The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

Abstract

Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [18F]SDM-16

“…The degree of SV2A occupancy by LEV was similar to previously reported with other SV2A PET tracers [19,21,26]. Based on the Lassen plot, the V ND of [ 18 F]SDM-16 in the monkey we imaged was 2.54 mL/cm 3 , which was lower than we previously determined for [ 18 F]UCB-H (7.89 mL/cm 3 ) [35], [ 11 C]UCB-J (6.27 mL/cm 3 ), [ 11 C]UCB-A (14.67 mL/ 13.6 ± 2.9 8.9 ± 2.0 6.6 ± 0.9 3.4 cm 3 ), and [ 18 F]SynVesT-1 (4.96 mL/cm 3 ), but higher than that of [ 18 F]SynVesT-2 (2.10 mL/cm 3 ).…”

“…While decreasing the tracer's K d value may eventually leads to undesired slow kinetics (low k 2 and long brain-toplasma equilibrium half-life), increasing f ND is an alternative but potentially more challenging approach to boost the specific PET signal, based on the equation BP ND = f ND *B max /K d . Using the averaged V ND and f P values, we calculated the f ND value of [ 18 F]SDM-16 to be 27%, which was higher than that of [ 18 F]UCB-H (6.1%, calculated from K 1 /k 2 using 2TCMc) [35], [ 11 C]UCB-J (7.3%), [ 18 F]SynVesT-1 (10.1%), and [ 18 F]SynVesT-2 (19.5%), assuming that these SV2A ligands enter the brain mainly through passive diffusion and are not subject to active influx or efflux transport, i.e., f ND = f P /V ND . We did not calculate the V ND and f ND values of Next, we calculated the BP ND values of the SV2A PET tracers using either CS as reference region or using the V ND derived from blocking studies.…”

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging

“…However, the reported radiosynthesis method of [ 18 F]UCB-J suffered from low radiochemical yield, which presents a major obstacle for small animal experiments unless alternative approaches with high radiochemical yields are developed. The relatively high non-specific brain uptake of [ 18 F]UCB-H was found in rat, non-human primate and human brain PET imaging studies ( Warnock et al, 2014 ; Bastin et al, 2020 ; Goutal et al, 2021 ). The second generation SV2A PET tracers ([ 18 F]SynVesT-1, [ 18 F]SynVesT-2, and [ 18 F]SDM-16) possess higher specific binding in the brain.…”

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of [18F]SDM-16

“…]UCB-H (6.1%, calculated from K1/k2 using 2TCM-c)[35], [ 11 C]UCB-J (7.3%), [18 F]SynVesT-1%), and [ 18 F]SynVesT-2 (19.5%), assuming that these SV2A ligands enter the brain mainly through passive diffusion and are not subject to active influx or efflux transport, i.e., fND = fP/VND. We did not calculate the VND and fND values of [ 11 C]UCB-A because of the lack of blocking data for [ 11 C]UCB-A.…”