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

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 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. MicroPET 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.

为提升[¹¹C]-MP-10的代谢稳定性，本研究设计并合成了一系列含氟的磷酸二酯酶10A（PDE10A）抑制剂。22种新衍生物中有20种对PDE10A表现出高活性与选择性：18a–j、19d–j、20a–b及21b的半数抑制浓度（IC₅₀）值达标。随后针对[¹⁸F]18a–e、[¹⁸F]18g及[¹⁸F]20a开展放化合成：通过在MP-10药效团的喹啉环（而非吡唑环）上引入¹⁸F完成标记，并进行体内评价。大鼠生物分布研究显示，在PDE10A富集的纹状体中，靶区放射性摄取量较非靶脑区高约2倍；该摄取比值在注射后5至30分钟内持续升高，其中[¹⁸F]18a–d与[¹⁸F]20a的提升尤为显著。对[¹⁸F]18d与[¹⁸F]20a开展的非人灵长类微型正电子发射断层扫描（MicroPET）研究表明，二者可清晰可视化纹状体，且具备适宜的平衡动力学特性与良好的代谢稳定性。上述结果提示，该策略有望开发出一种¹⁸F标记的正电子发射断层扫描（PET）显像剂，用于量化包括亨廷顿病与精神分裂症在内的中枢神经系统（CNS）疾病患者体内的PDE10A水平。