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 <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. 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.