Discovery of the First Brain-Penetrant Radioligands for Visualizing the GABA Transporter 1 (GAT-1): Synthesis, In Vitro Screening, and In Vivo Evaluation in Nonhuman Primates

The γ-aminobutyric acid (GABA) system regulates neuronal excitability in the central nervous system and is implicated in multiple neuropsychiatric and neurodegenerative disorders. GABA transporter 1 (GAT-1) is a key regulator of synaptic GABA levels but has been difficult to image in vivo due to the lack of blood-brain barrier (BBB)-permeable radioligands for positron emission tomography (PET). Here, we report the design, synthesis, and evaluation of novel tiagabine-based derivatives as brain-penetrant radioligands for GAT-1. Screening of 105 compounds identified four candidates (GATT-31, GATT-34, GATT-39, and GATT-44) with high GAT-1 affinity, appropriate lipophilicity, and low P-glycoprotein efflux liability. These ligands were radiolabeled via copper-mediated 18F-radiofluorination. PET imaging in nonhuman primates demonstrated good brain uptake of the radioligands. Among them, 18FGATT-44 appeared to be the most promising with good metabolic stability and high GAT-1 binding specificity. The discovery of BBB-penetrating radioligands enables, for the first time, in vivo imaging of GAT-1 in the brain.