Synthesis and investigation of substituted 1,5-diaryl-1H-1,2,4-triazoles for the discovery of 18F-labeled probes for imaging brain cyclooxygenase-1

The imaging of brain cyclooxygenase-1 (COX-1) with positron emission tomography (PET) is of interest for the study of neuropsychiatric disorders having a neuroinflammatory component and can be of value for developing improved drugs for their treatment. [¹¹C]PS13 is a high-performing radioligand for this purpose. However, the application of [¹¹C]PS13 is restricted to the site of production because of its short physical half-life (20.4 min). There is a need to have an effective PET radioligand for imaging brain COX-1 with longer-lived fluorine-18 (t_1/2 = 109.8 min) that can be broadly distributed to PET imaging centers. Here we describe the synthesis and investigation of 47 substituted 1,5-diaryl-1H-1,2,4-triazoles for the discovery of ¹⁸F-labeled ligands for imaging COX-1. We discovered two COX-1 ligands, namely 22 and 44, with affinities, selectivities, and Other properties similar to those of [¹¹C]PS13. [¹⁸F]22 and [¹⁸F]44 were prepared in good yields and high molar activities by single-step radiofluorination. We also established efficient syntheses of [¹¹C]22 and [¹¹C]44. Radioligands [¹¹C]22, [¹¹C]44, and [¹⁸F]44 readily entered monkey brain from plasma. However, no COX-1-specific binding was detected for [¹¹C]22. [¹¹C]44 showed specific binding that was similar to [¹¹C]PS13. Whole brain time-activity curves for [¹⁸F]44 under baseline condition were similar to those for [¹¹C]44. However, undesirable accumulation of radioactivity in skull indicated appreciable radiodefluorination. Such radiodefluorination would hamper quantification of brain COX-1. Further efforts are therefore needed to find an effective ¹⁸F-labeled PET radioligand for brain COX-1 imaging.

Brain; COX-1; Carbon-11; Fluorine-18; PET; Radioligand.