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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

descriptionPublicationkeyboard_double_arrow_right Article 15 Oct 2015Publisher:American Chemical Society (ACS)Journal:Journal of Medicinal Chemistry, volume 58, pages 8,584-8,600 (issn: 0022-2623, eissn: 1520-4804,

Authors: Hubert Flores; Zhude Tu; Jinda Fan; Xiang Zhang; Junfeng Li; Joel S. Perlmutter; Hongjun Jin;

doi: 10.1021/acs.jmedchem.5b01205

pmid: 26430878

pmc: PMC4697445

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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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.

Related Organizations

University of Mary
United States
Washington State University
United States

Keywords

Male, Fluorine Radioisotopes, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Brain, Rats, Rats, Sprague-Dawley, Macaca fascicularis, Positron-Emission Tomography, Animals, Humans

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BindingDB Entry 50046725: 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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