title: Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability.
abstract: In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies. Thus, we had synthesized and studied [(11)C]2 as a PET tracer for mGlu4, which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu4 ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu4. The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu4 ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Zhaoda
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Pekka
authors.initials: P
authors.lastname: Poutiainen
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States.
authors.forename: Ji-Kyung
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States. Electronic address: abrownell@partners.org.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D008861:Microsomes / Q000378:metabolism*; D015394:Molecular Structure; D010847:Picolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C000607836:N-phenylpicolinamide; D010847:Picolines; D018094:Receptors, Metabotropic Glutamate
keywords: Affinity; Metabolic stability; Metabotropic glutamate receptor subtype 4 (mGlu(4)); Positive allosteric modulator (PAM); Positron emission tomography (PET); Structure–affinity relationship (SAR)