Synthesis and first evaluation of [¹⁸F]fluorocyano- and [¹⁸F]fluoronitro-quinoxalinedione as putative AMPA receptor antagonists

Med Chem. 2014;11(1):13-20. doi: 10.2174/1573406410666140428151318.

Abstract

Derivatives of quinoxalinedione (QX) were chosen as chemical lead for the development of new radioligands of the AMPA receptor, since there are several examples of QX-derivatives with high affinity. The radiosyntheses of the new compounds 6-[(18)F]fluoro-7-nitro-QX([(18)F]FNQX) and 7-[(18)F]fluoro-6-cyano-QX ([(18)F]FCQX) with radiochemical yields of 8±2 and 3± 2%, respectively, as well as the evaluation of their binding properties to the AMPA-receptor were performed. A comparison of the Ki-values of the new QX-derivatives FCQX and FNQX with mono-substituted cyanoand nitro-QX shows negligibly small differences of affinity (within the range of 1.4 to 5 µM), but exhibits a tenfold lower affinity than derivatives with two electron withdrawing groups like the 7-cyano-6-nitro-compound CNQX and the 6,7- dinitro compound DNQX. Thus, with respect to the low affinity and a high non-specific binding with in vitro and ex vivo autoradiographic studies, the new compounds do not lend themselves for in vivo imaging.

MeSH terms

  • Animals
  • Autoradiography
  • Blood-Brain Barrier / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Excitatory Amino Acid Antagonists / chemical synthesis
  • Excitatory Amino Acid Antagonists / metabolism
  • Excitatory Amino Acid Antagonists / pharmacokinetics*
  • Female
  • Fluorine Radioisotopes
  • Kinetics
  • Mice
  • Nitro Compounds / chemical synthesis
  • Nitro Compounds / metabolism
  • Nitro Compounds / pharmacokinetics*
  • Positron-Emission Tomography
  • Quinoxalines / chemical synthesis
  • Quinoxalines / metabolism
  • Quinoxalines / pharmacokinetics*
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / metabolism
  • Staining and Labeling

Substances

  • Excitatory Amino Acid Antagonists
  • Fluorine Radioisotopes
  • Nitro Compounds
  • Quinoxalines
  • Receptors, AMPA