5-tert-Butyl-2-(4′-[¹⁸F]fluoropropynylphenyl)-1,3-dithiane oxides: potential new GABA_A receptor radioligands

Abstract 

As potential new ligands targeting the binding site of γ-aminobutyric acid (GABA) receptor ionophore, trans-5-tert-butyl-2-(4′-fluoropropynylphenyl)-2-methyl-1,1-dioxo-1,3-dithiane (1) and cis/trans-5-tert-butyl-2-(4′-fluoropropynylphenyl)-2-methyl-1,1,3,3-tetroxo-1,3-dithiane (2) were selected for radiolabeling and initial evaluation as in vivo imaging agents for positron emission tomography (PET). Both compounds exhibited identical high in vitro binding affinities (K_i=6.5 nM). Appropriate tosylate-substituted ethynyl precursors were prepared by multistep syntheses involving stepwise sulfur oxidation and chromatographic isolation of desired trans isomers. Radiolabeling was accomplished in one step using nucleophilic [¹⁸F]fluorination. In vivo biodistribution studies with trans-[¹⁸F]1 and trans-[¹⁸F]2 showed significant initial uptake into mouse brain and gradual washout, with heterogeneous regional brain distributions and higher retention in the cerebral cortex and cerebellum and lower retention in the striatum and pons–medulla. These regional distributions of the new radioligands correlated with in vitro and ex vivo measures of standard radioligands binding to the ionophore- and benzodiazepine-binding sites of GABA_A receptor in rodent brain. A comparison of these results with previously prepared radiotracers for other neurochemical targets, including successes and failures as in vivo radioligands, suggests that higher-affinity compounds with increased retention in target brain tissues will likely be needed before a successful radiopharmaceutical for human PET imaging can be identified.

Keywords: GABA, Picrotoxin, Tomography, emission computed, Fluorine-18