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.