioligand of formula (I), and 90 h in case of the radioligand of formula (II).
  • the screens were scanned using a Cyclone Plus Phosphor imager (Perkin Elmer) at 600 dpi in case of the radioligand of formula (I), or a Fujifilm BAS-5000 phosphor imager (Fujifilm, Tokyo, Japan) in case of the radioligand of formula (II), and analyzed using ImageJ (NIH).
  • ROIs Regions of interest (ROIs) were drawn over the entire pancreatic sections as well as over regions corresponding to islets of Langerhans and exocrine tissue.
  • pancreatic islets and exocrine tissue were obtained within the Nordic network for Clinical Islet Transplantation Laboratory in Uppsala, Sweden.
  • Pancreatic islets (93% islet purity) and exocrine tissues were homogenized in ice-cold 0.32 M sucrose by hand using a Dounce glass homogenizer using a polytron tissue homogenizer (Polytron® PT 3000, Kinematica AG, Littau, Switzerland) in ice-cold 0.32 M sucrose at a concentration of 6 mg/ml and then by hand using a Dounce glass homogenizer. Aliquots of the homogenates were stored at -80°C until used.
  • the potency of antagonists at human GPR44 was determined in vitro by quantifying the ability of unlabeled (2S)-2-(4-chloro-2-(2-chloro-4-(methylsulfonyl)phenoxy)phenoxy)- propanoic acid to displace binding of [ 3 H]ProstaglandinD 2 (PGD 2 ) from membranes of HEK293 cells transfected with human recombinant GPR44 and Ga16.
  • [ 3 H]PGD 2 was purchased from Perkin Elmer Life Sciences with a specific activity of 100-210 Ci/mmol. All other chemicals were of analytical grade.
  • HEK cells expressing recombinant human GPR44/Ga16 were routinely maintained in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% Foetal Bovine Serum (FBS, HyClone), 1 mg/mL G418 (geneticin), 2 mM L-glutamine and 1 % non-essential amino acids.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS Foetal Bovine Serum
  • G418 gene
  • 2 mM L-glutamine 1 mg/mL G418 (geneticin)
  • 1 % non-essential amino acids For the preparation of membranes, adherent transfected HEK cells were grown to confluence in two layer tissue culture factories (Fisher, catalogue number TKT- 170-070E). Maximal levels of receptor expression were induced by addition of 500 mM sodium butyrate for the last 18 hours of culture.
  • the adherent cells were washed once with phosphate buffered saline (PBS, 50 mL per cell factory) and detached by the addition of 50 mL per cell factory of ice-cold membrane homogenisation buffer [20 mM HEPES (pH 7.4), 0.1 mM dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonyl fluoride and 100 pg/mL bacitracin].
  • PBS phosphate buffered saline
  • ice-cold membrane homogenisation buffer 20 mM HEPES (pH 7.4), 0.1 mM dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonyl fluoride and 100 pg/mL bacitracin.
  • the assay was performed in white 384-well (Non-Binding surface (NBS) plates with clear bottom (Corning)).
  • NBS Non-Binding surface
  • the HEK cells membranes containing CRTh2 were coated onto wheat germ agglutinin coated polyvinyltoluene (PVT) scintillation proximity assay (SPA) beads (Perkin Elmer).
  • PVT wheat germ agglutinin coated polyvinyltoluene
  • SPA scintillation proximity assay
  • the beads were pelleted by centrifugation (800x g for 10 minutes at 4°C), washed once with assay buffer (50 mM HEPES pH 7.4 containing 5 mM magnesium chloride) and finally re-suspended in assay buffer at a bead concentration of 10 mg/mL.
  • assay buffer 50 mM HEPES pH 7.4 containing 5 mM magnesium chloride
  • Compounds, dissolved in dimethyl sulphoxide (DMSO) were added as 3x dilution series, starting at 3 ⁇ .
  • the volumes were normalised to 1 % DMSO in the final assay volume (50 ⁇ !_). 1 ⁇ of unlabelled (i.e.
  • DMR is measured by resonant waveguide grating (RWG) using an Epic biosensor (Corning).
  • RWG resonant waveguide grating
  • Epic biosensor Corning
  • the cells were plated at a density of 2x10 4 cells/well in 384-well fibronectin-coated Epic biosensor plates (Corning) and cultured at 37°C, 5% CO 2 for 24 h. On the day of experiment, the cells were washed with assay buffer (IxHBSS, 20 mmol/L HEPES (pH 7.4) and 0.2 % BSA) and allowed to equilibrate for 1 h inside the Corning Epic Biosensor at 26°C.
  • assay buffer IxHBSS, 20 mmol/L HEPES (pH 7.4) and 0.2 % BSA
  • Human primary islet cells were purchased from Prodo Laboratories, USA. Dissociated human islets cells were fixed with Fixation buffer I (BD Biosciences) at 37°C for 10 minutes. Cells were washed in DPBS without calcium and magnesium and permeabilized with Perm/Wash buffer (BD Biosciences). Cells were incubated over night at 4°C with primary antibodies, mouse anti-human GPR44 AlexaFluor 647 (BD Biosciences) or isotype AF647 control, rabbit anti-insulin-PE (Cell Signaling technology, Beverly, MA). Cells were washed twice in BD Perm/wash buffer and resuspended in DPBS without calcium and magnesium containing 2% FBS and 5mM EDTA. Analysis was performed on a BD LSR Fortessa (BD Biosciences).
  • Fluorescence-activated cell sorting analysis revealed that the GPR44 positive cells were also insulin positive.
  • the isotype control showed that the GPR44 antibody was specific ( Figure 5a).
  • FACS sorting of viable dissociated human islets cells were stained only with mouse anti-human GPR44 AlexaFluor 647 and the viability marker 7AAD (BD Biosciences) in DPBS without calcium and magnesium containing 2% FBS and 5mM EDTA. Sorting was performed using a BD FACS Arialll (BD Biosciences).
  • PET measurements were performed in anesthetized cynomolgus monkeys. Anesthesia was induced with an intramuscular (im) injection of Ketalar (Ketamine) and maintained by a continuous intravenous infusion (1 ml/kg/hr) of ketamine (4 mg/ml) and xylazine (0.4 mg/ml) using a syringe pump. Body temperature was maintained by a Bair Hugger model 505 (Arizant Healthcare, MN) and monitored by an oesophageal thermometer. Monkeys were fitted with indwelling catheters to allow for intravenous injection of radioligand and pretreatment drug, and blood sampling for determination of radioactivity in plasma, metabolism and plasma protein binding of radioligand.
  • the monkeys were observed continuously during the PET-CT experimental session. Continuous physiological monitoring was performed including non-invasive blood pressure, oxygen saturation (Sp0 2 ), ECG and pulse. The fluid balance was controlled during the whole experimental session by a continuous intravenous infusion of saline 9 mg/mL (2 mL/kg monkey/h) using a syringe pump. The monkeys were also monitored for any adverse effects related to the infusion of the radioligand of formula (I), corresponding to the title compound of Example 5, and GPR44 drug pretreatment with a compound of formula (XIV). After the experiment the monkeys were returned to the stables and observed for changes in appearance and behaviour, signs of ill health, and mortality.
  • the monkeys were positioned in the PET-CT system to allow PET imaging over the lung to kidney area. Distribution of the radioligand was measured in a Siemens PET/CT Biograph system. One low-dose CT was performed before intravenous administration of the radioligand, and this CT data was used for attenuation correction. The radioligand was injected as a bolus into a sural vein during 5 seconds with simultaneous start of PET-data acquisition. In a subsequent experiment monkeys were pretreated with a 10- min infusion of the GPR44 specific compound of formula (XIV), (1 mg/kg), starting 20 min before administration of the radioligand. Injected radioactivity was in the range of 130 to 260 MBq.
  • Radioactivity concentration (nCi/cm 3 ) in the ROIs for each PET measurement was decay-corrected to the time of injection and plotted versus time. PET data were analysed using the two-tissue compartment model.
  • V T The outcome parameter was the distribution volume (V T ).
  • Alternative approaches for V T estimation were also evaluated including Logan's linear graphical analysis and wavelet-aided parametric imaging using plasma input (PWAPI) (calculation of parametric image being restricted to voxels in the area of pancreas and spleen). The latter approach provided quantified images of voxel-wise estimates of V T .
  • PWAPI plasma input
  • the radioligand showed favourable kinetics for quantification of binding in the pancreas using ⁇ 20 min PET data and the 2-tissue compartment model ( Figures 6a and 6b).

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Abstract

La présente invention concerne des composés, en particulier ceux de formule (I) et de formule (II) décrits dans la description, ou des sels ou solvates pharmaceutiquement acceptables de ceux-ci, qui peuvent être utilisés en tant que radioligands dans des procédés d'imagerie de cellules bêta (BMI) in vitro, ex vivo et in vivo, en particulier en tant que radioligands de GPR44 pour visualiser des cellules bêta pancréatiques. L'invention concerne également un procédé de préparation de radioligands de formule (I) ou de formule (II), ainsi que des composés de formule (III), (IV) et (V) décrits dans la description, ou des sels ou solvates pharmaceutiquement acceptables de ceux-ci, qui sont utiles dans la préparation de composés de formule (I) et de formule (II).
PCT/EP2018/065562 2017-06-13 2018-06-12 Composés destinés à être utilisés en tant que radioligands Ceased WO2018229083A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018529A2 (fr) 2003-08-21 2005-03-03 Astrazeneca Ab Nouveaux composes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018529A2 (fr) 2003-08-21 2005-03-03 Astrazeneca Ab Nouveaux composes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HELLSTRÖM-LINDAHL EWA ET AL: "GPR44 is a pancreatic protein restricted to the human beta cell", ACTA DIABETOLOGICA, SPRINGER INTERNATIONAL, BERLIN, DE, vol. 53, no. 3, 14 October 2015 (2015-10-14), pages 413 - 421, XP035886985, ISSN: 0940-5429, [retrieved on 20151014], DOI: 10.1007/S00592-015-0811-3 *
MAHABUBA JAHAN: "Ph.D. Thesis: Development of Novel PET radioligands for Visualizing Beta Cell Mass and Amyloid Plaques", 2016, THE DEPARTMENT OF CLINICAL NEUROSCIENCE, KAROLINSKA INSTITUTET, Stockholm, ISBN: 978-91-7676-362-9, XP055489676 *
NUCL MED BIOL., vol. 24, no. 1, January 1997 (1997-01-01), pages 93 - 97
OLOF ERIKSSON ET AL: "In Vivo Visualization of ?-Cells by Targeting of GPR44", vol. 67, no. 2, 1 January 2018 (2018-01-01), pages 182 - 192, XP009506597, ISSN: 0012-1797, Retrieved from the Internet <URL:http://diabetes.diabetesjournals.org/content/67/2/182> [retrieved on 20171205], DOI: 10.2337/DB17-0764 *
SCHRODER R; JANSSEN N; SCHMIDT J; KEBIG A; MERTEN N; HENNEN S ET AL.: "Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements", NAT BIOTECHNOL., vol. 28, no. 9, September 2010 (2010-09-01), pages 943 - 9

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