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

被引:7
|
作者
Liu, Hui [1 ]
Jin, Hongjun [1 ]
Luo, Zonghua [1 ]
Yue, Xuyi [1 ]
Zhang, Xiang [1 ]
Flores, Hubert [2 ]
Su, Yi [1 ]
Perlmutter, Joel S. [1 ,2 ,3 ]
Tu, Zhude [1 ]
机构
[1] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Neurosci Phys Therapy & Occupat Therapy, St Louis, MO 63110 USA
来源
ACS CHEMICAL NEUROSCIENCE | 2018年 / 9卷 / 05期
关键词
Phosphodiesterase; 10A; PET radioligands; brain imaging in vivo characterization; nonhuman primates; psychotic disorders; POSITRON-EMISSION-TOMOGRAPHY; REFERENCE TISSUE MODEL; PHOSPHODIESTERASE; 10A; SUBCELLULAR-LOCALIZATION; DARPP-32; PHOSPHORYLATION; PRECLINICAL EVALUATION; BINDING; EXPRESSION; STRIATUM; TRACER;
D O I
10.1021/acschemneuro.7b00458
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-18-labeled PDE10A radioligands (F-18-TZ19106B and F-18-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-18-TZ19106B and F-18-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-18-TZ19106B had higher striatal uptake and tracer retention in NHP brains than F-18-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 F-18-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity of F-18-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-18-TZ19106B. Our results indicate that F-18-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.
引用
收藏
页码:1066 / 1073
页数:15
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