First-in-human Evaluation of 18F-SDM-8, A Novel Radiotracer for PET Imaging of Synaptic Vesicle Glycoprotein 2A

49 Objectives: Synaptic abnormalities are associated with many brain disorders, including Alzheimer’s disease, epilepsy, depression and schizophrenia. We have previously reported 11C-UCB-J as a PET tracer for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A), and as an imaging biomarker for synaptic density (1, 2). Recently we developed a novel 18F-labeled radiotracer 18F-SDM-8 with feasibility for translation to clinical diagnostic applications and demonstrated its excellent imaging and binding properties in nonhuman primates (3). The aim of this study was to evaluate this novel SV2A tracer in humans in comparison with 11C-UCB-J. Methods: PET scans with 18F-SDM-8 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 subject’s MR image to generate regional time-activity curves (TACs). TACs were then fitted with 1- and 2-tissue compartment (1TC, 2TC) models to derive regional distribution volume (VT) using the metabolite-corrected AIF. Non-displaceable binding potential (BPND) was calculated using centrum semiovale (white matter) as the reference region. Results: Injected activity dose of 18F-SDM-8 was 177.7 ± 9.7 MBq (0.21 ± 0.06 µg injected mass, n = 3). 18F-SDM-8 metabolized fairly quickly, with 25 ± 6% (n = 3) parent fraction at 30 min after tracer injection, similar to that of 11C-UCB-J (27 ± 9%, n = 9). Plasma free fraction (fP) was 0.30 ± 0.02 (n = 3). 18F-SDM-8 displayed high brain uptake and fast kinetics, with peak SUV of 10 in the putamen at ~10 min post-tracer injection (Figure 1). Regional TACs were fitted well with the 1TC model, while the 2TC model produced unreliable VT values in some regions. Mean K1 values (mL/cm3/min, Table 1) from the 1TC model ranged from 0.10 (centrum semiovale) to 0.38 (putamen) for 18F-SDM-8 and were similar to those of 11C-UCB-J (0.10 to 0.33). Mean 1TC VT values (mL/cm3) ranged from 3.8 (centrum semiovale) to 19.4 (temporal cortex) and were also very similar to those of 11C-UCB-J, with the centrum semiovale (CS) VT being slightly lower (3.6 for 18F-SDM-8 vs. 4.5 for 11C-UCB-J). As a measure of specific binding signal, mean BPND values of 18F-SDM-8 were ~ 42% higher than those 11C-UCB-J. Conclusions: The novel 18F-labeled SV2A radiotracer 18F-SDM-8 demonstrates outstanding characteristics in humans: fast and very high brain uptake, appropriate tissue kinetics, and high levels of specific binding signals. Taken together, 18F-SDM-8 appears to be an excellent radiotracer for imaging and quantification of SV2A in humans and holds great potential for future use in clinical diagnosis of diseases, as well as in multi-center clinical trials to monitor the efficacy of new drugs targeted at synaptic rescue and recovery. References1. Nabulsi NB, et al. J Nucl Med. 2016;57:777-784.2. Finnema SJ, et al. Sci Transl Med. 2016;8:348ra396. 3. Li S, et al. ACS Chem Neurosci. 2018, https://pubs.acs.org/doi/10.1021/acschemneuro.8b00526.