# US 11,306,089 B2 · Gamma-carboline compounds for the detection of Tau aggregates > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,306,089 B2 - Document ID: US11306089B2 - Status: Granted - Kind: B2 - Application number: 16/964,952 - Filed: 2019-01-22 - Published: 2021-02-18 - Granted: 2022-04-19 - Earliest claimed: 2018-01-24 - Assignees: Life Molecular Imaging SA - Applicants: Ac Immune SA; Life Molecular Imaging SA - Inventors: Mathias Berndt; Andre Müller; Felix Oden; Hanno Schieferstein; Heribert Schmitt-Willich; Heiko Kroth; Jérôme Molette - Web page: https://patentgrep.com/patent/US11306089B2 ## CPC - C07D 471/04: Ortho-condensed systems - A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom} - C07B 59/002: {Heterocyclic compounds} - C07D 513/14: Ortho-condensed systems - C07B 2200/05: Isotopically modified compounds, e.g. labelled - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The present invention relates to novel compounds of the formula (II) and formula (III) that can be employed in the selective Tau detection of disorders and abnormalities associated with Tau aggregates such as Alzheimer's disease and other tauopathies using Positron Emission Tomography (PET) Imaging. ## Claims ### Claim 1 A compound of the formula (II) as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; wherein R1 is selected from the group consisting of 18F, F and LG; R2 is H or PG; PG is a protecting group; LG is a leaving group, wherein the hydrogen in formula II are independently selected from 1H, 2H and 3H. ### Claim 2 (depends on 1) The compound according to claim 1, which is ### Claim 3 A compound of the formula (III) as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; wherein R1 is selected from the group consisting of 18F, F and LG; R2 is H or PG; PG is a protecting group; LG is a leaving group, wherein the hydrogen in the formula III are independently selected from 1H, 2H and 3H. ### Claim 4 (depends on 3) The compound according to claim 3, which is ### Claim 5 (depends on 1) The compound according to claim 1, wherein R1 is 18F and R2 is H, R1 is F and R2 is H, or R1 is LG and R2 is H or PG. ### Claim 6 (depends on 1) The compound according to claim 1, wherein LG is nitro, halogen or trimethyl ammonium. ### Claim 7 (depends on 1) The compound according to claim 1, wherein PG is tert-butyloxycarbonyl (BOC), triphenylmethyl (Trityl) or dimethoxytrityl (DMT). ### Claim 8 (depends on 1) The compound according to claim 1, wherein R1 is 18F and/or the compound contains at least one 3H. ### Claim 9 (depends on 8) A diagnostic composition comprising a compound as defined in claim 8 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. ### Claim 10 (depends on 8) A method of imaging Tau aggregates by positron emission tomography, comprising administering a diagnostically effective amount of a compound as defined in claim 8 to a patient and imaging Tau aggregates in the patient. ### Claim 11 (depends on 8) A method of diagnosing a disorder associated with Tau aggregates or a tauopathy by positron emission tomography, comprising administering a diagnostically effective amount of a compound as defined in claim 8 to a patient and imaging Tau aggregates in the patient. ### Claim 12 (depends on 11) The method according to claim 11, wherein the disorder is selected from Alzheimer's disease (AD), familial AD, Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, GSS with Tau, mutations in LRRK2, chronic traumatic encephalopathy, familial British dementia, familial Danish dementia, frontotemporal lobar degeneration, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, traumatic stress syndrome, epilepsy, Lewy body dementia (LBD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, atypical parkinsonism, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration, optic nerve drusen, optic neuropathy, optic neuritis, lattice dystrophy, Huntington's disease, ischemic stroke and psychosis in AD. ### Claim 13 (depends on 5) An in vitro screening tool, which comprises a compound according to claim 5 wherein R1 is F and R2 is H. ### Claim 14 (depends on 5) A method of preparing a compound as defined in claim 5 wherein R1 is 18F and R2 is H, the method comprising reacting a compound as defined in claim 5 wherein R1 is LG and R2 is H or PG with a [18F]fluorinating agent, wherein the method further comprises cleaving of the protecting group PG, if present. ### Claim 15 (depends on 5) A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of a compound as defined in claim 5, wherein R1 is LG and R2 is H or PG. ### Claim 16 (depends on 8) A method of collecting data for the diagnosis of a disorder associated with tau aggregates in a sample or a patient comprising: (a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with a compound as defined in claim 8; (b) allowing the compound to bind to the tau aggregate; (c) detecting the compound bound to the tau aggregate; and (d) optionally correlating the presence or absence of compound binding with the tau aggregate with the presence or absence of tau aggregate in the sample or specific body part or body area. ### Claim 17 (depends on 8) A method which comprises the steps of: (a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with the compound as defined in claim 8, which compound specifically binds to the tau aggregate; (b) allowing the compound to bind to the tau aggregate to form a compound/tau aggregate complex; (c) detecting the formation of the compound/tau aggregate complex; (d) optionally correlating the presence or absence of the compound/tau aggregate complex with the presence or absence of tau aggregate in the sample or specific body part or body area; and (e) optionally comparing the amount of the compound/tau aggregate to a normal control value wherein the method is a method of collecting data for determining a predisposition to a disorder associated with tau aggregates in a patient comprising detecting the specific binding of a compound as defined in claim 8 to a tau aggregate in a sample or in situ, or a method of collecting data for predicting responsiveness of a patient suffering from a disorder associated with tau aggregates and being treated with a medicament. ### Claim 18 (depends on 3) The compound according to claim 3, wherein R1 is 18F and/or the compound contains at least one 3H. ### Claim 19 (depends on 18) The compound according to claim 18, wherein R1 is 18F. ### Claim 20 (depends on 18) A diagnostic composition comprising a compound as defined in claim 18 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. ### Claim 21 (depends on 18) A method of imaging Tau aggregates, which comprises administering a diagnostically effective amount of a compound as defined in claim 18 to a patient and the imaging the Tau aggregates in the patient. ### Claim 22 (depends on 18) A method of diagnosing a disorder associated with Tau aggregates or a tauopathy, which comprises administering a diagnostically effective amount of a compound as defined in claim 18 to a patient and imaging the Tau aggregates in the patient. ### Claim 23 (depends on 22) The method according to claim 22, wherein the disorder is selected from Alzheimer's disease (AD), familial AD, Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Sträussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, GSS with Tau, mutations in LRRK2, chronic traumatic encephalopathy, familial British dementia, familial Danish dementia, frontotemporal lobar degeneration, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, traumatic stress syndrome, epilepsy, Lewy body dementia (LBD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, atypical parkinsonism, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidosis, primary retinal degeneration, macular degeneration, optic nerve drusen, optic neuropathy, optic neuritis, lattice dystrophy, Huntington's disease, ischemic stroke and psychosis in AD. ### Claim 24 (depends on 23) The method according to claim 23, wherein the disorder is Alzheimer's disease (AD). ### Claim 25 (depends on 3) An in vitro screening tool, which comprises a compound according to claim 3 wherein R1 is F and R2 is H. ### Claim 26 (depends on 3, 4) A method of preparing a compound as defined in claim 3 wherein R1 is 18F and R2 is H, the method comprising reacting a compound as defined in claim 4 wherein R1 is LG and R2 is H or PG with a [18F]fluorinating agent, wherein the method further comprises cleaving of the protecting group PG, if present. ### Claim 27 (depends on 3) A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed vial containing a predetermined quantity of a compound as defined in claim 3, wherein R1 is LG and R2 is H or PG. ### Claim 28 (depends on 18) A method of collecting data for the diagnosis of a disorder associated with tau aggregates in a sample or a patient comprising: (a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with a compound as defined in claim 18; (b) allowing the compound to bind to the tau aggregate; (c) detecting the compound bound to the tau aggregate; and (d) optionally correlating the presence or absence of compound binding with the tau aggregate with the presence or absence of tau aggregate in the sample or specific body part or body area. ### Claim 29 (depends on 18) A method which comprises the steps of: (a) bringing a sample or a specific body part or body area suspected to contain a tau aggregate into contact with the compound as defined in claim 18, which compound specifically binds to the tau aggregate; (b) allowing the compound to bind to the tau aggregate to form a compound/tau aggregate complex; (c) detecting the formation of the compound/tau aggregate complex; (d) optionally correlating the presence or absence of the compound/tau aggregate complex with the presence or absence of tau aggregate in the sample or specific body part or body area; and (e) optionally comparing the amount of the compound/tau aggregate to a normal control value wherein the method is a method of collecting data for determining a predisposition to a disorder associated with tau aggregates in a patient comprising detecting the specific binding of a compound as defined in claim 18 to a tau aggregate in a sample or in situ, or a method of collecting data for predicting responsiveness of a patient suffering from a disorder associated with tau aggregates and being treated with a medicament. ### Claim 30 (depends on 8) The compound according to claim 8, wherein R1 is 18F. ### Claim 31 (depends on 12) The method according to claim 12, wherein the disorder is Alzheimer's disease (AD).