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 ¹⁸F-labeled PDE10A radioligands (¹⁸F-TZ19106B and ¹⁸F-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 ¹⁸F-TZ19106B and ¹⁸F-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). ¹⁸F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than ¹⁸F-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 ¹⁸F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of ¹⁸F-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 ¹⁸F-TZ19106B. Our results indicate that ¹⁸F-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.

中文翻译：

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在非人灵长类动物大脑中的两个¹⁸ F标签的PDE10A PET放射性配体的体内表征

具有磷酸二酯酶10A（PDE10A）特定放射性配体的正电子发射断层扫描（PET）提供了一种无创且定量的成像工具，可在正常和患病条件下体内获取该酶的表达。我们最近报道了两种有效的¹⁸ F标记PDE10A放射性配体（¹⁸ F-TZ19106B和¹⁸ F-TZ8110）；在大鼠和非人类灵长类动物中的初步评估表明，两种示踪剂均具有稳定的代谢谱和出色的靶标与非靶标比率（纹状体/小脑）。在本文中，我们集中于¹⁸ F-TZ19106B和¹⁸ F-TZ8110的体内表征，以鉴定适用于体内PDE10A成像的放射性配体。我们直接比较了成年男性中这两种放射性示踪剂的microPET研究猕猴非人灵长类动物（NHPs）。¹⁸ F-TZ19106B具有较高的纹状体摄取和保留示踪剂在NHP脑比¹⁸ F-TZ8110，由任一标准化的摄取值（SUV的）定量或不可移动的结合电势（BP _ND使用基于参考模型分析估计）。使用PDE10A抑制剂MP-10进行的阻滞和置换研究表明¹⁸ F-TZ19106B与PDE10A的结合是特异性和可逆的。我们还证明了使用递增剂量的MP-10阻断剂（0.3、0.5、1.0、1.5和2.0 mg / kg），¹⁸ F-TZ19106B结合对不同数量的特异性结合位点的敏感性。用多巴胺D2样受体拮抗剂预处理可增强纹状体的摄取¹⁸ F-TZ19106B。我们的结果表明¹⁸ F-TZ19106B是用于体内PDE10A成像的有前途的放射性配体候选物，它可用于确定PDE10A抑制剂的靶标参与度，并可作为评估新型抗精神病疗法效果的工具。