Development of [18F]Flubatine, a promising radiotracer for the imaging of α4β2 nicotinic acetylcholine receptors (nAChRs)

The density of nicotinic acetylcholine receptor (nAChR) subtypes is reduced in brain of Alzheimer’s disease (AD) patients. Imaging of α4β2 receptors, the predominant subtype, could thus contribute to early diagnosis of AD. Existing radiotracers for α4β2 nAChRs have suffered from inadequate affinity, or very slow binding kinetics, but the novel compound [18F]Flubatine presents several advantages. Both enantiomers display high affinity in vitro and fast cerebral binding kinetics in living mice and pigs. Initial human PET imaging studies have confirmed high uptake in the thalamus, low non-specific binding, and attainment of equilibrium binding in less than two hours. Dosimetry studies in healthy human volunteers indicate that effective doses for (-)-[18F]Flubatine (< 10 mSv/300 MBq) are compatible with application in routine clinical studies.
We have described the organic synthesis of enantiomerically pure (–)-Flubatine and (+)-Flubatine. Moreover, several precursors with different protecting groups and leaving groups have been synthesized for optimised radiosynthesis. The best radiochemical results were obtained with a trimethylammonium precursor carrying a Boc-protecting group, employing a two-step radiosynthesis. Radiolabelling under phase transfer conditions afforded the protected 18F-intermediate in yields of 90%. Subsequent deprotection under mild conditions gave the final products with a radiochemical yield of 70±5%, and specific activity >350 GBq/µmol. [18F]Flubatine was stable in dilute HCl, NaOH and K2CO3 solutions, as well as under physiological conditions.