Clinical Radiosynthesis and Translation of [¹⁸F]OP-801: A Novel Radiotracer for Imaging Reactive Microglia and Macrophages

Positron emission tomography (PET) is a powerful toolfor studyingneuroinflammatory diseases; however, current PET biomarkers of neuroinflammationpossess significant limitations. We recently reported a promisingdendrimer PET tracer ([F-18]OP-801), which is selectivelytaken up by reactive microglia and macrophages. Here, we describefurther important characterization of [F-18]OP-801 in additionto optimization and validation of a two-step clinical radiosynthesis.[F-18]OP-801 was found to be stable in human plasma for90 min post incubation, and human dose estimates were calculated for24 organs of interest; kidneys and urinary bladder wall without bladdervoiding were identified as receiving the highest absorbed dose. Followingoptimization detailed herein, automated radiosynthesis and qualitycontrol (QC) analyses of [F-18]OP-801 were performed intriplicate in suitable radiochemical yield (6.89 +/- 2.23% decaycorrected), specific activity (37.49 +/- 15.49 GBq/mg), and radiochemicalpurity for clinical imaging. Importantly, imaging mice with tracer(prepared using optimized methods) 24 h following the intraperitonealinjection of liposaccharide resulted in the robust brain PET signal.Cumulatively, these data enable clinical translation of [F-18]OP-801 for imaging reactive microglia and macrophages in humans.Data from three validation runs of the clinical manufacturing andQC were submitted to the Food and Drug Administration (FDA) as partof a Drug Master File (DMF). Subsequent FDA approval to proceed wasobtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-humanimaging in healthy controls and patients with amyotrophic lateralsclerosis is underway.