In Vivo Rodent Studies with the Novel PET Tracer [18F]PGM028299: An Inhibitor of D-Amino Acid Oxidase

Abstract Abnormal N-methyl-d-aspartate receptor (NMDAr) function is implicated in schizophrenia and other neuropsychiatric disorders. Enhancing NMDAr signaling can be achieved by increasing synaptic d-serine levels through the inhibition of D-amino acid oxidase (DAAO). We report the synthesis and preclinical evaluation of [18F]2 ([18F]PGM028299), a novel PET radiotracer for imaging DAAO in the brain. Enzyme occupancy studies in rodents showed that [18F]2 is a displaceable ligand, with binding blocked dose dependently by the DAAO inhibitor luvadaxistat. Radiosynthesis was initially achieved via a copper-mediated radiofluorination. Subsequent optimization using a Sonogashira coupling strategy resulted in improved radiochemical yields. PET imaging studies demonstrated rapid brain uptake, with the highest retention observed in the cerebellum and brainstem, along with reversible tracer kinetics. Tracer kinetic modeling showed that specific binding was abolished following pharmacological challenge. Human dosimetry estimates indicated a favorable safety profile. These findings support [18F]2 as a promising PET tracer for in vivo DAAO imaging.