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 BPND estimates of [11C]TZ1964B were 3.72 by Logan Reference model (LoganREF) and 4.39 by simplified reference tissue model (SRTM); the BPND estimates 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 BPND values 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.
Highlights
Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme that hydrolyses cyclic adenosine monophosphate and cyclic guanosine monophosphate; its distribution is exclusively within striatal medium spiny neurons which are enriched in the striatum (Fujishige et al 1999; Coskran et al 2006)
This study provides a head-tohead comparison of [11C]TZ1964B and [18F]MNI659 for in vivo imaging of the nonhuman primate (NHP) brain by collecting double scans in a same subject in the same day
[11C]TZ1964B was obtained in high specific activity >296 GBq/mol, with radiochemical yield 20–30% and radiochemical purity >99%. [18F] MNI659 was obtained in high specific activity 37-74 GBq/ lmol, with radiochemical yield 20–30% and radiochemical purity >99%
Summary
Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme that hydrolyses cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); its distribution is exclusively within striatal medium spiny neurons which are enriched in the striatum (Fujishige et al 1999; Coskran et al 2006). Decreased PDE10A expression has been observed both in animal models and in patients with striatal pathologies, including Huntington disease (HD) and Parkinson disease (PD) (Hebb et al 2004; Giorgi et al 2011; Russell et al 2014; Niccolini et al 2015). These observations provided the rationale for exploring PDE10A inhibition as a therapy for neuropsychiatric and neurodegenerative diseases. Each ligand has its own set of advantages and disadvantages, a close comparison of these PDE10A radioligands could provide detailed information for choosing the appropriate radiotracer for particular clinical application
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