Error analysis for PET measurement of dopamine D2 receptor occupancy by antipsychotics

Background and aims: The clinical effect of antipsychotic drugs has been reported to be associated with a dopamine D2 receptor occupancy. This occupancy with antipsychotic drugs has been measured using PET by quantifying the binding potential (BP) of receptors with [11C]raclopride or [11C]FLB457 before and after antipsychotic administration. In this quantitative analysis, the uncertainty in estimated kinetic parameters depends on the signal-to-noise ratio of a time-activity curve (TAC) in tissue, which may differ according to injection dose, scan protocol, sensitivity of a PET camera and so on. In this study, the reliability of BP estimates in PET measurement of dopamine D2 receptor occupancy was investigated by means of the computer simulation and measured PET data in humans. The influence of scan protocol on the error of estimated BP was also evaluated. Methods: In the simulation study, 90-min scan TAC of the putamen for [11C]raclopride and the temporal cortex for [11C]FLB457 were created using measured TAC of the cerebellum as an input function and assumed k-values (R1=K1target/K1reference=0.97, k2=0.23, BP=3.2, 0.96, and 0.32 for [11C]raclopride, and R1=0.81, k2=0.05, BP=2.1, 0.63, and 0.21 for [11C]FLB457) with the simplified reference tissue model (SRTM) [1]. The noise was assumed to be Gaussian distribution whose variance was proportional to the true TAC, and added having the same level as observed in volume-of-interest (VOI) based TACs. One thousand noise-added TACs were realized, then kinetic parameters including BP were derived using the SRTM from these TACs, in which length of dynamic PET scan used for the parameter estimation were reduced from 90 to 20 min, and the mean value and SD were calculated. In the human study of [11C]raclopride (injected dose 215±16.6 MBq, specific radioactivity 185±49.6 GBq/μmol) and [11C]FLB457 (injected dose 216±16.2 MBq, specific radioactivity 213±22.6 GBq/μmol) with and without antipsychotics, replicated TACs were generated by resampling the fitting residuals of each frame with bootstrap approach [2][3], and the reliability of BP estimates was evaluated for various scan length. Results: In [11C]raclopride simulation study, a 30-min short PET scan gave us unbiased BP estimates as well as 90-min scan, and the deviation was under 10% in case of VOI-based estimation. Conversely, in [11C]FLB457, the mean value and SD of the BP estimates increased remarkably in case of the shorter scan than 60-min. In human study with [11C]raclopride both with and without antipsychotic administration, SD of the caudate and putamen was under 10% when the scan length was longer than 32 min. Meanwhile, in [11C]FLB457 study, the mean value increased and the SD of temporal cortex was over 10% when the scan length was shorter than 60 min. Conclusions: In a VOI analysis of [11C]raclopride study, the scan length can be shorten to 30 minutes. However, in [11C]FLB457 study, 60-min scan is required for a reliable estimation since its kinetics is slower.