PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction.

Abstract

Receptor occupancy (RO) studies using PET neuroimaging play a critical role in the development of drugs targeting the central nervous system (CNS). The conventional approach to estimate drug receptor occupancy consists in estimation of binding potential changes between two PET scans (baseline and post-drug injection). This estimation is typically performed separately for each scan by first reconstructing dynamic PET scan data before fitting a kinetic model to time activity curves. This approach fails to properly model the noise in PET measurements, resulting in poor RO estimates, especially in low receptor density regions. In this work, we evaluate a novel joint direct parametric reconstruction framework to directly estimate distributions of RO and other kinetic parameters in the brain from a pair of baseline and post-drug injection dynamic PET scans. The proposed method combines the use of regularization on RO maps with alternating optimization to enable estimation of occupancy even in low binding regions. Simulation results demonstrate the quantitative improvement of this method over conventional approaches in terms of accuracy and precision of occupancy. The proposed method is also evaluated in preclinical in-vivo experiments using 11C-MK-6884 and a muscarinic acetylcholine receptor 4 positive allosteric modulator drug, showing improved estimation of receptor occupancy as compared to traditional estimators. The proposed joint direct estimation framework improves RO estimation compared to conventional methods, especially in intermediate to low-binding regions. This work could potentially facilitate the evaluation of new drug candidates targeting the CNS.