Quantitative analysis of [¹⁸F]nifene kinetics in the nonhuman primate

Objectives [¹⁸F]Nifene targets α4β2 nicotinic AChRs and displays rapid in vivo equilibration times (<45 min). The goal of this work is to analyze the in vivo kinetic properties of [¹⁸F]nifene with both kinetic modeling and graphical analysis techniques.

Methods Dynamic PET experiments were performed on four rhesus monkeys (4F, 9-13 yr) with a MicroPET P4 scanner. Studies began with a high specific activity [¹⁸F]nifene injection followed by a coinjection of [¹⁸F]nifene and cold nifene at t=60 min. Sampling of arterial blood with metabolite analysis was performed throughout experiments to provide a parent radioligand input function. Data was analyzed with one-tissue (1TCM) and two-tissue compartment models (2TCM), Logan graphical methods, and the simplified reference tissue model (SRTM). Total distribution volumes (V_T) and nondisplaceable binding potentials (BP_ND) were used to compare regional binding of [¹⁸F]nifene. Regions examined include the antereoventral thalamus (AVT), lateral geniculate (LG), frontal cortex (FC), subiculum (SB), and cerebellum (CB).

Results The 1TCM was found to accurately model the data in all regions. No evidence for specific binding of [¹⁸F]nifene in the CB was detected from the co-injection studies, suggesting the CB as a valid reference region. V_T values of 6.9 ± 0.6 mL cm^-3 were found in the CB. 1TCM yielded BP_ND values of 1.60 ± 0.17, 1.35 ± 0.16, 0.26 ± 0.08 and 0.30 ± 0.07 in the AVT, LG, FC, and SB respectively using the CB as a reference region. In thalamic regions, there was close agreement (<5%) in BP_ND between 1TCM and Logan methods, whereas the 2TCM was consistently higher by 2-13% and the SRTM was consistently lower by 3-7%. For all subjects, BP_ND values in the FC were lower than the SB, suggesting sensitivity of [¹⁸F]nifene to small differences in binding despite lower BP_ND values.

Conclusions The fast kinetics and moderate binding potentials of [¹⁸F]nifene demonstrate favorable properties for the assay of α4β2 nAChR binding.

Research Support AA017706, CA14218