Receptor Occupancy & Animal PET

Occupancy studies are used to determine the effective dose and concentration needed to reach therapeutic drug levels in a given tissue.

in vivo Occupancy and Animal PET

in vivo occupancy studies are used to determine the actual level of receptor occupancy achieved by a given dose of a test drug. Animals are first dosed with the test compound and following a period for absorption a trace amount of radiolabeled test compound is administered to the animal. Radiolabeled compounds are detected and their level of receptor occupancy quantified via small animal PET or by dissecting out brain regions and direct counting in a gamma counter.

ex vivo occupancy determinations

ex vivo receptor occupancy studies can also be used to determine the percentage of receptor occupancy needed to reach behavioral or therapeutic efficacy. For drugs with a high affinity to their targeted receptor, the unlabeled test drug is administered to the animal. Receptor occupancy is subsequently measured in vitro immediately following sacrifice of the animal using in vitro autoradiography. A short non-equilibrium incubation time in the radiotracer is used to avoid appreciable dissociation of the unlabeled test drug before the termination of the assay. For drugs with a lower affinity for their target receptor an ex vivo estimate of receptor occupancy can be obtained by using custom-designed assays. In this approach a small amount of radiotracer is placed directly over brain sections from the drug-treated tissue section. Escape of the drug from the section during the radiotracer incubation period is minimized by the relatively small volume of the incubation solution over the slice.

Our mPET studies are performed using a Siemens Inveon PET/SPECT/CT scanner. Isotopes that can be used in our PET studies include 18F, 124I, 64Cu and a variety of radiometals.

PET studies can be to measure either receptor occupancy or tissue distribution of a labeled drug or competing unlabeled drug. Unlike in autoradiographic studies, the studies are non-terminal and hence the same animal can be used repeatedly.

Typical applications include:

i)  Real-time measurement of receptor occupancy by either the radiolabeled drug or a competing     unlabeled drug
ii)  Measuring tumor or tissue uptake of a PET/SPECT radiolabeled drug
iii) Preclinical testing of new PET/SPECT molecular imaging agents for disease diagnosis or as        disease biomarkers
iv) Preclinical testing of the efficacy of new drugs in disease models

Metis has extensive experience with cancer and CNS diseases models in rodents. Micro-PET/SPECT offers all the imaging advantages of autoradiography but in living animals. This allows subject to be imaged several times, lowering study costs with fewer subjects and opening up more sophisticated or robust experimental designs.