Characterization of the novel GlyT1 PET tracer [¹⁸F]MK-6577 in humans

Objectives This work presents human dosimetry, test-retest (TRT) and occupancy results of [¹⁸F]MK-6577, a novel glycine transporter-1 (GlyT1) PET tracer. GlyT1 inhibitors have emerged as potential treatments for schizophrenia due to their potentiation of NMDA receptor activity. A GlyT1 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection. The utility of this tracer in non-human primates has been demonstrated previously (Hamill et al, Synapse, 2011).

Methods Ten serial whole body scans were performed in 3 healthy subjects to measure the effective dose (ED). TRT scans with arterial input functions (AIF) were performed in 3 healthy subjects to determine the variability of the total volume of distribution (V_T), a receptor density index. In the occupancy studies, two scans were obtained per subject: one at baseline and another post dosing with MK-2637, a GlyT1 inhibitor. Occupancy scans were performed at varied times post-dose to check for hysteresis. AIF were not obtained in the occupancy cohort. Instead, regional V_T values were estimated using a population AIF from the TRT data. V_T values and Lassen plots were used to determine population mean V_ND, the non displaceable volume of distribution. Mean V_ND was then used to determine occupancy with cortex as a pseudo reference region (Gunn et al, Synapse, 2011). The drug plasma vs. occupancy data was fitted to an E_max model to estimate MK-2637 Occ₅₀ and Hill coefficient (E_max fixed to 100%).

Results (1) ED = 24.5±2.9 µSV/MBq (mean±SD). (2) The time-activity curves from TRT scans modeled satisfactorily using a 2 tissue-compartmental model. (2) Highest V_T was measured in the pons (6.7±0.9) and lowest in the cortex (2.1±0.5). (4) V_T TRT variability was <14% in all regions. (5) The occupancy scans indicated absence of a reference region and no hysteresis. (6) Mean V_ND = 1.2±0.4. (7) Occ₅₀ = 141 (SE=21) nM.

Conclusions [¹⁸F]MK-6577 is a promising PET tracer for measuring GlyT1 availability and occupancy in humans.