Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate.
Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate.
复制标题
含氟磷酸二酯酶10a（PDE10A）抑制剂的合成以及在啮齿动物和非人类灵长类动物中对F-18标记的PDE10A PET示踪剂的体内评估。
DOI：
10.1021/acs.jmedchem.5b01205
复制
发表时间：
2015-11-12
影响因子：
7.3
通讯作者：
Tu Z
中科院分区：
文献类型：
--
作者：
Li J;Zhang X;Jin H;Fan J;Flores H;Perlmutter JS;Tu Z
设计并合成了一系列含氟PDE 10A抑制剂，以提高[11 C]MP-10的代谢稳定性。22种新类似物中有20种对PDE 10A具有高效力和选择性：18 a-j、19 d-j、20 a-b和21 b对PDE 10A的IC 50值<5 nM。通过将18 F引入MP-10药效团的喹啉而不是吡唑部分，放射合成了7种F-18标记的化合物[18 F] 18 a-e、[18 F] 18 g和[18 F] 20 a，并进行了体内评价。大鼠的生物分布研究显示，富含PDE 10A的纹状体中的活性比非靶向脑区高约2倍;该比例在注射后5 - 30 min增加，特别是[18 F] 18 a-d和[18 F] 20 a。非人灵长类动物中[18 F] 18 d和[18 F] 20 a的微型PET研究提供了清晰的纹状体可视化，具有合适的平衡动力学和有利的代谢稳定性。这些结果表明，该策略可以确定18 F标记的PET示踪剂，用于定量患有CNS疾病（包括亨廷顿病和精神分裂症）的患者中的PDE 10 A水平。
A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia.