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

René Smits; Steffen Fischer; Achim Hiller; Winnie Deuther-Conrad; Barbara Wenzel; Marianne Patt; Paul Cumming; Jörg Steinbach; Osama Sabri; Peter Brust; Alexander Hoepping

doi:10.1016/j.bmc.2013.12.011

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

Bioorg Med Chem. 2014 Jan 15;22(2):804-12. doi: 10.1016/j.bmc.2013.12.011. Epub 2013 Dec 12.

Authors

Affiliations

¹ ABX Advanced Biochemical Compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany.
² Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstrasse-15, D-04318 Leipzig, Germany.
³ Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany.
⁴ ABX Advanced Biochemical Compounds GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany. Electronic address: hoepping@abx.de.

PMID: 24369841
DOI: 10.1016/j.bmc.2013.12.011

Abstract

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: 2-[(18)F]FA; 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine; 5-[(123)I]-5-iodo-3-(2(S)-azetidinylmethoxy)pyridine; 5-[(123)I]IA; AD; Alzheimers’s disease; Alzheimers’s disease (AD); Flubatine; Fluorine-18; HPLC; Nicotinic acetylcholine receptor (nAChR); PET; PSL/mm(2); ROI; high performance liquid chromatography; nAChR; nicotinic acetylcholine receptor; p.s.; particle size; photostimulated luminescence per area; positron emission tomography; regions of interest.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzamides* / chemical synthesis
Benzamides* / chemistry
Brain / diagnostic imaging
Brain / metabolism
Bridged Bicyclo Compounds, Heterocyclic* / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic* / chemistry
Crystallography, X-Ray
Female
Fluorine Radioisotopes
Humans
Kinetics
Male
Models, Molecular
Molecular Structure
Radionuclide Imaging
Radiopharmaceuticals* / chemical synthesis
Radiopharmaceuticals* / chemistry
Rats
Receptors, Nicotinic / metabolism*
Stereoisomerism
Swine

Substances

Benzamides
Bridged Bicyclo Compounds, Heterocyclic
Fluorine Radioisotopes
Radiopharmaceuticals
Receptors, Nicotinic
fluoronorchloroepibatidine
nicotinic receptor alpha4beta2