ACS Chem Neurosci. 2018 May 16;9(5):1066-1073. doi: 10.1021/acschemneuro.7b00458. Epub 2018 Feb 19.
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 F-labeled PDE10A radioligands (F-TZ19106B and 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 F-TZ19106B and 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). F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BP) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of 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 F-TZ19106B. Our results indicate that 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.
正电子发射断层扫描（PET）与磷酸二酯酶 10A（PDE10A）特异性放射性配体相结合，为在正常和患病条件下体内这种酶的表达提供了一种非侵入性和定量的成像工具。我们最近报道了两种有效的 F 标记 PDE10A 放射性配体（F-TZ19106B 和 F-TZ8110）；在大鼠和非人灵长类动物中的初步评估表明，这两种示踪剂都具有稳定的代谢谱和出色的靶标与非靶标比值（纹状体/小脑）。在此，我们专注于 F-TZ19106B 和 F-TZ8110 的体内特性研究，以确定一种适合用于 PDE10A 体内成像的放射性配体。我们直接比较了这两种放射性示踪剂在成年雄性食蟹猴非人灵长类动物（NHP）中的 microPET 研究。F-TZ19106B 在 NHP 大脑中的纹状体摄取和示踪剂保留率高于 F-TZ8110，这可以通过标准化摄取值（SUV）或使用基于参考的建模分析估算的不可置换结合潜力（BP）来量化。使用 PDE10A 抑制剂 MP-10 进行的阻断和置换研究表明，F-TZ19106B 与 PDE10A 的结合是特异性和可逆的。我们还使用递增剂量的 MP-10 阻断（0.3、0.5、1.0、1.5 和 2.0mg/kg）证明了 F-TZ19106B 结合到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 F-TZ19106B 在纹状体中的摄取。我们的结果表明，F-TZ19106B 是一种有前途的 PDE10A 体内成像放射性配体候选物，它可用于确定 PDE10A 抑制剂的靶标结合，并可用作评估新型抗精神病治疗效果的工具。
