Chemical compounds derived from normemantine and use of same in the medical field
Inventors
Guerret, Olivier • Dufour, Samuel • BELHADJ-TAHAR, Hafid
Assignees
Melchior Investissements Et Industries • Rest Therapeutics SAS
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Publication Number
US-9714212-B2
Publication Date
2017-07-25
Expiration Date
Abstract
The present invention concerns novel chemical compounds corresponding to formulae (I) and (II): (I) (II) which, when marked with fluorine-18, can be used as markers of NMDA receptors for carrying out studies with a scanner.
Core Innovation
The invention relates to memantine-derived fluoroethyl normemantine compounds for labeling NMDA receptors, including compounds of formula (I) and salts of formula (II). The compounds are defined with a counteranion X that indicates a counteranion from a biological environment or is selected from specified counteranions.
The invention further provides use of fluorine-18 (18F) in PET for locating 18F atoms and evaluating NMDA receptor behavior. The disclosed compounds are described as memantine-derived, and the document presents data supporting favorable properties relevant to in vivo evaluation, including water solubility and lipophilicity.
The document also describes methods and use cases for studying or assessing neurological and psychiatric disorders by administering the claimed compounds to a mammal or subject and using a positron emission scanner to locate 18F atoms. The neurological disease list explicitly includes Alzheimer’s disease, schizophrenia, Parkinson’s disease, Huntington’s disease, epilepsy, and perinatal ischemia.
Additionally, the document presents compound-related structures and precursor compounds P1 and P2 leading to compounds I and II, and includes characterization and comparative binding-related measurements. The reported characterization includes non-toxicity in mice at a high dose, and relative NMDA receptor affinity/inhibition comparisons with reference compounds including MK-801 (dizocilpine) and memantine.
Claims Coverage
The claims cover two main inventive features: counteranion-defined memantine-derived compounds of formula (I) and salts of formula (II), and administration of compounds (I), (II), (P1) or (P2) for selected neurological diseases. The scope also includes 18F-labeled aqueous injectable composition and PET-based evaluation of NMDA receptor behavior.
Counteranion-defined compound of formula (I) or salt of formula (II)
A chemical compound of formula (I), or a salt thereof of formula (II), wherein X indicates a counteranion from a biological environment or is selected from chloride, bromide, iodide, acetate, methane sulphonate, benzene sulphonate, camphosulphonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, or tosylate.
Fluorine-18 labeled aqueous intravenously injectable composition
An aqueous solution containing at least one compound of claim 1, wherein the fluorine atom is the radioisotope fluorine-18 (18F), the aqueous solution being injectable intravenously.
PET evaluation of NMDA receptor behavior using a positron emission scanner to locate 18F atoms
A method evaluates the behavior of NMDA receptors in a mammal with a neurological disease by injecting the mammal with a compound of claim 1 or 2 and using a positron emission scanner to locate fluorine-18 (18F) atoms.
Administration of formula (I)/(II) and precursors P1/P2 for treating specified neurological diseases
A method for treating a neurological disease selected from Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, epilepsy and perinatal ischemia in a subject in need thereof comprising the administration of at least one compound selected from compounds (I), (II), (P1) or (P2) to the said subject, wherein X indicates a counteranion from the biological environment or is selected from chloride, bromide, iodide, acetate, methane sulphonate, benzene sulphonate, camphosulphonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, or tosylate.
Overall, the claim scope centers on counteranion-defined formula (I) and formula (II) compounds, including 18F labeling for PET-based NMDA receptor evaluation, and on administering compounds (I), (II), and precursors (P1)/(P2) for treating a specified list of neurological diseases.
Stated Advantages
High water solubility.
Non-toxicity in mice at a high dose.
Favorable lipophilicity (logP).
In vivo biodistribution with brain uptake reported as about 12%ID at 3 min.
Reported brain/blood ratio of about 6.015 at 60 min.
Relative NMDA receptor affinity/inhibition data are reported, including IC50 comparisons versus MK-801 and memantine.
Documented Applications
PET-based labeling/evaluation of NMDA receptor behavior in a mammal with a neurological disease by injecting a compound and using a positron emission scanner to locate 18F atoms.
Treating a neurological disease selected from Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, epilepsy, and perinatal ischemia by administering at least one compound selected from compounds (I), (II), (P1), or (P2).
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