Gamma-carboline compounds for the detection of Tau aggregates
Inventors
Berndt, Mathias • Müller, Andre • Oden, Felix • Schieferstein, Hanno • Schmitt-Willich, Heribert • Kroth, Heiko • MOLETTE, Jérôme
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11306089-B2
Publication Date
2022-04-19
Expiration Date
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.
Core Innovation
The invention relates to gamma-carboline Tau imaging agents and provides compounds of formula (II) and formula (III), as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof. The disclosed compounds include detectably labeled embodiments, including embodiments in which R1 is 18F, and are described as selective PET imaging agents for Tau aggregates in tauopathies.
The document describes brominated and fluorinated heteroaromatic compounds, including intermediates and final tracer candidates, formed in multi-step synthetic routes and then converted to 18F-radiolabeled candidates for evaluation. The compounds are positioned as 18F-labeled Tau binders intended for imaging Tau aggregates in a patient, with reported preclinical binding evaluation in human AD brain homogenate competition experiments.
The invention is described as aiming for higher Tau affinity and selectivity over amyloid-beta and MAO enzymes, with favorable pharmacokinetics characterized by low healthy-brain signal, fast washout, and low defluorination. Comparative tracer performance is described in terms of signal-to-noise behavior in healthy versus AD homogenates, and the background contrasts prior Tau tracer 18F-AV-1451 (T807) with stated limitations including MAO-A off-target binding, basal ganglia signal, and limited differentiation in PSP.
The document further describes diagnostic compositions, kit concepts, and imaging approaches in which Tau aggregates in a patient are imaged after administration of a diagnostically effective amount of the compound. The problem addressed is the need for Tau-aggregate imaging in connection with Tau-aggregate disorders and tauopathy, including Alzheimer disease (AD) and other Tau-aggregate associated conditions.
Claims Coverage
The independent claims are directed to two gamma-carboline compound families, formula (II) and formula (III), each covering multiple pharmaceutically acceptable derivative forms and substitution options. The claim set further includes PET imaging use with Tau aggregates in a patient and diagnosis of Tau-aggregate disorders or tauopathy.
Formula (II) gamma-carboline Tau imaging compound
A compound of formula (II) and pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is selected from 18F, F and LG, R2 is H or PG, PG is a protecting group, LG is a leaving group, and the hydrogen atoms are independently selected from 1H, 2H and 3H.
Formula (III) gamma-carboline Tau imaging compound
A compound of formula (III) and pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is selected from 18F, F and LG, R2 is H or PG, PG is a protecting group, LG is a leaving group, and the hydrogen atoms are independently selected from 1H, 2H and 3H.
Positron emission tomography diagnosis of Tau-aggregate disorders
A method for diagnosing a Tau-aggregate disorder or tauopathy using positron emission tomography by administering a diagnostically effective amount of a specified compound and imaging Tau aggregates in a patient.
The claims primarily cover gamma-carboline Tau imaging compound families defined by formula (II) and formula (III) with R1 selected from 18F, F and LG, R2 selected from H or PG, and independently selected hydrogen isotopes 1H, 2H and 3H. The claim coverage also applies such compounds to diagnosing Tau-aggregate disorders or tauopathy by PET imaging of Tau aggregates in a patient.
Stated Advantages
Higher Tau affinity and selectivity over amyloid-beta and MAO enzymes.
Low healthy-brain signal.
Fast washout.
Low defluorination.
Improved selectivity and signal-to-noise for 18F-2 versus prior 18F-1, as stated in the document.
Improved Tau properties for 18F-3 with reduced MAO-A affinity, as stated in the document.
Documented Applications
Selective PET imaging of Tau aggregates for diagnosis of a Tau-aggregate disorder or tauopathy by imaging Tau aggregates in a patient after administering a diagnostically effective amount of the compound.
Use for Tau-aggregate/tauopathy disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease (PiD), and corticobasal degeneration (CBD).
Detection and data-collection use in which a tau-aggregate-suspected sample or body site is contacted with a tau-aggregate-binding compound to form a compound/tau aggregate complex, with detection of the complex and optional comparison/correlation to assess patient predisposition or predict treatment responsiveness for tau-aggregate-associated disorders.
Interested in licensing this patent?