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.

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