Synthesis and radiofluorination of 4-(6-fluoro-fluoren-9-on-2-yl)-1,4-diazabicyclo[3.2.2]nonane for imaging of alpha-7 nicotinic acetylcholine receptor (α7 nAChR) by PET

Aim: Until now, the two fluorinated dibenzothiophene sulfones [¹⁸F]ASEM⁽¹⁾ and its para fluorinated isomer [¹⁸F]DBT10⁽²⁾ have been developed from a novel class of α7 nicotinic acetylcholine receptor (nAChR) ligands based on the antiviral drug tilorone. The aim of this study is to investigate the effect of substituting the SO₂ by a CO linkage on the radiofluorination efficiency of the corresponding fluoren-9-one analogues and on radioligand parameters.
Methods: FLN-19 was prepared from 3-nitro-fluoren-9-one via bromination, fluorodenitration and Pd catalyzed cross coupling in 25% overall yield. A precursor with a nitro leaving group for radiolabelling was similarly obtained. Binding affinity for human nAChRs was evaluated in vitro by radioligand displacement experiments. [¹⁸F]FLN-19 was obtained via nucleophilic aromatic substitution. In vitro autoradiography of [¹⁸F]FLN-19 on pig brain slices was performed.
Results: FLN-19 binds with high affinity and selectivity to α7 nAChR (K_i = 1.18 nM, 288 nM, and 64.0 nM for α7, α4β2, and α3β4 nAChR, respectively). The highest nitro-to-fluoro conversion was obtained in DMF under microwave assisted heating (labeling yields ≈ 90%), and [¹⁸F]FLN-19 was prepared in ≥ 97% radiochemical purity. Binding of [¹⁸F]FLN-19 on pig brain slices was significantly reduced by α7 nAChR-specific ligands.
Conclusions: With [¹⁸F]FLN-19, a first fluorenone derived α7 nAChR radioligand was readily prepared, efficiently radiolabelled and successfully tested in first in vitro studies.

References

1. Horti A. G. et al. J Nucl. Med., 2014, 55, 672-677.
2. Teodoro R. et al. Molecules, 2015, 20, 18387-18421.