WO2018015307A1 - Tau pet imaging ligands - Google Patents
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- WO2018015307A1 WO2018015307A1 PCT/EP2017/067898 EP2017067898W WO2018015307A1 WO 2018015307 A1 WO2018015307 A1 WO 2018015307A1 EP 2017067898 W EP2017067898 W EP 2017067898W WO 2018015307 A1 WO2018015307 A1 WO 2018015307A1
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- FVULHHWBGORUIB-UHFFFAOYSA-N FCCOc(cn1)ccc1Cl Chemical compound FCCOc(cn1)ccc1Cl FVULHHWBGORUIB-UHFFFAOYSA-N 0.000 description 1
- ZRTZMLXATMUTHR-UHFFFAOYSA-N FCC[N-2]c(cc1)cnc1Cl Chemical compound FCC[N-2]c(cc1)cnc1Cl ZRTZMLXATMUTHR-UHFFFAOYSA-N 0.000 description 1
- ZSPDQLZRDMWBAH-UHFFFAOYSA-N FCCc(cc1)cnc1Nc1cc2ccncc2cc1 Chemical compound FCCc(cc1)cnc1Nc1cc2ccncc2cc1 ZSPDQLZRDMWBAH-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- 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
- C07B59/002—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the present invention relates to novel, selective radio labelled tau ligands which are useful for imaging and quantifying tau aggregates, using positron-emission tomography (PET).
- PET positron-emission tomography
- the invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue or a subject, in vitro or in vivo, and to precursors of said compounds.
- AD Alzheimer's Disease
- AD patients suffer from cognition deficits and memory loss as well as behavioural problems such as anxiety. Over 90% of those afflicted with AD have a sporadic form of the disorder while less than 10% of the cases are familial or hereditary. In the United States, about one in ten people at age 65 have AD while at age 85, one out of every two individuals are afflicted by AD. The average life expectancy from the initial diagnosis is 7-10 years, and AD patients require extensive care either in an assisted living facility or by family members. With the increasing number of elderly in the population, AD is a growing medical concern. Currently available therapies for AD merely treat the symptoms of the disease but not the underlying pathology causing the disease.
- neurofibrillary tangles which are generated by aggregates of hyperphosphorylated tau protein and amyloid plaques which form by aggregation of beta-amyloid peptide.
- tauopathies which additionally but not exclusively include tangle-only dementia (TD), argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease (PiD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
- TD tangle-only dementia
- ALD argyrophilic grain disease
- PSP progressive supranuclear palsy
- CBD corticobasal degeneration
- PiD Pick disease
- FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
- Tau aggregates may appear ultrastructurally as paired helical filaments (PHF), straight filaments (SF), randomly coiled filaments (RCF), or twisted filaments (TF); this variability translates into polymorphism.
- PHF paired helical filaments
- SF straight filaments
- RCF randomly coiled filaments
- TF twisted filaments
- a correlation of neurofibrillary tangles has been made with the level of cognitive impairment in AD and/or the chance of developing AD.
- diagnosis can still only be performed post-mortem by means of biopsy/autopsy. Examination based on history and statistical memory testing require clear evidence of impairment or dementia, and are often inaccurate or insensitive, and measurement of ⁇ peptides and total tau proteins in cerebrospinal fluid by lumbar puncture is invasive and amenable to adverse effects.
- Positron Emission Tomography is a non-invasive imaging technique that offers the highest spatial and temporal resolution of all nuclear imaging techniques and has the added advantage that it can allow for true quantification of tracer concentrations in tissues. It uses positron emitting radionuclides for detection. Several positron emission tomography radiotracers have been reported so far for imaging of tau aggregates (for a review, see for instance Ariza et al. J. Med. Chem. 2015, 58, 4365-4382). "Preclinical Characterization of 18 F-MK-6240, a promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles" in J. Nucl.
- Imaging 2010; 37(8): 1575-1593 reports on an isoquinoline compound [ n C]PKl 1195 which binds to peripheral cortical benzodiazepine receptors in activated microglia and which was further reported in "Carbon 11 -labeled Pittsburgh compound B and carbon 11 -labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer's disease in Arch. Neurol. 2009; 66(1): 60-67 as failing to show any differences in brain retention between patients and healthy volunteers.
- PET imaging of the human brain with the quinoline compound 18 F-THK5351 having high affinity to PHF was shown to be confounded by off-target binding to the enzyme monoamine oxidase MAO-B (Alzheimer's Research & Therapy 2017; 9;25 DOI 10.1186/sl3195-017-0253-y).
- MAO-B monoamine oxidase monoamine oxidase monoamine oxidase MAO-B
- the present invention relates to a compound having the Formula (I)
- At least one atom is radioactive
- R 2 is methyl, and either R 1 is F and R 3 is H, or R 1 is H and R 3 is F; or
- R 1 and R 3 are both H, and R 2 is selected from the group consisting of -Ci-4alkyl-F,
- the present invention relates to a compound of Formula ( ⁇ )
- R 2 is methyl, and either R 1 is 18 F and R 3 is H, or R 1 is H and R 3 is 18 F; or
- R 1 and R 3 are both H, and R 2 is selected from the group consisting of -Ci_4alkyl- 18 F,
- the invention relates to precursor compounds for the synthesis of the compounds of Formula (I) or ( ⁇ ), as previously defined.
- the present invention also relates to a compound of Formula (P-l)
- R 2 is methyl, and either R 1 is selected from the group consisting of Br, -NO2,
- R 3 is H, or R 1 is H and R 3 is selected from the group consisting of Br, -NO2, -[N(CH 3 ) 3 ] + , and 4-CH 3 -Ph-S0 2 -0-; or
- R 1 and R 3 are both H, and R 2 is selected from the group consisting of
- suitable anionic counterions include, but are not limited to trifluoroacetate (-[OC(0)CF 3 ] " ), an organic sulfonate (e.g. Ci- 4 alkylsulfonate, or phenylsulfonate wherein the phenyl may be optionally substituted with a Ci_ 4 alkyl, halo, or a nitro group) and tartrate.
- organic sulfonate e.g. Ci- 4 alkylsulfonate, or phenylsulfonate wherein the phenyl may be optionally substituted with a Ci_ 4 alkyl, halo, or a nitro group
- Ci- 4 alkylsulfonate include methanesulfonate (mesylate),
- the invention also relates to the reference materials of compounds of Formula (I) or ( ⁇ ), corresponding to the corresponding non-radio labelled compounds, herein referred to as compounds of Formula [ 19 F]-(I)
- R - is methyl, and either R 1 is F and R 3 is H, or R 1 is H and R 3 is F; or
- R 1 and R 3 are both H, and R 2 is selected from the group consisting of -Ci_ 4 alkyl-F,
- the invention also relates to a pharmaceutical composition comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
- said pharmaceutical composition is a diagnostic pharmaceutical composition.
- Said pharmaceutical composition is in particular, a sterile solution.
- illustrative of the invention is a sterile solution comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as described herein.
- the invention further relates to the use of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as an imaging agent.
- Exemplifying the invention is a use of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as described herein, for, or a method of, imaging a tissue or a subject, in vitro or in vivo.
- the invention relates to a compound of Formula (I), in particular a compound of Formula ( ⁇ ), for use in binding and imaging tau aggregates in patients suffering from, or suspected to be suffering from, a tauopathy.
- tauopathies are, for example, Alzheimer's disease, tangle-only dementia (TD), argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease (PiD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
- TD tangle-only dementia
- APD argyrophilic grain disease
- PSP progressive supranuclear palsy
- CBD corticobasal degeneration
- PiD corticobasal degeneration
- FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
- the tauopathy is Alzheimer's disease.
- the invention further relates to a compound of Formula (I), in particular a compound of Formula ( ⁇ ), for diagnostic imaging of tau aggregates in the brain of a subject, and to the use of the compound of Formula (I), in particular the compound of Formula ( ⁇ ), in binding and imaging tau aggregates in patients suffering from, or suspected to be suffering from, a tauopathy.
- tauopathies are, for example, Alzheimer's disease, tangle-only dementia (TD), argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease (PiD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
- the tauopathy is Alzheimer's disease.
- the invention also relates to a method for imaging a tissue or a subject, comprising contacting with or providing or administering a detectable amount of a labelled compound of Formula (I), in particular a labelled compound of Formula ( ⁇ ), as described herein to a tissue, or a subject, and detecting the compound of Formula (I), in particular the compound of Formula ( ⁇ ).
- a method of imaging a tissue, or a subject comprising contacting with or providing to a tissue, or a subject, a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as described herein, and imaging the tissue, or subject with a positron-emission tomography imaging system.
- the invention refers to a process for the preparation of a compound of Formula (I'-a) or (I'-b), referred to in particular hereinbelow as (I'-al), (I'-a2), (I'-bl), (I'-b2), (I'-b3), or a pharmaceutically acceptable salt or a solvate thereof as described herein, comprising
- Typical conditions for the activation of the precursors of Formulae (P-bl), (P-b2) and (P-b3) include for instance, methanesulfonyl chloride as activating agent, dry dimethyl sulfoxide (DMSO) as solvent, at room temperature for a sufficient period of time to drive the reaction to completion, typically, 10 minutes.
- DMSO dry dimethyl sulfoxide
- the preparation of the compound of Formula (I'-b3) will include the additional steps of protecting the amine functionality with a suitable protecting group, such as for example tert-butyloxycarbonyl (Boc) or alternative suitable amine protecting group, and subsequently cleaving such protecting group, using typically trifluoroacetic acid (TFA) when the protecting group is Boc.
- a suitable protecting group such as for example tert-butyloxycarbonyl (Boc) or alternative suitable amine protecting group
- TFA typically trifluoroacetic acid
- a suitable source of 18 F ⁇ is, for example 4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane potassium fluoride- [ 18 F] (1 : 1) (also referred to as
- Suitable conditions include, those appropriate for nucleophilic substitution known in the art, for example, using DMSO or DMF as solvent, in particular DMSO, under conventional heating or microwave irradiation (e.g. 50 W), for example at about 90-160 °C, or at about 120-160 °C, in particular at about 90 or 160 °C, for a sufficient period of time to enable the reaction to proceed to completion, for example 10 min when the reaction is performed under microwave irradiation.
- microwave irradiation e.g. 50 W
- Figure 1 shows in vitro autoradiography (ARG) using [ 18 F]Co. No. 1 (7.4 kBq /
- Figure 2 shows a comparison between the ARG shown in Fig. 1 (A), and adjacent human AD brain slices incubated with [ 18 F]Co. No.l (7.4 kBq / 500 / slice) in the presence of authentic reference compound Co. No. 1 (B) or T808 (C) at 1 ⁇ /L.
- Figure 3 shows incubation with 10 nM [ 3 H]Co. No. 1 on human basal ganglia (striatal) tissue (A), followed by treatment with 10 ⁇ Co. No. 1 (B) or 10 ⁇
- FIG. 3D shows incubation with 10 nM [ 3 H]Co. No. 1 on human AD tissue (parietal-temporal cortex, Braak stage VI) having confirmed tau and amyloid pathology by IHC as shown in Figure 4.
- Figure 3E shows incubation with 10 nM
- Figure 3F shows incubation with 10 nM [ 3 H]THK5351 on human basal ganglia tissue, and treatment with 10 ⁇ Co. No. 1 (G) or 10 ⁇ THK5351 (H).
- Figure 31 shows incubation with [ 3 H]THK-5351 on human AD tissue (parietal-temporal cortex, Braak stage VI) with confirmed tau and amyloid pathology as shown in Figure 4.
- Figure 3J shows incubation with 10 nM [ 3 H]THK5351 on human AD tissue (lateral-occipital gyrus, Braak stage 0) with confirmed amyloid pathology but no tau pathology as shown in Figure 5.
- Figure 3K shows incubation with 3 nM [ 3 H]-AV-45 on human basal ganglia (K), the aforementioned human AD tissue containing both amyloid beta and tau pathology (L) and the aforementioned human AD tissue containing amyloid beta but no taupathology (M).
- Figure 4 shows 4G8 and AT8 IHC of amyloid and tau pathology in AD brain slices from parietal-temporal cortex region of the same patient as the slices used for the images in Figure 3.
- Figure 5 shows an adjacent human AD brain slice (lateral-occipital gyrus, female) to the one used in Figure 3E and Figure 3 J.
- the presence of ⁇ -amyloid plaques (A, B) and absence of tau tangles (C, D) was confirmed with immunohistochemistry using respectively 4G8 and AT8 antibodies.
- FIG. 6 shows IHC confirmation of the expression of MAO-B (left) and MAO-
- Figure 7 shows incubation with 0.2 mCi/mL [ 18 F]Co. No. 1 on human AD tissue slices (parieto-temporal cortex, Braak stage VI) (A), and treatment with 10 ⁇ Clorgiline (B), 10 ⁇ Deprenyl (C) and 10 ⁇ Co. No. 1 (D).
- Figure 8 shows AT8 and 4G8 IHC of respectively tau and amyloid pathology in adjacent AD brain slices (parietal-temporal cortex, Braak stage VI) to the ones referred to in Figure 7.
- Figure 9 shows ⁇ time-activity curves expressed as standardized uptake values (SUV) for [ 18 F]Co. No. 1 and Figure 10 shows ⁇ time-activity curves for [ 18 F]T807 (C) in the whole brain of three female Wistar rats.
- Three separate studies are shown: a baseline scan (only tracer), a pre-treatment experiment (cold Co. No.1 or T807, 10 mg/kg injected subcutaneously 60 min prior to radiotracer injection), and a chase study (cold Co. No. l or T807, 1 mg/kg injected intravenously 30 min after radiotracer injection).
- Figure 11 shows %SUV m ax curves of small animal PET time-activity curves of
- Figure 12 shows ⁇ time-activity curves for [ 18 F]Co.
- No. 1 and Figure 13 shows ⁇ time-activity curves for [ 18 F]T807 in the whole brain, corpus callosum, cerebellum, enthorinal cortex and skull of a rhesus monkey.
- Figure 14 shows %SUV m ax curves of small animal ⁇ time-activity curves of
- the compound of Formula (I) is in particular a compound of Formul
- R 1 is F and R 3 is H, or R 1 is H and R 3 is F; or a pharmaceutically acceptable salt or a solvate thereof.
- the compound of Formula (I) is a compound of Formula (I '-a)
- R 1 is 18 F and R 3 is H, or R 1 is H and R 3 is 18 F;
- the compound of Formula (I) is in particular a compound of Formu
- R 2 is selected from the group consisting -Ci_ 4 alkyl-F, -OCi_ 4 alkyl-F, and -NR 4 -Ci_ 4 alkyl-F, wherein R 4 is H or methyl;
- the compound of Formula (I) is a compound of Formula (I'-b)
- R 2 is selected from the group consisting of -Ci_ 4 alkyl- 18 F, -OCi- 4 alkyl- 18 F, and
- the compound of Formula (I), in particular of Formula ( ⁇ ), is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-oxidethyl
- the precursor compound for the synthesis of the compound of Formula (I) or ( ⁇ ), as previously defined is in particular a compound of Formula (P-l)
- R 2 is methyl, and either R 1 is selected from the group consisting of Br, -NO2, -[N(CH 3 ) 3 ] + , and 4-Me-Ph-S0 2 -0-, and R 3 is H, or R 1 is H and R 3 is selected from the group consisting of Br, -NO2, -[N(CH 3 ) 3 ] + , and 4-Me-Ph-S0 2 -0-; or
- R 1 and R 3 are both H, and R 2 is selected from the group consisting of
- the invention also relates to the reference material corresponding to the non- radio labelled compound 1, corresponding to the [ 19 F]-compound
- the compound of Formula [ 19 F]-(I) is in particular compound of Formula [ 19 F]- I-a
- R 1 is F and R 3 is H, or R 1 is H and R 3 is F; or a pharmaceutically acceptable salt or a solvate thereof.
- the compound of Formula [ 19 F]-(I) is in particular a compound of Formula (I-b)
- R 2 is selected from the group consisting of -Ci-4alkyl-F, -OCi_4alkyl-F, and
- [ 19 F]-Co. No. 1 has shown potent binding (pICso 8.24) to extracted human tau aggregates in a radio label displacement assay using an internally made tritium analogue of compound T-808 (T-808 is developed by Siemens, see for example, J. Alzheimers Dis. 2014, 38, 171-184), and which is referred to herein as [ 3 H]-T808.
- Co. No. 1 shows weak binding to extracted human amyloid-beta aggregates (pICso 5.18) in a radio label displacement assay using an internally made tritium analogue of
- Florbetapir also known as Amyvid® from Eli Lilly and Co., or AV-45, see for example, J. Nucl. Med. 2010, 51, 913-920), and which is referred to herein as
- [ 3 H]-AV-45 A description of the protocols is provided hereinafter.
- [ 3 H]-T808 was obtained by subjecting a solution of the bromo precursor (1 eq.) in methanol to catalytic tritiation over palladium on carbon (5%) in the presence of diisopropylethylamine (5 eq.) at room temperature.
- the bromo precursor was obtained by bromination of T808 with N-bromosuccinimide (1 eq.) in acetonitrile.
- [ 3 H] -AV-45 was obtained by Iridium catalyzed (Crabtree's catalyst) tritium exchange of AV-45 dissolved in dichloromethane.
- the compound of Formula (I), in particular the compound of Formula ( ⁇ ), and compositions comprising the compound of Formula (I), in particular the compound of Formula ( ⁇ ), can be used for imaging a tissue, or a subject, in vitro or in vivo.
- the invention relates to a method of imaging or quantifying tau aggregates in a tissue, or a subject in vitro or in vivo.
- the method of imaging tau aggregates comprises providing a subject, in particular a patient, with a detectable quantity of a compound of Formula (I), in particular a compound of Formula ( ⁇ ).
- the invention relates to a method of imaging tau-aggregate deposits comprising the steps of providing a subject with a detectable quantity of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), allowing sufficient time for the compound of Formula (I), in particular the compound of Formula ( ⁇ ), to be associated with tau aggregate deposits, and detecting the compound associated with tau aggregate deposits.
- the compound of Formula (I), in particular the compound of Formula ( ⁇ ) can be administered intravenously, for example, by injection with a syringe or by means of a peripheral intravenous line, such as a short catheter.
- the compound of Formula (I), in particular the compound of Formula ( ⁇ ), or a sterile solution comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ) may in particular be administered by intravenous administration in the arm, into any identifiable vein, in particular in the back of the hand, or in the median cubital vein at the elbow.
- the invention relates to a method of imaging a subject, comprising the intravenous administration of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as defined herein, or a composition, in particular, a sterile formulation, comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ), to the subject, and imaging the subject with a positron- emission tomography imaging system.
- a method of imaging a subject comprising the intravenous administration of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), as defined herein, or a composition, in particular, a sterile formulation, comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ), to the subject, and imaging the subject with a positron- emission tomography imaging system.
- the invention relates to a method of quantifying tau aggregation deposits in a subject, comprising the intravenous administration of a compound of Formula (I), in particular a compound of Formula ( ⁇ ), or a composition comprising a compound of Formula (I), in particular a compound of Formula ( ⁇ ), to the subject, and imaging with a positron-emission tomography imaging system.
- the compound is provided to a subject in a detectable quantity and after sufficient time has passed for the compound to become associated with the tau aggregation deposits, the labelled compound is detected noninvasively.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
- Ci-4alkyl shall denote a straight or branched saturated alkyl group having 1 , 2, 3 or 4 carbon atoms, respectively e.g. methyl, ethyl, 1 -propyl, 2-propyl, butyl and the like.
- Acceptable salts of the compounds of the invention are those wherein the counterion is pharmaceutically acceptable.
- salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether
- the pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salt forms that the compounds according to the invention are able to form.
- Said salts can be obtained by treating the base form of the compounds according to the invention with appropriate acids, for example inorganic acids, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic
- inorganic acids for example hydrohalic acid, in
- salt forms can be converted into the free base form by treatment with an appropriate base.
- some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- subject refers to a human, who is or has been the object of treatment, observation or experiment. Unless otherwise stated, “subject” includes non- symptomatic humans, presymptomatic humans and human patients. PREPARATION
- the compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
- the compounds can be prepared according to the following synthesis methods.
- the compound of Formula (II-a') can be prepared for example, by reaction of isoquinolin-6-amine with 6-bromo-3-methyl-2-nitropyridine or 2-bromo-5-methyl-4- nitropyridine under Buchwald-Hartwig amination conditions.
- the compounds according to the present invention find various applications for imaging tissues, or a subject, both in vitro and in vivo. Thus, for instance, they can be used to map the differential distribution of tau aggregate deposits in subjects of different age and sex. Further, they allow one to explore for differential distribution of tau aggregate deposits in subjects afflicted by different diseases or disorders, including Alzheimer's disease, but also other diseases caused by tau aggregate deposits, i.e. other tauopathies.
- radioligand is administered in trace amounts, i.e. in detectable amounts for PET imaging, no therapeutic effect may be attributed to the administration of the radioligands according to the invention.
- ACN or MeCN means acetonitrile, "aq.” means aqueous, “tBuOH” means tert-butanol, “DCM” means dichloromethane, “DIPE” means diisopropyl ether, “DIPEA” means N,N-diisopropylethylamine, “DMF” means N,N- dimethylformamide, “DMSO” means dimethyl sulfoxide, "Et 2 0” means diethyl ether, “EtOAc” means ethyl acetate, “h” means hours, “HPLC” means high-performance liquid chromatography, “LCMS” means liquid chromatography/mass spectrometry, “MeOH” means methanol, “min” means minutes, “m.p.” means melting point, "org” means organic, “Pd 2 (dba)3” means tris(dibenzylideneacetone)dipalladium(0),”prep”
- Thin layer chromatography was carried out on silica gel 60 F254 plates (Merck) using reagent grade solvents. Open column chromatography was performed on silica gel, mesh 230-400 particle size and 60 A pore size (Merck) under standard techniques. Automated flash column chromatography was performed using ready-to-connect disposable cartridges purchased from Grace (GraceResolvTM cartridges) or Teledyne ISCO (RediSep® cartridges), on irregular silica gel, particle size 35-70 ⁇ on an ISCO CombiFlash or Biotage IsoleraTM Spektra apparatus.
- TMS tetramethylsilane
- HPLC purifications were carried out on a GILSON Semi-Preparative System, operated by Trilution software, equipped with a Phenomenex Gemini CI 8 100 A column (100 mm long x 30 mm I.D.; 5 ⁇ particles) at RT °C, with a flow rate of 40 mL/min using a gradient elution in 20 min as indicated in the synthetic protocols.
- the injection volume was 8000 ⁇ . Acquisition frequency was set to 284 nm for the UV-Dual detector.
- Tetramethyltin (0.736 mL, 5.309 mmol) was added to a mixture of 5-bromo-4- fluoropyridin-2-amine (0.338 g, 1.77 mmol, CAS 944401-69-8),
- Trimethylboroxine (0.256 mL, 1.83 mmol) was added to a stirred solution of 5-bromo- 6-fluoropyridin-2-amine (0.291 g, 1.52 mmol, CAS 944401-65-4),
- Deoxo-Fluor® (50% in toluene, 1.67 mL, 3.807 mmol) was added dropwise to a solution of 2-chloro-5-(2-fluoroethyl)pyridine (0.400 g, 2.538 mmol, CAS 117528-28- 6) in dry DCM (15 mL) at 0 °C. After 1 min, the cold bath was removed and reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aq. sat. NaHC0 3 and extracted with DCM. The organic layer was washed with water, dried with (MgSC ⁇ ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane from 0/100 to 70/30). The desired fractions were collected and concentrated in vacuo yielding intermediate 4 (0.193 g, 45%).
- Method 1 TFA (4 mL, 53.3 mmol) was added to a mixture of intermediate 12 (1.71 g, 5.33 mmol, 75% pure) in 20 mL DCM at 0°C and then the mixture was stirred at rt for 150 min. Next, the mixture was diluted with DCM and washed with an aq. sat. sol. of NaHC0 3 . The org layer was separated, dried (MgS0 4 ), filtered and concentrated in vacuo to provide intermediate 13 (1.91 g, 53% pure, quantitative), which was used as such.
- Method 1 Formaldehyde (37% in water, 2.185 mL, 29.162 mmol) was added to a solution of intermediate 13 (obtained from method 1, 1.91 g, 9.721 mmol, 53% pure) in a mixture of acetic acid (0.835 mL) and MeOH (20 mL). Then NaBH 3 CN (1.83 g, 29.162 mmol) was added portion wise. The mixture was stirred at rt overnight (15 h). A sat. sol. of NaHC0 3 was added and the mixture was extracted with EtOAc. The org layers were dried over MgS0 4 , filtered and concentrated.
- the org layer was dried over MgS0 4 , filtered and the solvent was evaporated in vacuo.
- the crude product was purified by flash column chromatography (silica; DCM/MeOH, from 100/0 to 95/5). The desired fractions were collected and concentrated in vacuo. The product was further purified by reverse phase from 70%>
- Method 2 KF (10.2 g, 175.7 mmol) was added to intermediate 2 (obtained from method 2, 9.85 g, 35.14 mmol) in DMSO (236 mL). The resulting mixture was stirred for 16 h at 160 °C, after which LCMS showed full conversion. Water and DCM were added, the biphasic mixture was shaken, and then filtered over dicalite®. The org. layer was separated and the aq. layer extracted with DCM. The combined org layers were dried (MgS0 4 ), filtered and evaporated to dryness. The red-brown residue was purified by flash column chromatography over 120 g silica gel using a gradient
- Compound 3 can be also made alternatively from intermediate 20, for example, by formation of the corresponding methanesulfonate or 4-toluenesulfonate followed by displacement with a source of fluoride.
- the product was further purified by preparative HPLC (from 75% [25 mM NH 4 HC0 3 ] - 25% [ACN: MeOH 1 : 1] to 38% [25 mM NH 4 HC0 3 ] - 62% [ACN: MeOH 1 : 1]). The desired fractions were collected and the solvent was evaporated. The product was triturated with Et 2 0 and filtrated to yield compound 5 (0.042 g, 31%).
- K3PO4 (0.544 g, 2.565 mmol), Pd 2 (dba) 3 (0.049 g, 0.0534 mmol) and Xantphos (0.052 g, 0.0891 mmol) were added to a solution of intermediate 13 (0.168 g, 0.891 mmol) in THF (6 mL) while nitrogen was bubbling. After 10 min, isoquinolin-6-amine (0.128 g, 0.891 mmol) was added and the mixture was stirred at rt for 10 min. Then, the mixture was heated at 100 °C for 16 h.
- the crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo. The product was further purified by preparative HPLC (from 75%> [25 mM NH 4 HC0 3 ] - 25% [ACN: MeOH 1 : 1] to 0% [25 mM NH 4 HC0 3 ] - 100% [ACN: MeOH 1 : 1]). The desired fractions were collected and the solvent was evaporated. The crude was dissolved in DCM, HC1 (5 N in 2-propanol) was added and the mixture was concentrated in vacuo.
- the nonradioactive reference material for T808 was synthesized by Janssen Research & Development (a division of Janssen Pharmaceutica NV, Beerse, Belgium) following literature reports (Declercq L., Celen S., Lecina J. et al. Molecular Imaging 2016, 75,1- 151). All chemicals and reagents were purchased from commercial sources and used without further purification. HPLC analysis was performed on a LaChrom Elite HPLC system (Hitachi, Darmstadt, Germany) connected to a UV detector set at 254 nm.
- the HPLC eluate after passing through the UV- detector, was led over a 3 -inch Nal (Tl) scintillation detector connected to a single channel analyzer (GABI box; Raytest, Straubenhardt, Germany). Data were acquired and analyzed using GINA Star (Raytest) data acquisition systems.
- GINA Star Raytest
- the crude product was purified by HPLC method: Macherey + Nagel Nucleodur Gravity CI 8, 5 ⁇ , 8 x 150 mm column; mobile phase A: water with 0.1% TFA, B: acetonitrile with 0.1% TFA; isocratic at 27% B; flow rate 3.1 mL/min, 230 nm and 254 nm, 20 °C.
- HPLC the pH of the collected product fractions was set to neutral with an aqueous solution of NaHC03 (10%>). The volume of the mixture was reduced on a rotary evaporator. Then the product was extracted with a Phenomenex StrataX cartridge (3 mL, 100 mg), which was eluted with ethanol (5 mL).
- the product received was further purified by HPLC under basic conditions: Macherey + Nagel Nucleodur Sphinx RP, 5 ⁇ , 8 x 150 mm; mobile phase A: 10 mM NH 4 OAc with 0.05% NH 4 OH, B: acetonitrile; isocratic at 46.5% B; flow rate 3.1 mL/min, 230 nm and 254 nm, 20 °C.
- the volume of the collected product fractions was reduced on a rotary evaporator. Then the product was extracted with a Phenomenex StrataX cartridge (3 mL, 100 mg), which was eluted with ethanol (5 mL).
- the radiochemical purity of [ 3 H] Co. No. 1 was determined to be >99% by the following HPLC method: Column: Macherey + Nagel Nucleodur Sphinx RP (5 ⁇ ), 4.6 x 150 mm, Column temperature: 30°C, Mobile phase A: 10 mM NH 4 OAc with 0.05% v/v NH 4 OH in water, Mobile phase B: Acetonitrile, Flow rate: 1.0 mL/min, Injection volume: 5 ⁇ , Detection wavelength: UV at 254 nm, Elution gradient:
- the radioactivity flow detector was a Berthold LB 513 with Zinsser Quickszint Flow 302 cocktail at a flow rate of 3.0 mL/min.
- Fluoride-18 ([ 18 F]F ⁇ ) was produced by an 18 0(p,n) 18 F nuclear reaction in a Cyclone 18/9 cyclotron (Ion Beam Applications, Louvain-la-Neuve, Belgium) by irradiation of 2 mL of 97 % enriched 18 0-H 2 0 (Rotem HYOX18, Rotem Industries, Beer Sheva, Israel) with 18-MeV protons.
- the crude radiolabelling mixture was diluted with 0.6 mL preparative buffer (0.01 M Na 2 HP0 4 pH 7.4 and EtOH (60:40 v/v)) and purified using reverse phase HPLC (RP-HPLC) on an XBridge C 18 column (5 ⁇ , 4.6 mm x 150 mm; Waters, Milford, U.S.A.) eluted with a mixture of Na 2 HP0 4 pH 7.4 and EtOH (60:40 v/v) at a flow rate of 0.8 mL/min and with UV detection at 254 nm. [ 18 F]Co. No. 1 eluted at 27 min.
- the purified radiotracer solution was diluted with saline to obtain an ethanol concentration ⁇ 10%, suitable for intravenous injection.
- the solution was subsequently passed through a 0.22- ⁇ filter (Millex-GV, Millipore, Billerica, MA, U.S.A.) to obtain a sterile product.
- Quality control was performed using RP-HPLC on an XBridge column (C 18 , 3.5 ⁇ , 3.0 mm x 100 mm; Waters, Milford, U.S.A.) eluted with a mixture of 0.01 M Na 2 HP0 4 pH 7.4 and CH 3 N (68:32 v/v) at a flow rate of 0.8 mL/min.
- UV detection was performed at 254 nm. [ 18 F]Co. No. 1 eluted at 8 min.
- Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
- melting points were determined in open capillary tubes on a Mettler Toledo MP50. Melting points were measured with a temperature gradient of 10 °C/minute. Maximum temperature was 300 °C. The melting point data was read from a digital display and checked from a video recording system.
- HPLC High Performance Liquid Chromatography
- MS Mass Spectrometer
- tune parameters e.g. scanning range, dwell time. ..
- ions allowing the identification of the compound's nominal mono iso topic molecular weight (MW).
- Data acquisition was performed with appropriate software.
- Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] ⁇ (deprotonated molecule).
- CHN Carbon, Hydrogen and Nitrogen
- Enriched aggregated tau fractions were prepared according to a slightly modified version of the protocol described by Greenberg and Davies (Greenberg S.G., Davies P. A preparation of Alzheimer paired helical filaments that displays distinct T ⁇ proteins by polyacrylamide gel electrophoresis. Proc. Natl. Acad. Sci. 1990; 87: 5827-5831) using human AD brain tissue (occipital cortex with high tau fibril load). Briefly, frozen human AD brain samples ( ⁇ 10 g) were homogenized with 10 vol of cold
- homogenization buffer (10 mM Tris, 800 mM NaCl, 1 mM EGTA, 10 % sucrose, pH 7.4 containing PhosSTOP phosphatase and cOmplete EDTA-free protease inhibitor (Roche, Vilvoorde, Belgium)) on ice. After centrifugation at 27 000 x g for 20 min at 4 °C the supernatant was recovered and 1% (w/v) N-lauroylsarcosine and 1% (v/v) 2- mercaptoethanol were added. The N-lauroylsarcosine/2-mercaptoethanol supernatant was incubated for 2 h at 37 °C while shaking on an orbital shaker.
- Enriched aggregated ⁇ -amyloid preps were prepared from frozen human AD brain samples (10 g - occipital cortex with high amyloid plaques load) that were
- the competitive radioligand binding assays measure the binding of a radiolabeled reference ligand in the presence of a dose response concentration range of test compounds.
- aggregated tau preps were diluted to 100 ⁇ g protein/ml in PBS buffer with 5% ethanol.
- 3 H-T808 specific activity; 32.97 Ci/mmol
- Nonspecific binding was defined as the number of counts remaining in the presence of 50 ⁇ Thioflavin T (common beta sheet binder).
- the unbound ligand is removed by filtration of the binding mixtures over GF/B glass filters using a Filtermate 96 harvester instrument (Perkin Elmer, Zaventem, Belgium).
- the filters were washed three times with PBS buffer containing 20% ethanol. After overnight drying of the filter plate, Microscint O liquid (Perkin Elmer) was added and the amount of radiolabeled ligand bound to the fibrils is measured by liquid scintillation counting in a Topcount instrument (Packard Instrument Company, Connecticut, USA).
- IC 50 half-maximal inhibitory concentration
- [ 19 F]-Co. No. 1 showed potent binding (pICso 8.24, corresponding to a Ki of 2.4 nM) to extracted human tau using [ 3 H]-T808 and weak binding to extracted human amyloid- beta aggregates (pICso 5.18, corresponding to a Ki of 3.2 ⁇ ) using [ 3 H]-AV-45 in this radio label displacement assay.
- IMMU OHISTOCHEMIST Y (IHC): M&M HUMAN BRAIN
- Human AD brain blocks (Braak stage V-VI) were snap-frozen, sliced with a cryostat (20 ⁇ thickness) and stored at -80°C until used for immunohistochemistry. Slices were dried, fixed in formalin and incubated with hydrogen peroxide (DAKO, S2023) for 5 minutes and blocking reagent (PBSlx + 0.05% Triton X-100) during 1 hour.
- Anti- amyloid or anti-tau antibody [(4G8, Covance, SIG-38220), 1/500 dilution in antibody diluent with background reducing components (DAKO, S3022) or (AT8 (Bierna et al, EMBO J.
- AD slices were immunostained with anti-tau (AT8) and anti- ⁇ antibodies (4G8), to correlate with [ 18 F]Co. No. 1 binding.
- [ 3 H]-THK5351 also binds to AD tissue containing only ⁇ plaques (tau negative) and thus confirms the low selectivity of THK-5351 ( Figure 31, J).
- [ 3 H]-AV-45 (selective for ⁇ plaques) binds both tau and ⁇ pathology (Ap+/tau+, Tissue #28391) and ⁇ pathology only ( ⁇ +Ztau-, Tissue #92/050) human tissues as expected (Figure 3L-M).
- Figure 4 Tissue #92/050: Figure 5
- striatal tissue Figure 6
- a dynamic 120-min ⁇ scan with [ 18 F]Co. No.l or [ 18 F]T807 was acquired on a Focus 220 ⁇ scanner (Concorde Microsystems, Knoxville, TN, U.S.A.) on three female Wistar rats simultaneously. The rats were kept under gas anaesthesia during the whole procedure (2.5% isoflurane in 0 2 at 1 L/min flow rate). Scans were acquired in list mode and acquisition data were Fourier rebinned in 24 time frames (4 x 15 s, 4 x 60 s, 5 x 180 s, 8 x 300 s, 3 x 600 s).
- cold reference compound Co. No. 1 or T807 was dissolved in a mixture of 5% DMSO, 5% Tween 80 and 40% (2-hydroxypropyl)-P-cyclodextrin, filtered through a 0.22- ⁇ membrane filter (Millex-GV, Millipore) prior to injection.
- a dynamic 120-min ⁇ scan with [ 18 F]Co. No. 1 or [ 18 F]T807 was performed with a Focus 220 ⁇ scanner on a rhesus monkey (6 y-old male Macaca mulatta, 7.6 kg), that was sedated with ketamine (Ketalar ® ) and xylazine (Rompun ® ) via intramuscular (IM) injection.
- ketamine Ketalar ®
- Rompun ® xylazine
- IM intramuscular
- Scans were acquired in list mode and Fourier rebinned in 24 time frames (4 x 15 s, 4 x 60 s, 5 x 180 s, 8 x 300 s, 3 x 600 s). Data were reconstructed using a 3D maximum a posteriori (3D- MAP) iterative reconstruction. TACs of the whole brain were generated using VOIs with PMOD software. Radioactivity concentration in the brain is expressed as SUV as a function of time after tracer injection. Scans were started immediately after IV injection of 185 MBq of [ 18 F]Co. No. 1 or [ 18 F]T807 via the vena saphena of the right leg. For the pre-treatment study, cold reference compound Co. No.
- TACs and %SUV max results of the 120-min baseline scan of [ 18 F]Co. No. 1 and [ 18 F]T807 are shown in Figures 12-14 (TACs and %SUV max ).
- TACs of the baseline scan of [ 18 F]Co. No. 1 in the brain show high initial brain uptake (SUV value of ⁇ 5.4 in the total brain) with a rapid wash-out ( Figure 12).
- TACs of the baseline scan of [ 18 F]T807 in the brain show a slower initial brain uptake (SUV value of -1.3) and wash-out (Figure 13).
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