Abstract
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Objectives: Ever since the discovery of PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) as an in vivo biomarker for synaptic density, SV2A PET has been used widely in brain imaging, as changes in cerebral synaptic density are associated with a variety of neuropsychiatric diseases.1 Nonetheless, SV2A PET may also have utility beyond the brain, as SV2A is also expressed in peripheral tissues and enriched in several types of cancers.2 To investigate SV2A expression in peripheral tissues and explore the communications between the peripheral and central nervous systems (CNS), a metabolically stable tracer is desirable in order to minimize the confounding effect of radiometabolites. To this end, we synthesized an 18F-labeled SV2A ligand, [18F]SDM-16, with high in vivo stability, and characterized it in nonhuman primates.
Methods: SDM-16 was synthesized from commercially available starting materials and assayed for in vitro binding affinities. The enantiopure 18F-labeled [18F]SDM-16 was synthesized via aromatic radiofluorination of an arylstannane precursor, which was in turn made from a chiral intermediate, (R)-4-(3-bromo-5-fluorophenyl)pyrrolidin-2-one, the absolute configuration of which was confirmed by X-ray crystallography. Baseline and Levetiracetam blocking scans were performed on a FOCUS 220 scanner. A displacement experiment with Levetiracetam (30 mg/kg, i.v., given at 120 min post-injection of [18F]SDM-16) was also carried out to determine the binding reversibility. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional brain time-activity curves (TACs) were fitted with one-tissue compartment (1TC) model to obtain volume of distribution (VT). Binding potential (BPND) was calculated using the nondisplaceable volume of distribution (VND) obtained from the blocking study, where BPND = (VT/VND)-1. Results: Racemic SDM-16 was synthesized in 3 steps with 44% overall yield, and was found to have high binding affinity (Ki= 3.7 nM) to human SV2A. [18F]SDM-16 (Fig.1a) was successfully prepared from the enantiopure precursor in >99.9% radiochemical and enantiomeric purity, as determined by chiral HPLC analysis. Molar activity at the end of synthesis was 283 ± 42 GBq/µmol (n=4). In rhesus monkeys, [18F]SDM-16 metabolized slowly, with 88 ± 8% and 81 ± 8% intact tracer present at 30 and 120 min post-injection (n=3), compared with 70 ± 7%, 42 ± 13%, and 40 ± 6% intact tracer present at 30 min post-injection of [11C]UCB-A (n=5), [18F]SynVesT-1 (n=5)3, and [11C]UCB-J (n=11)4, respectively (Fig.1b). Plasma free fraction was 69%, slightly lower than [11C]UCB-A (75%), but much higher than [11C]UCB-J (46%), which is consistent with the relative lipophilicity (LogD) of these tracers: [18F]SDM-16 (1.65), [11C]UCB-A (1.10), [11C]UCB-J (2.46). [18F]SDM-16 displayed high brain uptake (peak SUV of 5.8-9.4 in grey matter), with a slow kinetic profile, similar to [11C]UCB-A (Fig.1c/d). The reversible binding of [18F]SDM-16 was demonstrated in the displacement experiment with Levetiracetam, which significantly reduced the uptake in high binding regions (Fig.1e/f). TACs were well fitted with 1TC model to derive regional VT values, which ranged from 6.8 to 39.9 mL/cm3. Based on the Lassen plot, SV2A occupancy was calculated to be 81% with VND being 3.23 mL/cm3. BPND values were calculated to be from 1.89 to 11.37 using VND as reference (Table 1).
Conclusions: We have successfully synthesized [18F]SDM-16 and evaluated its imaging characteristics in rhesus monkeys. [18F]SDM-16 appears to be a metabolically stable SV2A PET tracer with high specific binding in NHP brain. Therefore, [18F]SDM-16 may have potential applications in the visualization and quantification of SV2A in both CNS and peripheral organs.
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