Receptor Occupancy

In vitro Receptor Autoradiogarphy, and In vivo/Ex vivo Receptor Occupancy

Tests used for CNS drug development such as receptor autoradiography, ex vivo and in vivo receptor occupancy (RO) offer a simple yet powerful way to:

  • Determine the tissue distributions of target of interest.
  • Obtain Ki values by displacement assay on brain slices. (Figure 1)
  • Monitor the interaction of drug candidates with their targets in the brain after peripheral administration to select best leads and eliminate inferior compounds. A drug candidate has to be potent and possess good ‘drug-like’ properties to achieve significant brain occupancy of its target. (Figure 2)
  • Better understand the pharmacokinetic and pharmacodynamic relationships of a drug candidate. Especially, ex vivo RO can be used to better understand the percentage of receptor occupancy required for behavioral efficacy. (Figure 2)

Beta-imaging technology, developed by Biospace, France, and used by scientists at PsychoGenics, significantly shortens the time needed for assessment of specific binding in the brain (hours versus weeks for tritiated ligands), which makes it possible to use ex vivo RO (an assay that could provide crucially important preclinical data for preclinical and clinical candidate selection) as a screening tool.

Receptor autoradiography to calculate Ki values on endogenously expressed receptors

PsychoGenics Publications

Click here for more validation data.

Figure 2. High correspondence between behaviorally active doses of sazetidine in the forced swim test (Fig 2A) and ɑ4β2 nicotinic acetylcholine receptor (nAChR) occupancy in the brain (Fig 2B). Specifically, sazetidine was inactive in the forced swim test at 0.3 mg/kg (i.p) and showed very low receptor occupancy at this dose (<10%). In contrast, doses of sazetidine (1 and 3 mg/kg, i.p.) that produced robust behavioral activity in the forced swim test, corresponded with high levels of occupancy at the ɑ4β2 nAChRs (~40% and ~90% respectively).

Currently, we have developed protocols for ex vivo receptor occupancy and receptor autoradiography studies for the following targets:

  • Nicotinic ɑ4ɑ2 acetylcholine receptor
  • Adenosine A1 and A2a receptors
  • Norepinephrine transporter
  • Dopamine transporter
  • Phosphodiesterase 4 (PDE4) enzyme
  • Serotonin receptors


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