PET imaging of α4β2* nicotinic acetylcholine receptors: quantitative analysis of 18F-nifene kinetics in the nonhuman primate.

UNLABELLED: The PET radioligand 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine ((18)F-nifene) is an α4β2* nicotinic acetylcholine receptor (nAChR) agonist developed to provide accelerated in vivo equilibrium compared with existing α4β2* radioligands. The goal of this work was to analyze the in vivo kinetic properties of (18)F-nifene with both kinetic modeling and graphical analysis techniques.

METHODS

Dynamic PET experiments were performed on 4 rhesus monkeys (female; age range, 9-13 y) using a small-animal PET scanner. Studies began with a high-specific-activity (18)F-nifene injection, followed by a coinjection of (18)F-nifene and unlabeled nifene at 60 min. Sampling of arterial blood with metabolite analysis was performed throughout the experiment to provide a parent radioligand input function. In vivo kinetics were characterized with both a 1-tissue-compartment model (1TCM) and a 2-tissue-compartment model, Logan graphical methods (both with and without blood sampling), and the multilinear reference tissue model. Total distribution volumes and nondisplaceable binding potentials (BP(ND)) were used to compare regional binding of (18)F-nifene. Regions examined include the anteroventral thalamus, lateral geniculate body, frontal cortex, subiculum, and cerebellum.

RESULTS

The rapid uptake and binding of (18)F-nifene in nAChR-rich regions of the brain was appropriately modeled using the 1TCM. No evidence for specific binding of (18)F-nifene in the cerebellum was detected on the basis of the coinjection studies, suggesting the suitability of the cerebellum as a reference region. Total distribution volumes in the cerebellum were 6.91 ± 0.61 mL/cm(3). BP(ND) values calculated with the 1TCM were 1.60 ± 0.17, 1.35 ± 0.16, 0.26 ± 0.08, and 0.30 ± 0.07 in the anteroventral thalamus, lateral geniculate body, frontal cortex, and subiculum, respectively. For all brain regions, there was a less than 0.04 absolute difference in the average BP(ND) values calculated with each of the 1TCM, multilinear reference tissue model, and Logan methods.

CONCLUSION

The fast kinetic properties and specific regional binding of (18)F-nifene promote extension of the radioligand into preclinical animal models and human subjects.