A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of SDM-16

Zheng, C.; Holden, D.; Zheng, M.-Q.; Pracitto, R.; Wilcox, K. C.; Lindemann, M.; Felchner, Z.; Zhang, L.; Tong, J.; Fowles, K.; Finnema, S. J.; Nabulsi, N.; Carson, R. E.; Huang, Y.; Cai, Z.

doi:10.1101/2021.06.25.449978

bioRxiv · 10.1101/2021.06.25.449978

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of SDM-16

Zheng, C.·Holden, D.·Zheng, M.-Q.·Pracitto, R.·Wilcox, K. C.·Lindemann, M.·Felchner, Z.·Zhang, L.·Tong, J.·Fowles, K.·Finnema, S. J.·Nabulsi, N.·Carson, R. E.·Huang, Y.·Cai, Z.

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Abstract

PurposeTo 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. MethodsThe 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. ResultsRacemic 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. ConclusionWe 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.

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Zheng, C., Holden, D., Zheng, M.-Q., Pracitto, R., Wilcox, K. C., Lindemann, M., Felchner, Z., Zhang, L., Tong, J., Fowles, K., Finnema, S. J., Nabulsi, N., Carson, R. E., Huang, Y., Cai, Z.. 2021-06-25. A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of SDM-16. https://doi.org/10.1101/2021.06.25.449978

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