# US 10,865,207 B2 · Compounds for imaging Tau protein aggregates

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- Number: US 10,865,207 B2
- Document ID: US10865207B2
- Status: Granted
- Kind: B2
- Application number: 16/319,808
- Filed: 2017-07-21
- Published: 2019-08-29
- Granted: 2020-12-15
- Earliest claimed: 2016-07-22
- Assignees: AC Immune SA; Life Molecular Imaging SA
- Applicants: Ac Immune S.A.; Life Molecular Imaging SA
- Inventors: Heiko Kroth; Jérôme Molette; Hanno Schieferstein; Andre Müller; Heribert Schmitt-Willich; Mathias Berndt; Felix Oden
- Web page: https://patentgrep.com/patent/US10865207B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- C07B 59/002: {Heterocyclic compounds}
- G01N 33/60: involving radioactive labelled substances
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- G01N 2800/2821: Alzheimer
- G01N 2800/2835: Movement disorders, e.g. Parkinson, Huntington, Tourette
- G01N 2800/7047: Fibrils-Filaments-Plaque formation
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to novel compounds of the formula (I) 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 (I)
as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;
wherein R1 is 18F and R2 is H.

### Claim 2

A compound of the formula (I)
as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof; wherein R1 is F and R2 is H.

### Claim 3

A compound of the formula (I)
as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof;
R1 is LG, wherein LG is nitro, halogen or trimethyl ammonium;
R2 is H or PG;
PG is a protecting group;
LG is a leaving group.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein PG is tert-butyloxycarbonyl (BOC), triphenylmethyl (Trityl) or dimethoxytrityl (DMT).

### Claim 5 (depends on 2)

The compound according to claim 2, wherein the compound is detectably labeled with 2H, 3H.

### Claim 6 (depends on 1)

A diagnostic composition comprising a compound as defined in claim 1 and optionally a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

### Claim 7 (depends on 1)

A method of preparing a compound as defined in claim 1 comprising reacting a compound of the formula (I)
wherein R1 is a leaving group (LG) and R2 is H or protecting group (PG), with a [18F]fluorinating agent, wherein the method further comprises cleaving of the protecting group PG, if present.

### Claim 8 (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.

### Claim 9 (depends on 5)

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 5;
(b) allowing the compound to bind to the tau aggregate;
(c) detecting the compound bound to the tau aggregate; and
(d) collecting data for the diagnosis of the disorder associated with tau aggregates in the sample or the specific body part or body area;
(e) 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 10 (depends on 5)

A method of determining the amount of tau aggregate in a tissue and/or a body fluid comprising:
(a) providing a sample representative of the tissue and/or body fluid under investigation;
(b) bringing the sample into contact with a compound as defined in claim 5;
(c) testing the sample for the presence of tau aggregate with the compound;
(d) determining the amount of compound bound to the tau aggregate; and
(e) calculating the amount of tau aggregate in the tissue and/or body fluid.

### Claim 11 (depends on 5)

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 5 to a tau aggregate in a sample or in situ which comprises the steps of:
(a) bringing the sample or a specific body part or body area suspected to contain the tau aggregate into contact with the compound as defined in claim 5, 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) collecting data for determining the predisposition to the disorder associated with tau aggregates in the patient;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 12 (depends on 5)

A method of collecting data for monitoring residual disorder in a patient suffering from a disorder associated with tau aggregates who has been treated with a medicament, wherein the method comprises:
(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 5, 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) collecting data for monitoring residual disorder in the patient suffering from the disorder associated with tau aggregates who has been treated with the medicament;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 13 (depends on 5)

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 comprising:
(a) bringing a sample or a specific body part or body area suspected to contain an tau aggregate into contact with a compound as defined in claim 5, 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) collecting data for predicting responsiveness of the patient suffering from the disorder associated with tau aggregates and being treated with the medicament;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 14 (depends on 9)

The method of claim 9, wherein the disorder associated with tau aggregates is a tauopathy, 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, 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, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, certain prion diseases (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 (Dutch type), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, 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, and lattice dystrophy, or atypical parkinsonism.

### Claim 15 (depends on 14)

The method of claim 14, wherein the tauopathy is a 3R tauopathy or a 4R tauopathy.

### Claim 16 (depends on 9)

The method of claim 9, wherein the body part or body area comprises the brain or the eye.

### Claim 17 (depends on 9)

The method of claim 9, wherein the detecting comprises positron emission tomography imaging.

### Claim 18 (depends on 1)

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 1;
(b) allowing the compound to bind to the tau aggregate;
(c) detecting the compound bound to the tau aggregate; and
(d) collecting data for the diagnosis of the disorder associated with tau aggregates in the sample or the specific body part or body area;
(e) 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 19 (depends on 1)

A method of determining the amount of tau aggregate in a tissue and/or a body fluid comprising:
(a) providing a sample representative of the tissue and/or body fluid under investigation;
(b) bringing the sample into contact with a compound as defined in claim 1;
(c) testing the sample for the presence of tau aggregate with the compound;
(d) determining the amount of compound bound to the tau aggregate; and
(e) calculating the amount of tau aggregate in the tissue and/or body fluid.

### Claim 20 (depends on 1)

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 1 to a tau aggregate in a sample or in situ which comprises the steps of:
(a) bringing the sample or a specific body part or body area suspected to contain the tau aggregate into contact with the compound as defined in claim 1, 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) collecting data for determining the predisposition to the disorder associated with tau aggregates in the patient;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 21 (depends on 1)

A method of collecting data for monitoring residual disorder in a patient suffering from a disorder associated with tau aggregates who has been treated with a medicament, wherein the method comprises:
(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 1, 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) collecting data for monitoring residual disorder in the patient suffering from the disorder associated with tau aggregates who has been treated with the medicament;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 22 (depends on 1)

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 comprising:
(a) bringing a sample or a specific body part or body area suspected to contain an tau aggregate into contact with a compound as defined in claim 1, 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) collecting data for predicting responsiveness of the patient suffering from the disorder associated with tau aggregates and being treated with the medicament;
(e) 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
(f) optionally comparing the amount of the compound/tau aggregate to a normal control value.

### Claim 23 (depends on 22)

The method of claim 22, wherein the disorder associated with tau aggregates is a tauopathy, 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, 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, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, postencephalitic Parkinsonism, myotonic dystrophy, Tau panencephalopathy, AD-like with astrocytes, certain prion diseases (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 (Dutch type), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, 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, and lattice dystrophy, or atypical parkinsonism.

### Claim 24 (depends on 23)

The method of claim 23, wherein the tauopathy is a 3R tauopathy or a 4R tauopathy.

### Claim 25 (depends on 18)

The method of claim 18, wherein the body part or body area comprises the brain or the eye.

### Claim 26 (depends on 18)

The method of claim 18, wherein the detecting comprises positron emission tomography imaging.