title: 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.
abstract: A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [(11)C]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 [(18)F]18a-e, [(18)F]18g, and [(18)F]20a were radiosynthesized by (18)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 ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [(18)F]18a-d and [(18)F]20a. MicroPET studies of [(18)F]18d and [(18)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 (18)F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington's disease and schizophrenia.
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Jinda
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Hubert
authors.initials: H
authors.lastname: Flores
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Department of Radiology and ‡Department of Neurology, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology*; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000032:analysis* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005462:Fluorine Radioisotopes; D010726:Phosphodiesterase Inhibitors; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases