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

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• 作者：Junfeng Li ; Xiang Zhang ; Hongjun Jin ; Jinda Fan ; Hubert Flores ; Joel S. Perlmutter ; Zhude Tu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8584-8600
• 全文大小：934K
• ISSN：1520-4804

文摘

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鈥?b>j, 19d鈥?b>j, 20a鈥?b>b, and 21b had IC₅₀ values <5 nM for PDE10A. Seven F-18 labeled compounds [¹⁸F]18a鈥?b>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 鈭?-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鈥?b>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鈥檚 disease and schizophrenia.