¹⁸F-SDM-8: A novel radiotracer for PET imaging of synaptic density

Objectives: Structural disruption and alterations of synapses are associated with many brain disorders, including Alzheimer’s disease, epilepsy, depression and schizophrenia. We have previously reported the PET radiotracer ¹¹C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in non-human primates and humans [1, 2]. The aim of our project was to develop novel ¹⁸F-labelled SV2A tracers with comparable or improved imaging properties and feasibility for translation to clinical diagnostic applications. Here we report the synthesis of ¹⁸F-SDM-8 and its in vivo evaluation in rhesus monkeys.

Methods: The novel compound SDM-8 was synthesized and assayed for in vitro binding affinities. The radioligand ¹⁸F-SDM-8 was radiolabeled by ¹⁸F-substitution of an iodonium ylide precursor. PET imaging with ¹⁸F-SDM-8 (90 min baseline scan followed by displacement with the selective SV2A ligand levetiracetam (30 mg/kg) was conducted on a Focus-220 scanner to assess the ligand’s pharmacokinetic and in vivo binding properties. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and calculation of binding parameters with kinetic models.

Results: SDM-8 was found to have high SV2A binding affinity (K_i = 0.58 nM) in vitro, which was similar to that of UCB-J (0.27 nM). ¹⁸F-SDM-8 was prepared in molar activity of 17.76 GBq/µmol and 99% radiochemical purity. In rhesus monkey, ¹⁸F-SDM-8 showed a moderate metabolism rate with 62% of parent tracer remaining at 30 min post-injection. Plasma free fraction was 40%. In the brain, it displayed very high uptake with peak SUV > 10, and fast and reversible kinetics, with peak uptake around 30 min. A displacement study with levetiracetam (30 mg/kg) given at 90 min post-injection reduced uptake in high binding regions to the level in the white matter, demonstrating binding specificity towards SV2A. Regional distribution volumes (V_T, see Table) were derived using the 1-tissue compartment (1TC) model from 90 min of data and were similar to those of ¹¹C-UCB-J. Regional binding potential (BP_ND) values were calculated using centrum semiovale (white matter) as the reference region and ranged from 0.86 in the brainstem to 4.85 in the cingulate cortex, similar in magnitude to that of ¹¹C-UCB-J.

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Conclusions: We have successfully synthesized ¹⁸F-SDM-8 and evaluated its imaging characteristics in rhesus monkey. ¹⁸F-SDM-8 displayed the same attractive imaging properties as ¹¹C-UCB-J: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding signals. Given the longer half-life of F-18 and feasibility for central production and distribution, ¹⁸F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders. References: 1. Nabulsi N. et al. J. Nucl. Med. 2016, 57, 777 2. Finnema S. et al. Sci. Transl. Med. 2016, 8, 348ra96