title: Characterization of the novel GlyT1 PET tracer [18F]MK-6577 in humans.
abstract: 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, [(18) F]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 [(18) F]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 µSV/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 (VT  = 6.7 ± 0.9, BPND  = 4.1 ± 0.43) and lowest in the cortex (VT  = 2.1 ± 0.5, BPND  = 0.60 ± 0.23). VT 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 (Occ50 ) of MK-2637 was determined using two methods: A: Lassen plot with a population input function (Occ50  = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ50  = 141 nM, SE = 21 nM).
authors.affiliation: Merck, West Point, Pennsylvania.
authors.forename: Aniket D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria-Bohórquez
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.forename: Jan
authors.initials: J
authors.lastname: De Hoon
authors.forename: Anne
authors.initials: A
authors.lastname: Van Hecken
authors.forename: Marleen
authors.initials: M
authors.lastname: Depre
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
mesh_terms: D000328:Adult; D001549:Benzamides / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D015331:Cohort Studies; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; C000599710:MK-6577; D019275:Radiopharmaceuticals; C493268:SLC6A9 protein, human; D013449:Sulfonamides
keywords: GlyT1 receptor PET tracer; glycine transporter 1 receptor; population input function; proof-of-concept studies