title: Comparison of [11C]TZ1964B and [18F]MNI659 for PET imaging brain PDE10A in nonhuman primates.
abstract: Phosphodiesterase 10A (PDE10A) inhibitors show therapeutic effects for diseases with striatal pathology. PET radiotracers have been developed to quantify in vivo PDE10A levels and target engagement for therapeutic interventions. The aim of this study was to compare two potent and selective PDE10A radiotracers, [11C]TZ1964B and [18F]MNI659 in the nonhuman primate (NHP) brain. Double scans in the same cynomolgus monkey on the same day were performed after injection of [11C]TZ1964B and [18F]MNI659. Specific uptake was determined in two ways: nondisplaceable binding potential (BPND) was calculated using cerebellum as the reference region and the PDE-10A enriched striatum as the target region of interest (ROI); the area under the time-activity curve (AUC) for the striatum to cerebellum ratio was also calculated. High-performance liquid chromatography (HPLC) analysis of solvent-extracted NHP plasma identified the percentage of intact tracer versus radiolabeled metabolites samples post injection of each radiotracer. Both radiotracers showed high specific accumulation in NHP striatum. [11C]TZ1964B has higher striatal retention and lower specific striatal uptake than [18F]MNI659. The BPNDestimates of [11C]TZ1964B were 3.72 by Logan Reference model (LoganREF) and 4.39 by simplified reference tissue model (SRTM); the BPNDestimates for [18F]MNI659 were 5.08 (LoganREF) and 5.33 (SRTM). AUC ratios were 5.87 for [11C]TZ1964B and 7.60 for [18F]MNI659. Based on BPNDvalues in NHP striatum, coefficients of variation were ~10% for [11C]TZ1964B and ~30% for [18F]MNI659. Moreover, the metabolism study showed the percentage of parent compounds were ~70% for [11C]TZ1964B and ~50% for [18F]MNI659 60 min post injection. These data indicate that either [11C]TZ1964B or [18F]MNI659 could serve as suitable PDE10A PET radiotracers with distinguishing features for particular clinical application.
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Junbin
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurology Washington University School of Medicine St. Louis Missouri.
authors.forename: Hubert
authors.initials: H
authors.lastname: Flores
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.affiliation: Molecular NeuroImaging LLC New Haven Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri; Department of Neurology Washington University School of Medicine St. Louis Missouri; Department of Neuroscience Physical Therapy and Occupational Therapy Washington University School of Medicine St. Louis Missouri.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Molecular NeuroImaging LLC New Haven Connecticut.
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
authors.affiliation: Department of Radiology Washington University School of Medicine St. Louis Missouri.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
keywords: Comparison; PDE10A; PET radiotracer; nonhuman primates; tracer kinetics; tracer metabolism; tracer uptake