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Publication Number
US-12552800-B2
Publication Date
2026-02-17
Expiration Date
Abstract
The present invention relates to novel compounds of formula (I), or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, that can be employed in the imaging of alpha-synuclein aggregates and determining an amount thereof. Furthermore, the compounds can be used for diagnosing a disease, disorder or abnormality associated with an alpha-synuclein aggregates, including, but not limited to, Lewy bodies and/or Lewy neurites (such as Parkinson's disease), determining a predisposition to such a disease, disorder or abnormality, prognosing such a disease, disorder or abnormality, monitoring the evolution of the disease in a patient suffering from such a disease, disorder or abnormality, monitoring the progression of such a disease, disorder or abnormality and predicting responsiveness of a patient suffering from such a disease, disorder or abnormality to a treatment thereof.
Core Innovation
The invention provides compounds of formula (I), or detectably labelled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof. The compounds include an aryl or a heteroaryl that is directionally selected from specified ring variants defined by R0 and R1, together with further structural definitions for R2, Z, Z1, p, m, and the position of bonding marked by an asterisk. The disclosure includes halo, C1-C4 alkyl, C1-C4 alkoxy, and non-aromatic monocyclic heterocyclyl ring options containing 1 or 2 heteroatoms, each optionally substituted with at least one halo.
The detectably labelled embodiments include radiolabels such as 2H, 3H, and 18F, and the labelled compounds are tied to detection, imaging, and diagnostic use. Related compound classes are also defined by formulas (IV-F), (IV-H), and (IV-J), with explicit 19F and bromo, chloro, or iodo definitions and additional leaving-group-related embodiments where stated. The document further includes labelled and precursor-type compound relationships in radiopharmaceutical contexts.
The subject matter is framed for detection and/or diagnosis of a disease, disorder, or abnormality associated with alpha-synuclein aggregates. The disclosure also states imaging contexts, including positron emission tomography imaging of alpha-synuclein aggregates, and includes test kit and radiopharmaceutical preparation kit embodiments. The compounds are described as selective for alpha-synuclein aggregates and as supporting imaging and quantification in vivo, ex vivo, and in vitro.
Claims Coverage
The independent claims across the input items cover five inventive feature groups: formula (I) compounds with directionally selected aryl/heteroaryl substituents; detectably labelled formula (I) compounds, including 2H, 3H, and 18F embodiments; selected compounds from formulas (IV-F), (IV-H), and (IV-J) with defined 19F and halogen options; a test kit for detection and/or diagnosis associated with alpha-synuclein aggregates; and a kit for preparing a radiopharmaceutical preparation. The recurring inventive features are the constrained structural definitions for R0, R1, R2, Z, Z1, p, and m, together with the explicit detectably labelled and kit-based application contexts.
Directionally selected aryl or heteroaryl in formula (I)
A compound of formula (I), or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein an aryl or heteroaryl is directionally selected from defined R0 and R1 options and includes a 4- to 6-membered non-aromatic monocyclic heterocyclyl ring radical containing 1 or 2 heteroatoms optionally substituted with at least one halo.
Defined R2, Z, Z1, p, and m substituent framework
The compound of formula (I) wherein R2 is selected from defined options for R2a, R2a′, R2b, R2c, R2c′, R2d, and R2e; Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z1 is independently N, NH, O, or S; p is 0, 1 or 2; m is 0 or 1; and * is the position of bonding.
Detectably labelled compound of formula (I)
A detectably labelled compound of formula (I), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, with the same directionally selected aryl/heteroaryl and variable definitions as formula (I).
Detectably labelled compound with 2H, 3H, or 18F
The detectably labelled compound of formula (I) wherein the compound is labelled with 2H, 3H, or 18F.
Selected compounds of formulas (IV-F), (IV-H), and (IV-J)
A compound selected from the group consisting of a compound of formula (IV-F), a compound of formula (IV-H), and a compound of formula (IV-J), each with stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate options, and with fluorine defined as 19F and X defined as bromo, chloro, or iodo, with R6 comprising at least one X where stated.
Test kit for detection and/or diagnosis of alpha-synuclein aggregates
A test kit for the detection and/or diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates, wherein the test kit comprises at least one compound of formula (I) or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.
Kit for preparing a radiopharmaceutical preparation
A kit for preparing a radiopharmaceutical preparation that comprises at least one sealed vial containing at least one compound defined by the specified structural class.
Overall, the claim coverage centers on structurally constrained formula (I) compounds and related detectably labelled embodiments, expands to selected compound families (IV-F, IV-H, IV-J) with explicit 19F and halogen definitions, and includes kit claims for alpha-synuclein aggregate detection/diagnosis and radiopharmaceutical preparation.
Stated Advantages
Enables positron emission tomography imaging of alpha-synuclein aggregates.
Supports detection and/or diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates.
Selective binding to alpha-synuclein aggregates with high affinity and selectivity over other protein aggregates.
Supports imaging and quantification in vivo, ex vivo, and in vitro.
Addresses limitations of existing biomarkers by enabling selective brain-penetrant probes with suitable properties.
Documented Applications
Positron emission tomography (PET) imaging of alpha-synuclein aggregates.
Detection and/or diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates.
Imaging and quantification of alpha-synuclein aggregate pathology, including Lewy bodies and Lewy neurites.
Diagnosis and prognosis for a disease, disorder, or abnormality associated with alpha-synuclein aggregates.
Monitoring disease progression.
Predicting treatment responsiveness.
Radiopharmaceutical preparation using a kit comprising a sealed vial containing at least one compound defined in the specified structural class.
PET pharmacokinetics in a non-human primate using an 18F-labelled example.
An ongoing first-in-human PET study of 18F-Example-1.
Biological characterization using radiobinding assays and autoradiography with human brain-derived alpha-synuclein aggregates.
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