Harada Akina, Suzuki Kazunori, Miura Shotaro, Hasui Tomoaki, Kamiguchi Naomi, Ishii Tsuyoshi, Taniguchi Takahiko, Kuroita Takanobu, Takano Akihiro, Stepanov Vladimir, Halldin Christer, Kimura Haruhide
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Nucl Med Biol. 2015 Feb;42(2):146-54. doi: 10.1016/j.nucmedbio.2014.09.005. Epub 2014 Sep 28.
Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey.
Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey.
T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [(3)H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [(3)H]T-773 bound to a single high affinity site of PDE10A with Kd values of 12.2±2.2 and 4.7±1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [(11)C]T-773 showed good brain penetration and striatum-selective accumulation.
These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A.
磷酸二酯酶10A（PDE10A）是一种双底物磷酸二酯酶，可水解环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP），并选择性地在纹状体中等棘状神经元中表达。最近的研究表明，抑制PDE10A是治疗精神分裂症和亨廷顿舞蹈症等疾病的一种新方法。正电子发射断层扫描（PET）占有率研究可为PDE10A抑制剂的开发提供有用信息。我们发现T-773作为PDE10A的PET放射性配体候选物，并通过体外放射自显影和对猴子的PET研究对其性质进行了研究。
通过体外酶抑制试验、体外放射自显影和对猴子的PET研究对T-773作为PDE10A的PET放射性配体进行了分析。
T-773在体外对人重组PDE10A2表现出高结合亲和力和选择性；酶抑制试验中的半数抑制浓度（IC50）值为0.77nmol/L，对其他磷酸二酯酶的选择性超过2500倍。在使用小鼠、大鼠、猴子或人类脑切片的放射自显影研究中，放射性标记的T-773选择性地积聚在纹状体中。在Pde10a基因敲除小鼠的脑切片中未观察到这种选择性积聚。大鼠脑切片中[(3)H]T-773与PDE10A的结合受到选择性PDE10A抑制剂MP-10的竞争性抑制。在大鼠脑切片中，[(3)H]T-773与PDE10A的一个单一高亲和力位点结合，在尾状核-壳核和伏隔核中的解离常数（Kd）值分别为12.2±2.2和4.7±1.2nmol/L。在一项猴子PET研究中，[(11)C]T-773表现出良好的脑渗透性和纹状体选择性积聚。
这些结果表明[(11)C]T-773是一种潜在的PDE10A的PET放射性配体。
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