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Synthesis and biological evaluation of both enantiomers of [18F]flubatine, promising radiotracers with fas kinetics for the imaging of α4β2-nicotinic acetylcholine receptors

Smits, R.; Fischer, S.; Hiller, A.; Deuther-Conrad, W.; Wenzel, B.; Patt, M.; Cumming, P.; Steinbach, J.; Sabri, O.; Brust, P.; Hoepping, A.


Both enantiomers of the epibatidine analogue flubatine display high affinity towards the α4β2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with diverse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2μg/kg for (-)-flubatine and 1.55μg/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient (18)F-radiolabelling in radiochemical yields >60% and specific activities >750GBq/μmol, thus making the radioligands practical for clinical investigation.

Keywords: Alzheimers’s disease (AD); Nicotinic acetylcholine receptor (nAChR); Flubatine; PET; Fluorine-18


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