σ1 Receptor occupancy: PET study
Kinetic modelling using a two-tissue compartment model for [11C]SA-4503 performed poorly in some ROIs (including the caudate, the region with the lowest uptake). (Sakata et al., 2007) The alternative MA1 model produced an acceptable fit for all 198 TACs (corresponding to 9 ROIs in 22 PET scans obtained from the 7 participants who received MR309 and one additional subject with baseline PET scan only) in accordance with prior studies. (Ichise, Toyama, Innis & Carson, 2002; Mansur et al., 2019) Representative TACs and MA1 model fits are shown in Figure 3.
In all ROIs a dose-dependent reduction in [11C]SA-4503 VT was observed following MR309 administration. The occupancy plot method produced broadly consistent estimates of [11C]SA-4503 VND across subjects (range of 11.0 to 23.2 mL/cm3). Brain σ1R occupancy ranged between 30.5% and 74.9% across the participants who received a single oral dose of 200–800 mg MR309 (Table 3).
Single-dose MR309 PK data obtained in the PET study are summarized in the supplementary appendix. Of the four PK– σ1R occupancy models, Model 1 best described the relationship between MR309 plasma concentration and corresponding σ1R occupancy and was selected to describe [11C]SA-4503 PK/brain kinetics (Tables 1, 4). Using Model 1, the estimated EC50 was 1380 ng/mL (95% CI: 778 to 1981 ng/mL), with Emax fixed to 100% and Hill slope fixed to 1 (Figure 4).
In the PK study, MR309 200 mg BID, the proposed dose for further evaluation, yielded steady state plasma concentrations within an approximate range of 2000–4000 ng/mL (Table 1). Using the plasma concentration–σ-1R occupancy model, this was calculated to correspond to an estimated brain σ1R occupancy ranging between 59–74% (Figure 4).