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Nucl Med Biol. 2015 Jun;42(6):570-7. doi: 10.1016/j.nucmedbio.2014.08.003. Epub 2014 Aug 8.

Evaluation of [(18)F]-(-)-norchlorofluorohomoepibatidine ([(18)F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates.

Author information

  • 1PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: frederic.bois@yale.edu.
  • 2PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
  • 3PET 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.

Abstract

INTRODUCTION:

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).

CONCLUSION:

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.

KEYWORDS:

Flubatine; NCFHEB; Nicotine; Nicotinic acetylcholine receptors; PET; Rhesus monkeys

PMID:
25858513
PMCID:
PMC4441617
DOI:
10.1016/j.nucmedbio.2014.08.003
[PubMed - indexed for MEDLINE]
Free PMC Article
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