PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-¹⁸F-FMeNER-D₂

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-¹¹C-MRB and (S,S)-¹⁸F-FMeNER-D₂, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-¹¹C-MRB and defluorination with (S,S)-¹⁸F-FMeNER-D₂, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated ¹⁸F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-¹⁸F-FMeNER-D₂ PET. Methods: We analyzed our previous (S,S)-¹⁸F-FMeNER-D₂ PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-¹⁸F-FMeNER-D₂ became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-¹⁸F-FMeNER-D₂ These results suggest that we can accurately quantify NET density with a 90-min (S,S)-¹⁸F-FMeNER-D₂ scan in broad brain areas.