RT Journal Article SR Electronic T1 Characterization of the novel GlyT1 PET tracer [18F]MK-6577 in humans JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 321 OP 321 VO 55 IS supplement 1 A1 Joshi, Aniket A1 Sanabria, Sandra A1 Bormans, Guy A1 De Lepeleire, Inge A1 Koole, Michele A1 Van Hecken, Anne A1 Depre, Marleen A1 de Hoon, Jan A1 Van Laere, Koenraad A1 Hamill, Terence YR 2014 UL http://jnm.snmjournals.org/content/55/supplement_1/321.abstract AB 321 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 (VT), 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 VT values were estimated using a population AIF from the TRT data. VT values and Lassen plots were used to determine population mean VND, the non displaceable volume of distribution. Mean VND 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 Emax model to estimate MK-2637 Occ50 and Hill coefficient (Emax 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 VT was measured in the pons (6.7±0.9) and lowest in the cortex (2.1±0.5). (4) VT TRT variability was <14% in all regions. (5) The occupancy scans indicated absence of a reference region and no hysteresis. (6) Mean VND = 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.