Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [C-11]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.

Automated summary

The traditional design of PET target engagement studies involves baseline scan and subsequent scans after drug administration. Researchers propose an alternative design, the displacement study, where the drug is administered during an ongoing scan, resulting in reduced radiation exposure and costs. They develop kinetic models to analyze PET displacement data, modifying existing compartment models to accommodate time-variant increase in occupancy. Through simulations and application to PET data from pigs, the proposed models show promise in estimating target occupancy from a single displacement scan.