Comparison of [¹¹C]TZ1964B and [¹⁸F]MNI659 for PET imaging brain PDE10A in nonhuman primates

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 (BP_ND) 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 BP_ND estimates of [¹¹C]TZ1964B were 3.72 by Logan Reference model (LoganREF) and 4.39 by simplified reference tissue model (SRTM); the BP_ND 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 BP_ND 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.