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

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 11; no. 1; p. 13
• Main Authors: Olma, Sebastian, Ermert, Johannes, Sihver, Wiebke, Coenen, Heinz H
• Format: Journal Article
• Language: English
• Published: Netherlands 2014
• Subjects: 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
• ISSN: 1875-6638

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.