文摘
A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [<sup>11sup>C]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 IC<sub>50sub> values <5 nM for PDE10A. Seven F-18 labeled compounds [<sup>18sup>F]18a鈥?b>e, [<sup>18sup>F]18g, and [<sup>18sup>F]20a were radiosynthesized by <sup>18sup>F-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 [<sup>18sup>F]18a鈥?b>d and [<sup>18sup>F]20a. MicroPET studies of [<sup>18sup>F]18d and [<sup>18sup>F]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 <sup>18sup>F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington鈥檚 disease and schizophrenia.