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Publication Number
US-12589087-B2
Publication Date
2026-03-31
Expiration Date
Abstract
Methods of use, pharmaceutical formulations, and labeled versions of compounds are provided of compounds that penetrate the blood-brain barrier and influence the balance of excitatory versus inhibitory neurotransmission by enantiomer selective modulation of glutamate and GABA metabolism. In some embodiments, a glutamatergic false neurotransmitter is S-2-methylglutamate (S-2MeGlu). In some embodiments a GABAergic false neurotransmitters is R-4 aminopentanomic acid (4APA) or S-4 aminopentanomic acid (S-4APA), with high penetration of the blood brain barrier and low toxicity, therein providing useful pharmacologic or imaging agents.
Core Innovation
The invention describes enantiomer-selective false neurotransmitters that penetrate the blood-brain barrier and alter the balance of excitatory to inhibitory neurotransmission. The approach uses stereoselective modulation within the GABA shunt or the glutamate-glutamine cycle, including glutamate-glutamine metabolism involving glutamine synthetase (GS) and glutaminase (GLS1). Specific enantiomers are used so that metabolism is modulated in an enantiomer-selective manner rather than without stereochemical selectivity.
The patent further describes glutamatergic false neurotransmitters and GABAergic false neurotransmitters to influence excitatory/inhibitory balance. A glutamatergic false neurotransmitter example is (S)-2-methylglutamate (S-2MeGlu), which is converted by glutamine synthetase to (S)-2-methylglutamine (S-2MeGln). For a GABAergic false neurotransmitter, (R)-4-aminopentanoic acid (R-4APA) and (S)-4-APA are described as replacing GABA in synaptosomes with minimal receptor activity.
The invention characterizes (R)-4APA as a GABAergic false neurotransmitter within the GABA shunt/glutamate-glutamine cycle framework to alter balance of excitatory to inhibitory neurotransmission. The described formulations and labeled compounds are stated as enabling pharmacologic treatment and PET molecular imaging, including radiolabeled PET imaging labels such as 18F, 11C, and 15O.
Claims Coverage
The partial independent-claim set provided covers a method of altering excitatory-to-inhibitory neurotransmission by administering an agent that provides enantiomeric selective metabolism modulation in the GABA shunt or the glutamate-glutamine cycle. Dependent claim refinements specify particular conditions, particular enantiomeric agents, a false neurotransmitter limitation, and a formulation option with an excipient.
Enantiomeric selective metabolism modulation in the GABA shunt or glutamate-glutamine cycle
Administering an effective dose of an agent that provides enantiomeric selective metabolism modulation in the GABA shunt or glutamate-glutamine cycle.
Altering excitatory to inhibitory neurotransmission balance
A method of altering balance of excitatory to inhibitory neurotransmission by administering an effective dose of an agent that provides enantiomeric selective metabolism modulation in the GABA shunt or glutamate-glutamine cycle.
Parkinson’s disease application of the metabolism-modulating method
The method is carried out where the individual has Parkinson’s disease.
Enantiomer-specific agent option: (S)-2-methylglutamate or (R)-4-aminopentanoic acid
The compound is either (S)-2-methylglutamate or (R)-4-aminopentanoic acid.
Enantiomer-specific agent option: enantiomer of 2-methylglutamine (2-MeGln)
The enantiomer of 2-methyl-glutamine (2-MeGln) is used as the agent.
False neurotransmitter functionality reducing glutaminergic neural activity
The agent is a false neurotransmitter to reduce glutaminergic neural activity.
Pharmaceutically acceptable formulation with effective dose and excipient
A pharmaceutically acceptable formulation includes an effective dose of an agent that modulates metabolism with enantiomeric selectivity in the GABA shunt or glutamate-glutamine cycle, together with a pharmaceutically acceptable excipient.
Across the provided claims, the core coverage is a method that alters excitatory-to-inhibitory neurotransmission by administering an effective dose of an enantiomerically selective metabolism-modulating agent targeting the GABA shunt or the glutamate-glutamine cycle, with dependent refinements specifying Parkinson’s disease use, false neurotransmitter functionality, particular enantiomeric agents, and a pharmaceutically acceptable formulation including an excipient.
Stated Advantages
The described approach alters the balance of excitatory to inhibitory neurotransmission.
The document states minimal receptor activity for the GABAergic false neurotransmitters in synaptosomes.
The described formulations and labeled compounds enable pharmacologic treatment and PET molecular imaging.
Enables enantiomer-specific functional effects in vivo, including greater displacement of endogenous GABA and greater GABA release upon high-K potassium-induced release for (R)-4APA compared with (S)-4APA.
Provides stable brain concentrations for both 4APA enantiomers up to about 6 hr after IP dosing, with rapid serum clearance.
Supports a GABAergic false neurotransmitter concept positioned to alter excitatory-inhibitory (E-I) balance.
Shows behavior effects with no mortality and dose-dependent reduction in locomotion and exploration, with longer-lasting effects for (R)-4APA.
Documented Applications
Epilepsy
Autism
Mood disorders
Psychosis
Alzheimer’s disease
Parkinson’s disease
PET molecular imaging
Diagnostic/therapeutic/imaging uses related to excitatory-inhibitory (E-I) balance in diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD).
Downstream disease-model efficacy summaries for S-2MeGlu in PD and AD models and for R-4APA in PD models.
Initial PET imaging results using radiolabeled C-2MeGlu (described as radiolabeled 2MeGlu).
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