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).