RT Journal Article SR Electronic T1 A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.06.25.449978 DO 10.1101/2021.06.25.449978 A1 Chao Zheng A1 Daniel Holden A1 Ming-Qiang Zheng A1 Richard Pracitto A1 Kyle C. Wilcox A1 Marcel Lindemann A1 Zachary Felchner A1 Li Zhang A1 Jie Tong A1 Krista Fowles A1 Sjoerd J. Finnema A1 Nabeel Nabulsi A1 Richard E. Carson A1 Yiyun Huang A1 Zhengxin Cai YR 2021 UL http://biorxiv.org/content/early/2021/06/25/2021.06.25.449978.abstract AB Purpose To investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18F]SDM-16, in nonhuman primate brains.Methods The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region.Results Racemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (Ki = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was −9±8%, and averaged absolute TRV (aTRV) was 10±7% for all analyzed brain regions.Conclusion We have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.Competing Interest StatementThe authors have declared no competing interest.