Estimating neurotransmitter kinetics with ntPET: A simulation study of temporal precision and effects of biased data

We recently introduced neurotransmitter PET (ntPET), an analysis technique that estimates the kinetics of stimulus-induced neurotransmitter (NT) release. Here, we evaluate two formulations of ntPET. The arterial (ART) approach measures the tracer input function (TIF) directly. The reference (REF) approach derives the TIF from reference region data. Arterial sampling is considered the gold standard in PET modeling but reference region approaches are preferred for reduced cost and complexity. If simulated PET data with unbiased TIFs were analyzed using ART or REF, temporal precision was better than 3 min provided NT concentration peaked less than 30 min into the scanning session. The consequences of biased TIFs or stimulus-induced changes in tracer delivery were also evaluated. ART TIFs were biased by the presence of uncorrected radiometabolites in the plasma whereas REF TIFs were biased by specific binding in the reference region. Simulated changes in tracer delivery emulated ethanol-induced blood flow alterations observed previously with PET. ART performance deteriorated significantly if metabolites amounted to 50% of plasma radioactivity by 60 min. The accuracy and precision of REF were preserved even if the reference region contained 40% of the receptor density of the target region. Both methods were insensitive to blood flow alterations (proportional changes in K(1) and k(2)). Our results suggest that PET data contain information--heretofore not extracted--about the timing of NT release. The REF formulation of ntPET proved to be robust to many plausible model violations and under most circumstances is an appropriate alternative to ART.