Radiosynthesis of (S)-[¹⁸F]T1: The first PET radioligand for molecular imaging of α3β4 nicotinic acetylcholine receptors

Recent pharmacologic data revealed the implication of α3β4 nicotinic acetylcholine receptors (nAChRs) in nicotine and drug addiction. To image α3β4 nAChRs in vivo, we aimed to establish the synthesis of a [¹⁸F]-labelled analog of the highly affine and selective α3β4 ligand (S)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine ((S)-T1). (S)-[¹⁸F]T1 was synthesized from ethynyl-4-[¹⁸F]fluorobenzene ([¹⁸F]5) and (S)-azidoquinuclidine by click reaction.
After a synthesis time of 130 min (S)-[¹⁸F]T1 was obtained with a radiochemical yield (non-decay corrected) of 4.3 ± 1.3%, a radiochemical purity of > 99% and a molar activity of > 158 GBq/µmol. The brain uptake and the brain-to-blood ratio of (S)-[¹⁸F]T1 in mice at 30 min post injection were 2.02 (SUV) and 6.1, respectively.
According to an ex-vivo analysis, the tracer remained intact (> 99%) in brain. Only one major radiometabolite was detected in plasma and urine samples. In-vitro autoradiography on pig brain slices revealed binding of (S)-[¹⁸F]T1 to brain regions associated with the expression of α3β4 nAChRs, which could be reduced by the α3β4 nAChR selective drug AT-1001. These findings make (S)-[¹⁸F]T1 a potential tool for the non-invasive imaging of α3β4 nAChRs in the brain by PET.