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

Abstract

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

[18F]-Radiolabelled Nanoplatforms: A Critical Review of Their Intrinsic Characteristics, Radiolabelling Methods, and Purification Techniques

“…Ensuring that data are transposable is thus a huge challenge. The methodology used for the structural characterization of generation 4 PAMAM dendrimers radiolabelled with fluorine-18 [55,56] is certainly an example to follow. However, this example surely represents the ideal case, given that a dendrimer is a macromolecular system which is easier to characterize than other types of nanoparticles.…”

“…Its radiolabelling allowed to evaluate its ability to detect innate immune activation in mice following lipopolysaccharide challenge [55]. This family of dendrimers is currently under clinical trial for the study of neuroinflammatory diseases in humans [56]. Interestingly, dendrimers have been used to stabilize inorganic nanoparticles.…”

“…The radiochemical purity was then checked using analytical HPLC (C18-column, eluent: water 0.1% TFA/ACN). More recently, various works based on the radiosynthesis and preclinical evaluation of a G4 PAMAM hydroxyl dendrimer (called OP-801) as a [ 18 F]-PET tracer were reported [55,56]. A click chemistry strategy (CuAAC bioconjugation) was used to radiofluorinate the dendrimer, named [ 18 F]-OP-801.…”

Human Glial Cells as Innovative Targets for the Therapy of Central Nervous System Pathologies

“…Thus, new tracers with an additional discriminating ability are needed. In this respect, a new PET radiotracer, named [ 18 F]OP-801, which is selectively taken up by phagocytic microglia and macrophages in the brain is currently on the way to its first-inhuman phase I/II clinical trial for the monitoring and evaluation of neuroinflammation in patients [70]. Additionally, a number of proteins expressed by microglial cells are currently under evaluation for their reliability as markers of microglia activation and for the possibility of being visualized thanks to selective radioligands [66].…”

Application of Functionalized Zn-Based Metal–Organic Frameworks (Zn-MOFs) with CuO in Heterocycle Synthesis via Azide–Alkyne Cycloaddition

“…Despite extensive research and the development of various strategies, only a few sustainable and economical approaches have been reported for synthesizing complex chemical structures. Click chemistry, particularly the copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction, has emerged as a suitable method for the architecture and synthesis of pharmaceutical and biological compounds. − The term “click” refers to the facile joining of molecular building blocks through rapid reactions that provide high product yields, are versatile, simple to use, and easy to purify. − This reaction has found wide applications in diverse scientific disciplines, including pharmaceuticals, polymer chemistry, and materials science. − The CuAAC click reaction is an effective and attractive tool for the 1,3-dipolar cycloaddition of azides and terminal alkynes, leading to the formation of macro-1,4-disubstituted-1,2,3-triazole derivatives in the presence of copper-containing catalysts. − …”