TY - JOUR

T1 - Kinetic models for estimating occupancy from single-scan PET displacement studies

AU - Laurell, Gjertrud Louise

AU - Plavén-Sigray, Pontus

AU - Johansen, Annette

AU - Raval, Nakul Ravi

AU - Nasser, Arafat

AU - Aabye Madsen, Clara

AU - Madsen, Jacob

AU - Hansen, Hanne Demant

AU - Donovan, Lene Lundgaard

AU - Knudsen, Gitte Moos

AU - Lammertsma, Adriaan A.

AU - Ogden, R. Todd

AU - Svarer, Claus

AU - Schain, Martin

N1 - Publisher Copyright: © The Author(s) 2023.

PY - 2023

Y1 - 2023

N2 - 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 [11C]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.

AB - 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 [11C]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.

KW - Displacement

KW - drug occupancy

KW - kinetic modelling

KW - PET

KW - synaptic density

U2 - 10.1177/0271678X231168591

DO - 10.1177/0271678X231168591

M3 - Journal article

C2 - 37070382

AN - SCOPUS:85153370411

VL - 43

SP - 1544

EP - 1556

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 9

ER -