title: Evaluation of [(18)F]-(-)-norchlorofluorohomoepibatidine ([(18)F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates.
abstract: BACKGROUND
  The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4β2 receptor radiotracer [(18)F]-(-)-NCFHEB ([(18)F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo.
  
  
  METHODS
  [(18)F]-(-)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC.
  
  
  RESULTS
  [(18)F]-(-)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 ± 16.1 GBq/μmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98-100% of [(18)F]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9 ± 1.0 mL/cm(3) (n = 2), or 6.6 ± 1.1 mL/cm(3) after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [(18)F]-(-)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, and cerebellum = 0.10 ± 0.29).
  
  
  CONCLUSIONS
  An efficient microfluidic synthetic method was developed for preparation of [(18)F]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [(18)F]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4β2 receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [(18)F]2-FA and comparable to [(18)F]AZAN. These results confirm previous findings and support further examination of [(18)F]-(-)-NCFHEB in humans.
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: frederic.bois@yale.edu.
authors: Frederic
authors: F
authors: Bois
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Jean-Dominique
authors: JD
authors: Gallezot
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Ming-Qiang
authors: MQ
authors: Zheng
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Shu-Fei
authors: SF
authors: Lin
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors: Irina
authors: I
authors: Esterlis
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors: Kelly P
authors: KP
authors: Cosgrove
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Richard E
authors: RE
authors: Carson
authors: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Yiyun
authors: Y
authors: Huang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine
keywords: Flubatine; NCFHEB; Nicotine; Nicotinic acetylcholine receptors; PET; Rhesus monkeys