title: Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.
abstract: In recent years, mGlu4 has received great research attention because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). A specific mGlu4 PET radioligand could be an important tool in understanding the role of mGlu4 in both healthy and disease conditions, and also for the development of new drugs. In this study, we synthesized four new N-(methylthiophenyl)picolinamide derivatives 11-14. Of these ligands, 11 and 14 showed high in vitro binding affinity for mGlu4 with IC50 values of 3.4nM and 3.1nM, respectively, and suitable physicochemical parameters. Compound 11 also showed enhanced metabolic stability and good selectivity to other mGluRs. [(11)C]11 and [(11)C]14 were radiolabeled using the [(11)C]methylation of the thiophenol precursors 20a and 20c with [(11)C]CH3I in 19.0% and 34.8% radiochemical yields (RCY), and their specific activities at the end of synthesis (EOS) were 496±138GBq/μmol (n=6) and 463±263GBq/μmol (n=4), respectively. The PET studies showed that [(11)C]11 accumulated fast into the brain and had higher uptake, slower washout and 25% better contrast than [(11)C]2, indicating improved imaging characteristics as PET radiotracer for mGlu4 compared to [(11)C]2. Therefore, [(11)C]11 will be a useful radioligand to investigate mGlu4 in different biological applications.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th St., Suite 2301, Charlestown, MA 02129, USA.
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 St., Suite 2301, Charlestown, MA 02129, USA.
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 St., Suite 2301, Charlestown, MA 02129, USA.
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 St., Suite 2301, Charlestown, MA 02129, USA.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Darshini
authors.initials: D
authors.lastname: Kuruppu
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuroscience Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th St., Suite 2301, Charlestown, MA 02129, USA.
authors.forename: Ji-Kyung
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Neuroscience Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th St., Suite 2301, Charlestown, MA 02129, USA. Electronic address: abrownell@mgh.harvard.edu.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D010848:Picolinic Acids; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D013876:Thiophenes; C108823:metabotropic glutamate receptor 4
keywords: Metabotropic glutamate receptor subtype 4 (mGlu(4)); PET; Positive allosteric modulator (PAM)