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PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement.
PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement.
- Source :
-
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2024 Dec; Vol. 50 (2), pp. 372-377. Date of Electronic Publication: 2024 Oct 16. - Publication Year :
- 2024
-
Abstract
- Regulation of dopamine activity has important clinical consequences, most notably in schizophrenia. LB-102, N-methyl amisulpride, is a novel dopamine D <subscript>2/3</subscript> /5-HT <subscript>7</subscript> inhibitor being developed as a treatment for schizophrenia and other psychiatric disorders. The characteristic that is common to all current antipsychotics is their engagement of D <subscript>2</subscript> dopamine receptors. The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET) with <superscript>11</superscript> C raclopride as a radiotracer. Results of this study (NCT04588129) showed that steady-state once daily oral dosing of 50 mg LB-102 afforded striatal dopamine occupancy (RO) in the desired 60-80% range consistently over the course of 24 h. Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions. A similar phenomenon has recently been reported with a non-racemic version of amisulpride [1]. LB-102 was generally safe and well-tolerated at all doses. Results of this study were used to inform dosing in a subsequent Phase 2 clinical study in schizophrenia patients.<br />Competing Interests: Competing interests: VTG and MSH are consultants to, and shareholders of, LB Pharmaceuticals. AE, ZP, and ARV are employees and shareholders of LB Pharmaceuticals. DFW has WUSTL contracts with Eisai, Anavex, LB Pharma, Roche, Intracellular Technologies and is a paid consultant to Engrail Therapeutics and he and his CNAMI lab are supported by NIH (NIMH, NIDA, NIA, NIAAA) and the McDonnell Center for Systems Neuroscience at Washington University. GN has WUSTL contracts with COMPASS pathways, Usona Institute and Alkermes, Inc.; she has served as a paid consultant for Carelon, Novartis and Alkermes, Inc.; she and her staff in the Healthy Mind Lab are supported by research funding from the NIMH, the Health Resources and Services Administration (HRSA), the Patient Centered Outcomes Research Institute (PCORI); the Sidney R. Baer Jr. Foundation and the Barnes Jewish Hospital Foundation; the Institute for Clinical Translational Sciences, the Taylor Family Institute for Innovative Psychiatric Research, the Mallinckrodt Institute of Radiology and the McDonnell Center for Systems Neuroscience at Washington University. Gerhard Gründer is a paid consultant to LB Pharmaceuticals. GBC, NC, EL, HK, LT, IV, THS declare no conflict of interest.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Male
Adult
Female
Young Adult
Amisulpride pharmacology
Amisulpride administration & dosage
Raclopride
Dose-Response Relationship, Drug
Receptors, Dopamine D2 metabolism
Receptors, Dopamine D2 drug effects
Middle Aged
Corpus Striatum drug effects
Corpus Striatum metabolism
Corpus Striatum diagnostic imaging
Positron-Emission Tomography
Antipsychotic Agents pharmacology
Antipsychotic Agents administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1740-634X
- Volume :
- 50
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 39414986
- Full Text :
- https://doi.org/10.1038/s41386-024-01951-x