Ace Therapeutics provides custom-developed receptor occupancy analyses based on customer-defined parameters to determine the binding of anti-psychotic drugs to their specific targets.

Introduction of In Vivo and Ex Vivo Receptor Occupancy Assay

The number of receptors occupied by a drug is a central structure for understanding drug action in the brain. An important feature of antipsychotic drugs is the occupancy of dopamine (DA) D2 receptors. Measurement of target occupancy has been a key factor in assessing the target engagement of antipsychotic drugs. Therefore, the detection of in vivo and ex vivo receptor occupancy is important for assessing new drug targets for disorders such as negative symptoms/cognitive impairment in schizophrenia and refractory depression.

Fig. 1 In vivo binding of glucocorticoid receptor (GR) on promoter regions of miR-218a-1, -2, Slit2, Slit3. (Yoshino Y, et al., 2022)

Receptor Occupancy Assay Services

Ace Therapeutics uses two approaches to measure the occupancy of drug receptors in vivo and ex vivo. In one approach, the drug and radioligand used to measure occupancy compete in vivo. In the other method, the drug is injected into a live animal, the animal is killed, and the radioligand competes for available receptors ex vivo.

For in vivo receptor occupancy, we use liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and can use single or multiple tracers simultaneously in the same animal.

For ex vivo receptor occupancy, we perform ex vivo receptor occupancy studies using DMPK and/or behavioral assays, thus providing a valuable link between ex vivo activity, drug exposure at the site of interest, and in vivo efficacy. We offer three types of ex vivo radioligand binding assays: competition, saturation, and kinetics. All of these can be performed in recombinant cell lines or using natural tissues from rat and mouse brains (in membrane preparations or tissue sections).

Our services can be used to determine

• Central receptor occupancy for a range of drug doses
• Occupancy in different brain regions of the same animal
• Occupancy of the same animal on a range of targets
• Time course of occupancy

What Can We Help You Achieve in Psychiatry?

• Assessing the biodistribution and target engagement of antipsychotic drugs in animal brain
• Analysis of binding sites associated with adverse side effects of antipsychotics
• Investigating the relationship between the dose of antipsychotics and 5-hydroxytryptamine transporter occupancy
• Providing mechanistic insights related to the potential emergence of withdrawal symptoms in antidepressant treatment
• Investigating the relationship between psychiatric-related visuospatial memory performance and serotonin transporter protein (5-HTT) occupancy
• Better understanding of the pharmacokinetic and pharmacodynamic relationships of drug candidates (PK/PD)
• Understanding the percentage of receptor occupancy required for behavioral efficacy

Ace Therapeutics has expertise in designing custom studies to meet the precise needs of our clients by developing new assays using custom-synthesized radioligands. We are dedicated to improving anti-psychotic drug discovery lead optimization process protocols by assaying receptor occupancy that determines target engagement levels. If you are interested in this service please make an inquiry to learn how we can support you in your project.

Reference

1. Yoshino Y, Roy B, Dwivedi Y. Corticosterone-mediated regulation and functions of miR-218-5p in rat brain. Sci Rep. 2022, 12(1):194.