Radiosynthesis of novel ¹⁸F-labelled derivatives of indiplon as potential GABA_A receptor imaging tracers for PET

The involvement of gamma amino butyric acid (GABA) receptors in a variety of neurological and psychiatric diseases has promoted the development and use of radiolabelled benzodiazepines (BZ) for brain imaging by PET. However, these radioligands are unable to distinguish between the various subtypes of GABA_A receptors. Novel non-BZ such as the pyrazolo-pyrimidine indiplon proved to be selective for the alpha₁-subunit of the GABA_A receptor. Here, we describe the syntheses of four novel ¹⁸F-labelled indiplon derivatives. Radiosyntheses were performed via n.c.a. ¹⁸F-nucleophilic substitution starting from the tosyl, bromo, and 4-nitrobenzoyl precursors to obtain fluorine substituted N-alkylamide side chain derivatives of indiplon, followed by multistep purification using semi-preparative high-performance liquid chromatography and solid phase extraction. Tosyl and bromo precursors were converted into ¹⁸F-labelled indiplon derivatives with good and reproducible radiochemical yield (RCY) (35–70%, decay corrected), high radiochemical purity (>/= 98.5%), and high specific activity ( > 150 GBq/lmol). By contrast, a low RCY (5–10%) and specific activity (10–15 GBq/lmol) were achieved for the 4-nitrobenzoyl precursor.