[F-18]XTRA: first-in-human PET imaging of alpha 4 beta 2 nicotinic acetylcholine receptors.

358 Objectives Molecular research suggests region-specific decline in α4β2-nicotinic acetylcholine receptors (α4β2-nAChR) over the course of normal aging, Alzheimer’s disease and mild cognitive impairment. Use of the established α4β2-nAChR radiotracer, [18F]2-FA, to examine changes in this receptor system is limited by low signal-to-noise ratio. The more recent radiotracer, [18F]AZAN, may not have sufficient affinity to examine extra-thalamic α4β2-nAChR sites. We recently developed [18F]XTRA, which has higher binding affinity for α4β2-nAChR compared to [18F]2-FA and [18F]AZAN. We present the first human PET neuroimaging study using [18F]XTRA. Methods Five healthy young subjects underwent dynamic [18F]XTRA brain PET on a high resolution research tomograph. Regional brain time-activity curves (TACs) were analyzed with metabolite-corrected arterial input functions. Two-tissue-three-compartment (2T3C) modelling and plasma reference graphical analysis methods were applied to obtain regional volume of distribution (VT). Using corpus callosum (CC) as a reference region, non-displaceable binding potential (BPND) values were calculated. Results [18F]XTRA rapidly entered the brain, with extra-thalamic regional TACs peaking by 8 min post-injection (p.i.). Thalamic regions peaked after 70 min p.i. In all regions, the kinetic behavior of [18F]XTRA was sufficiently described by 2T3C modelling. Logan plots approached asymptotes by 20 min. VT estimates using both methods are highly correlated, and remained consistent for any scan duration 90 min or longer. [18F]XTRA showed high VT across all brain regions (e.g., 75 mL/cm3 in thalamus, 18 mL/cm3 in frontal cortex). Conclusions [18F]XTRA is a new, highly specific PET radioligand for estimation of α4β2-nAChR, with characteristics that favor use for studying α4β2-nAChR in humans.