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Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent 18 F-labeled PDE10A radioligands ( 18 F-TZ19106B and 18 F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization of 18 F-TZ19106B and 18 F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs). 18 F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than 18 F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BP ND ) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of 18 F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 18 F-TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of 18 F-TZ19106B. Our results indicate that 18 F-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.

In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

In Vivo Characterization of Two ¹⁸F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains