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

Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type-1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [F-18]MK-6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [F-18]MK-6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK-2637. Studies were also performed to measure radiation burden and the baseline test-retest (T-RT) variability of the tracer. The effective dose from sequential whole-body dosimetry scans in three male subjects was estimated to be 24.5 +/- 2.9 mu SV/MBq (mean +/- SD). The time-activity curves from T-RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (V-T = 6.7 +/- 0.9, BPND = 4.1 +/- 0.43) and lowest in the cortex (V-T = 2.1 +/- 0.5, BPND = 0.60 +/- 0.23). V-T T-RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ(50)) of MK-2637 was determined using two methods: A: Lassen plot with a population input function (Occ(50) = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ(50) = 141 nM, SE = 21 nM). (C) 2014 Wiley Periodicals, Inc.