Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates.

Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity ( K = 0.58 nM). F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, F-SDM-8 displayed very high uptake with peak standardized uptake value (SVU) greater than 8 and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity toward SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. By comparing to C-UCB-J, F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multisite distribution, F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders.