18F-XTRA PET for Enhanced Imaging of the Extrathalamic α4β2 Nicotinic Acetylcholine Receptor

Abstract

Reduced density of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) in the cortex and hippocampus of the human brain has been reported in aging and patients with neurodegenerative disease. This study assessed the pharmacokinetic behavior of ¹⁸F-(-)-JHU86428 (¹⁸F-XTRA), a new radiotracer for in vivo PET imaging of the α4β2-nAChR, particularly in extrathalamic regions of interest in which the α4β2-nAChR is less densely expressed than in thalamus. ¹⁸F-XTRA was also used to evaluate the α4β2-nAChR in the hippocampus in human aging. Methods: Seventeen healthy nonsmoker adults (11 men, 6 women; age, 30-82 y) underwent PET neuroimaging over 90 or 180 min in a high-resolution research tomograph after bolus injection of ¹⁸F-XTRA. Methods to quantify binding of ¹⁸F-XTRA to the α4β2-nAChR in the human brain were compared, and the relationship between age and binding in the hippocampus was tested. Results:¹⁸F-XTRA rapidly entered the brain, and time-activity curves peaked within 10 min after injection for extrathalamic regions and at approximately 70 min in the thalamus. The 2-tissue-compartment model (2TCM) predicted the regional time-activity curves better than the 1-tissue-compartment model, and total distribution volume (V_T) was well identified by the 2TCM in all ROIs. V_T values estimated using Logan analysis with metabolite-corrected arterial input were highly correlated with those from the 2TCM in all regions, and values from 90-min scan duration were on average within 5% of those values from 180 min of data. Parametric images of V_T were consistent with the known distribution of the α4β2-nAChR across the brain. Finally, an inverse correlation between V_T in the hippocampus and age was observed. Conclusion: Our results extend support for use of ¹⁸F-XTRA with 90 min of emission scanning in quantitative human neuroimaging of the extrathalamic α4β2-nAChR, including in studies of aging.

Keywords: 18F-XTRA; PET imaging; healthy aging; nicotinic acetylcholine receptor.

FIGURE 1.

Time–activity curves from ¹⁸F-XTRA imaging in a representative subject who underwent 180 min of continuous emission imaging. (A) Radioactivity curves in total plasma and in the portion of unmetabolized ¹⁸F-XTRA parent are shown with activity shown as percentages of injected dose per mL plasma normalized to body weight in grams (SUV%). (B) Radioactivity curves spanning 180 min in 10 ROIs are shown. Time–activity curves are shown as percentages of injected dose per cm³ tissue normalized to body weight in grams (SUV%). (C) The 2TCM showed better fit to observed tissue time–activity curves than the 1TCM in all ROIs. Observed activity (data in shapes) and model curves (solid curve, 2TCM; dotted curve, 1TCM) over 90 min from thalamus, frontal cortex, and corpus callosum are shown. CTX = cortex.

FIGURE 2.

Comparison between ¹⁸F-XTRA regional V_T values using 2TCM and Logan graphical analysis using 90-min data from 17 healthy individuals. After exclusion of outlier thalamic data from 1 individual, regional V_T values from 2TCM were highly correlated with those from the Logan method (Spearman rho = 0.986, P = 0.000). Results from secondary regression analysis are also shown. V_T is in units of mL cm⁻³.

FIGURE 3.

Assessment of relative stability in ¹⁸F-XTRA regional V_T values from 180 min of data compared with values produced from truncated (by 5-min intervals down to 90 min) scan duration. Data from 7 healthy individuals who underwent 180-min emission scans were included. V_T estimates are in units of mL cm⁻³. Percentage of absolute difference between V_T values from 180 min of data and V_T values from shortened scan duration are plotted for each of the 10 ROIs. CTX = cortex.

FIGURE 4.

Parametric images of V_T of ¹⁸F-XTRA, estimated using Logan graphical analysis with metabolite-corrected arterial input function and 90-min data from 1 representative healthy participant. Transaxial views of PET/MR images demonstrate high V_T values in thalamus and lower V_T values in other cortical and subcortical regions. There is no apparent region without binding of ¹⁸F-XTRA.