Abstract
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Objectives: Early stage Alzheimer’s disease (AD) is associated with regional synapse loss. PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A), [11C]UCB-J [1] and [18F]UCB-H [2], have confirmed in vivo synaptic density loss in hippocampus of AD subjects. We recently developed an alternative radioligand, [18F]SynVestT-2 ([18F]SDM-2), with faster kinetics and lower nonspecific binding in the non-human primate brain. The aim of this study was to evaluate this SV2A tracer in humans in comparison with [11C]UCB-J, [18F]SynVesT-1 ([18F]SDM-8), and [18F]UCB-H.
Methods: PET scans with [18F]SynVesT-2 were acquired for 120 min on a High Resolution Research Tomograph (HRRT) scanner. Arterial blood samples were drawn for metabolite analysis and construction of the arterial input function (AIF). Regions of interest (ROIs) were defined with an atlas and individual subjects’ MR image to generate time-activity curves (TACs). TACs were then fitted with 1- and 2- tissue compartment (1TC, 2TC) models to derive regional distribution volumes (VT) using the metabolite corrected AIF. Nondisplaceable binding potential (BPND) was calculated using centrum semiovale (white matter) as the reference region [3].
Results: Injected activity dose of [18F]SynVesT-2 was 4.78 +/- 0.15 mCi (n= 2). The parent fraction of [18F]SynVesT-2 in plasma was 23 +/- 4% (n=2) at 30 min after tracer injection, similar to that of [11C]UCB-J (27 +/- 9%, n=9) and [18F]SynVesT-1 (25 +/- 6%, n=3). Plasma free fraction (fp) was 0.35 +/- 0.06 (n=2). As predicted by our nonhuman primate studies, [18F]SynVesT-2 displayed high brain uptake and fast kinetics, with peak SUV of 8 in the dorsolateral prefrontal cortex (dlPFC) and putamen at 7 min post injection. Regional TACs were fitted well with the 1TC model; while 2TC model produced unreliable VT values in some regions. K1 values (mL/cm3/min) from the 1TC model ranged from 0.12 (centrum semiovale) to 0.38 (thalamus) for [18F]SynVesT-2 and were similar to those of [18F]SynVesT-1 (0.11-0.34) and UCB-J (0.1-0.33). 1TC VT values (mL/cm3) ranged from 2.1 (centrum semiovale) to 8.1 (putamen) and were significantly lower than those of [18F]SynVesT-1 (~53% of the mean value) and [11C]UCB-J (~58%). As a measure of specific binding, mean BPND values of [18F]SynVesT-2 were 42% lower than those of [18F]SynVesT-1, and 24% lower than those of [11C]UCB-J (table 1), but three fold higher than those of UCB-H [4]. Importantly, regional VT of [18F]SynVesT-2 can be estimated reliably with 20 min of scan time(-1±5% different from 120-min value), much shorter than the 60 min required for [11C]UCB-J and [18F]SynVesT-1 [5].
Conclusions: The novel radiotracer [18F]SynVesT-2 demonstrates good imaging characteristics in humans with high brain uptake, fast kinetics, and high specific binding. These pharmacokinetic properties would shorten the length of a required scanning time and possibly negate the need for arterial blood sampling, decreasing the burden on this patient population and facilitate large scale clinical trials.
