Authors
Mayca Onega, Eimear Howley, Charlotte Fieldhouse, Sarah Almond, William Farnaby, Catrina Kerr, Philip Mitchell, Rosa Fradley, Toshal Patel, Matt Barnes, Christopher Coello, Roger N Gunn, Nicholas Keat, Sharon Ashworth, Sac-Pham Tang, Lisa A Wells, Eugenii A Rabiner, Jan Passchier, Johannes Tauscher, David Miller, Christophe Plisson
Published in
Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20761-20771. Sep 10, 2026.
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.
PMID:
42720458
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.
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