Compounds for imaging Tau protein aggregates
Inventors
Kroth, Heiko • MOLETTE, Jérôme • Darmency, Vincent • Schieferstein, Hanno • Müller, Andre • Schmitt-Willich, Heribert • Berndt, Mathias • Oden, Felix • Gabellieri, Emanuele
Assignees
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Publication Number
US-10835624-B2
Publication Date
2020-11-17
Expiration Date
Abstract
The present invention relates to novel compounds of the formula (II) 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 disclosure relates to novel Tau-aggregate imaging compounds of formula (II) for positron emission tomography (PET). The compounds are defined with substituents R1 and R2, including isotope-labeled variants in which R1 includes 18F, and the invention includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs.
The disclosure frames the invention as addressing limitations of reported Tau tracers, including off-target binding and non-specific brain signal, as well as reduced reliability in non-AD tauopathies. The preferred 18F-labeled compounds show improved properties for Tau aggregate imaging across tauopathies, including affinity/selectivity for Tau aggregates/isoforms associated with 3R and 4R tauopathies.
The document further states low affinity for amyloid-beta and MAO-A, reduced background and detection limit due to low signal in healthy brain, good brain uptake with fast washout, low long-term retention, and no in vivo defluorination. The provided figure descriptions include autoradiography results, washout curves, and human PET imaging in controls, AD, and PSP.
Claims Coverage
The partial content contains three independent claims. Together, they cover specific formula (II) Tau-aggregate imaging compounds with defined R1/R2 substituent constraints, including pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs.
18F at R1 with hydrogen at R2 in formula (II)
A compound according to formula (II), as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is 18F and R2 is H.
Fluorine at R1 with hydrogen at R2 in formula (II)
A compound according to formula (II), as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is F and R2 is H.
Leaving group at R1 and hydrogen or protecting group at R2 in formula (II)
A compound according to formula (II), as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is LG; R2 is H or PG; wherein PG is a protecting group and wherein LG is nitro, halogen or trimethyl ammonium.
Diagnostic composition containing the 18F-labeled compound with pharmaceutically acceptable carriers
A diagnostic composition that includes the compound of formula (II) with R1 as 18F and R2 as H, optionally together with a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.
Tau-aggregate disorder diagnosis via binding, detection, and diagnostic data acquisition
A method for diagnosing a disorder associated with tau aggregates by contacting a patient sample or body part with the specified compound, allowing binding to tau aggregates, detecting the bound compound, collecting diagnostic data, and optionally correlating binding with the presence or absence of tau aggregates.
Quantifying tau aggregates by determining bound compound and calculating tau aggregate amount
A method for determining the amount of tau aggregate in a tissue and/or body fluid by contacting a representative sample with the specified compound, testing for tau aggregate, determining how much compound is bound to it, and calculating the tau aggregate amount.
Positron emission tomography imaging as the detection modality
The detecting step is performed using positron emission tomography imaging.
Radiolabeling preparation using an [18F]fluorinating agent with LG selection and protecting-group handling
A method for preparing a compound defined in the claims by reacting a compound of formula (II) with an [18F]fluorinating agent, where R1 is an LG selected from nitro, halogen, or trimethyl ammonium and R2 is H or a protecting group (PG), and further cleaving the protecting group PG if present.
Claim coverage is centered on formula (II) Tau-aggregate imaging compounds with defined R1 and R2 constraints, together with salts, hydrates, solvates, prodrugs, and polymorphs, plus diagnostic composition, radiolabeling preparation, and tau-aggregate diagnostic and quantification workflows using PET.
Stated Advantages
High tau binding in AD brain homogenate for 18F-1, 18F-2, and 18F-3a.
Strong AD versus healthy control signal-to-noise, with best performance reported for 18F-3a.
Low affinity to amyloid-beta.
Reduced off-target MAO A/B affinity for 18F-3a.
No de-fluorination and superior Tau-PET tracer characteristics for 18F-3a versus comparative regioisomers.
Improved affinity/selectivity for Tau aggregates/isoforms associated with 3R and 4R tauopathies.
Low affinity for amyloid-beta and MAO-A.
Reduced background and detection limit due to low signal in healthy brain.
Good brain uptake with fast washout.
Low long-term retention.
No in vivo defluorination.
Documented Applications
Tau-PET tracer performance evaluation using Tau binding in AD brain homogenate versus healthy control brain homogenate.
Mouse PET/CT uptake and washout observations.
Human dynamic PET observations in AD/PSP and non-demented controls.
Imaging and diagnosis using the specified compounds for disorders associated with tau aggregates, with diagnostic data optionally correlated with the presence or absence of tau aggregates.
Determining the amount of tau aggregate in tissue and/or body fluid by contacting a representative sample with a compound, testing for tau aggregate, determining how much compound is bound, and calculating the tau aggregate amount.
Positron emission tomography imaging for the detecting step in the diagnostic method.
Human PET imaging in controls, AD, and PSP (progressive supranuclear palsy) as described in the figure descriptions.
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