Radiosynthesis and preliminary PET evaluation of (18)F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile for imaging AMPA receptors

Gengyang Yuan; Graham B Jones; Neil Vasdev; Steven H Liang

doi:10.1016/j.bmcl.2016.07.078

Radiosynthesis and preliminary PET evaluation of (18)F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile for imaging AMPA receptors

Bioorg Med Chem Lett. 2016 Oct 1;26(19):4857-4860. doi: 10.1016/j.bmcl.2016.07.078. Epub 2016 Aug 9.

Authors

Gengyang Yuan¹, Graham B Jones², Neil Vasdev³, Steven H Liang⁴

Affiliations

¹ Department of Chemistry & Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA; Gordon Center for Medical Imaging & Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA.
² Department of Chemistry & Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA.
³ Gordon Center for Medical Imaging & Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA. Electronic address: [email protected].
⁴ Gordon Center for Medical Imaging & Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA. Electronic address: [email protected].

Abstract

To prompt the development of (18)F-labeled positron emission tomography (PET) tracers for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, we have prepared (18)F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile ([(18)F]8). The radiosynthesis was achieved by a one-pot two-step method that utilized a spirocyclic hypervalent iodine(III) mediated radiofluorination to prepare the (18)F-labeled 1-bromo-3-fluorobenzene ([(18)F]15) intermediate with K(18)F. A subsequent copper(I) iodide mediated coupling reaction was carried out with 2-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile (10) to [(18)F]8 in 10±2% uncorrected radiochemical yield relative to starting (18)F-fluoride with >99% radiochemical purity and 29.6±7.4Gbq/μmol specific activity at the time of injection. PET imaging studies with the title radiotracer in normal mice demonstrated good brain uptake (peak standardized uptake value (SUV)=2.3±0.1) and warrants further in vivo validation.

Keywords: AMPA receptor; Fluorine-18; Perampanel; Positron emission tomography; Radiotracer.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Blood-Brain Barrier
Brain / metabolism
Fluorine Radioisotopes / administration & dosage*
Mice
Positron-Emission Tomography
Receptors, AMPA / metabolism*

Substances

Fluorine Radioisotopes
Receptors, AMPA

Grants and funding

K01 DA038000/DA/NIDA NIH HHS/United States