Compounds for imaging Tau protein aggregates
Inventors
Kroth, Heiko • MOLETTE, Jérôme • Schieferstein, Hanno • Müller, Andre • Schmitt-Willich, Heribert • Berndt, Mathias • Oden, Felix
Assignees
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Publication Number
US-10865207-B2
Publication Date
2020-12-15
Expiration Date
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.
Core Innovation
The invention relates to PET Tau-imaging using compounds of formula (I), together with pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs. The compounds are intended for selective detection of Tau aggregates in Alzheimer’s disease and non-AD tauopathies, and are framed for fluorinated labeling, including radiolabeled compounds.
The disclosed objective is to achieve high Tau affinity and selectivity with favorable pharmacokinetics and no in vivo defluorination. The compound scope includes embodiments where R1 is 18F, F, or a leaving group and R2 is H or a protecting group, and the document also describes diagnostic and monitoring methods based on binding to Tau aggregates and detection of the bound compound or compound-tau aggregate complex.
The document further describes PET imaging detection on body parts or body areas comprising the brain or the eye, and diagnostic data generation by correlating compound binding with the presence or absence of Tau aggregates. It also describes compositions, diagnostic kits, and sealed vial configurations for preparing radiopharmaceutical preparations.
Claims Coverage
The document includes three independent claims. The coverage focuses on formula (I) chemical entities with defined substituent constraints, leaving-group/protecting-group precursor variants, and associated diagnostic and monitoring use involving tau-aggregate binding and detection.
Fluorinated compound of formula (I) with R1 being 18F and R2 being H
A compound of the formula (I), together with pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is 18F and R2 is H.
Compound of formula (I) with R1 being F and R2 being H
A compound of the formula (I), together with pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof, wherein R1 is F and R2 is H.
Compound of formula (I) with a leaving group and protecting group framework
A compound of the formula (I), together with 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.
Diagnostic data by contacting suspected samples with a Tau-aggregate binding compound
A method for diagnosing a disorder associated with tau aggregates by contacting a suspected sample or body area with a specified compound, allowing the compound to bind to the tau aggregate, detecting the compound bound to the tau aggregate, collecting diagnostic data, and optionally correlating compound binding with the presence or absence of the tau aggregate.
Determining amount of tau aggregate via bound-compound measurement
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 aggregates using the compound, determining the amount of compound bound to the tau aggregates, and calculating the tau aggregate amount.
Monitoring residual disorder after medicament via tau-aggregate complex formation
A method for monitoring residual disorder in a patient with a disorder associated with tau aggregates after medicament treatment by contacting a suspected sample or body area with a tau-aggregate binding compound, detecting formation of a compound-tau aggregate complex, and collecting data related to presence or amount of tau aggregates versus a normal control, with optional correlation and optional comparison.
PET imaging detection on brain or eye
The detecting step uses positron emission tomography imaging, performed on a body part or body area comprising the brain or the eye.
Radiolabeling and optional deprotection for preparing the compound
A method for preparing a compound of formula (I) by reacting a compound of formula (I) with a [18F] fluorinating agent, where R1 is a leaving group and R2 is H or a protecting group, and optionally cleaving the protecting group PG if present.
Kit including a sealed vial with predetermined compound for radiopharmaceutical preparation
A kit for preparing a radiopharmaceutical preparation that includes a sealed vial containing a predetermined amount of a compound as defined where R1 is a leaving group and R2 is H or PG.
The claim set centers on defined formula (I) Tau-imaging compounds with specific R1/R2 constraints and on diagnostic and monitoring methods that detect compound binding or complex formation with Tau aggregates. The coverage also includes PET imaging detection, brain or eye contexts, radiolabeling-related preparation, and a kit with a sealed vial for radiopharmaceutical preparation.
Stated Advantages
High Tau affinity/selectivity with favorable pharmacokinetics.
No in vivo defluorination.
Addresses limitations of prior art Tau tracer 18F-1/AV-1451, including off-target binding to MAO-A, high basal ganglia signal, and reduced reliability in PSP and non-AD tauopathies.
Improved properties for 18F-4 versus prior art 18F-1 and 18F-2 and comparative examples.
Documented Applications
Diagnosing a disorder associated with tau aggregates using diagnostic data collected by detecting a compound bound to tau aggregates.
Determining the amount of tau aggregate in a tissue and/or body fluid by measuring the amount of compound bound to tau aggregates.
Monitoring residual disorder in a patient with a tau-aggregate-associated disorder after medicament treatment using detection of compound-tau aggregate complex formation and collecting data versus a normal control.
PET imaging detection using the defined compounds, including detection in the brain or the eye.
Imaging and diagnostic use in diagnostic compositions and diagnostic kits, including preparing radiopharmaceutical preparations using a sealed vial with a predetermined amount of compound.
Imaging and diagnostic correlation involving Tau aggregate presence or amount and collection of diagnostic data.
Tau binding competition assays in Alzheimer disease brain homogenate, with selectivity versus amyloid-beta and off-target binding evaluation versus MAO-A and MAO-B in control brain homogenates.
Autoradiography in human brain slices including AD, PSP, PiD, and healthy control.
PET pharmacokinetic evaluation in healthy mice.
An initial human imaging study using PET/CT showing robust brain uptake and differential Alzheimer disease pattern uptake for 18F-4.
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