Abstract
PurposeTo quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [11C]UCB-A, [11C]UCB-J, and [18F]SynVesT-1.MethodsThe racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [18F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (fP), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Nondisplaceable binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region.ResultsSDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (Ki = 0.9 nM) to human SV2A among all reported SV2A ligands. [18F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The 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 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions.ConclusionWe have successfully synthesized a novel SV2A PET tracer [18F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [18F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [18F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain.
Highlights
Proteins in the synaptic vesicle glycoprotein 2 (SV2) family located in presynaptic terminals are essential components of synaptic vesicles [1]
While the current metabolically labile synaptic vesicle glycoprotein 2A (SV2A) Positron emission tomography (PET) tracers are suitable for brain PET imaging due to the BBB preventing their radiometabolites from entering the brain, a more metabolically stable and higher binding affinity radiotracer is desirable for the investigation of SV2A expression in the whole central nervous system (CNS), to minimize the potential confounding effect of radiometabolites
After chiral resolution of the racemic products, (R)-9 and (R)-15 were obtained with enantiomeric excess (e.e.) greater than 99%
Summary
Proteins in the synaptic vesicle glycoprotein 2 (SV2) family located in presynaptic terminals are essential components of synaptic vesicles [1]. SV2A PET has potential applications beyond the brain, as SV2A is expressed in the all central nervous system (CNS) [11]. While the current metabolically labile SV2A PET tracers are suitable for brain PET imaging due to the BBB preventing their radiometabolites from entering the brain, a more metabolically stable and higher binding affinity radiotracer is desirable for the investigation of SV2A expression in the whole CNS, to minimize the potential confounding effect of radiometabolites. The spinal cord expresses SV2A with a much lower Bmax than the brain dose [12], and is protected by blood-spinal cord barrier (BSCB) rather than BBB. The difference between the permeability of BBB and BSCB may render spinal cord potentially more susceptible to the confounding effect of radiometabolites of PET tracers [13, 14]
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